\r\n\tEqually important are the consequences deriving from the extraordinary nature of the present times. The COVID-19 pandemic and the restrictive measures to contain the infection (lockdown and "physical distancing" in primis) have revolutionized the lives, and a distortion/modification of habits, rhythms, arrangements will continue to be necessary. \r\n\tGovernments have implemented a series of actions to mitigate the spread of infections and alleviate the consequent pressure on the hospital system. On the other hand, the Covid-19 pandemic has caused a series of other cascading effects that will probably be much more difficult to mitigate and which expose to complex consequences. The past two years have brought many challenges, particularly for healthcare professionals, students, family members of COVID-19 patients, people with mental disorders, the frail, the elderly, and more generally those in disadvantaged socio-economic conditions, and workers whose livelihoods have been threatened. Indeed, the substantial economic impact of the pandemic may hinder progress towards economic growth as well as progress towards social inclusion and mental well-being.
\r\n
\r\n\t \r\n\tAlthough in all countries the knowledge on the impact of the pandemic on mental health is still limited and mostly derived from experiences only partially comparable to the current epidemic, such as those referring to the SARS or Ebola epidemics, it is likely that the demand for intervention it will increase significantly in the coming months and years. The extraordinary growth of scientific research in the field of neuroscience now offers the possibility of a new perspective on the relationship between mind and brain and generates new scenarios in understanding the long wave of the pandemic and in the prospects for treatment. Moreover, the pandemic also has led to opportunities to implement remote monitoring and management interventions.
\r\n
\r\n\t \r\n\tOverall this volume will address the complex relationship existing between COVID-19, mental health, acquired knowledge, and possible interventions taking a highly multidisciplinary approach; from physiological and psychobiological mechanisms, and neuromodulation through medical treatment, psychosocial interventions, and self-management.
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Devoted researcher of the European Innovation Partnership on Active and Healthy Aging, appointed Assistant Specialty Chief Editor of Frontiers in Psychology -Neuropsychology and Scientific Director of the Italian National Institute of Philanthropy.",coeditorOneBiosketch:"An academic and industrial investigator involved in basal research, drug discovery, and development of potential psychiatric drugs, covering depression, anxiety, OCD, schizophrenia, and sexual dysfunctions.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo",profilePictureURL:"https://mts.intechopen.com/storage/users/233998/images/system/233998.png",biography:"Sara Palermo has an MSc in clinical psychology and a PhD in experimental neuroscience. She is specialty chief editor of Frontiers in Psychology, Neuropsychology, and scientific director of the Italian National Institute of Philanthropy, Filantropolis. She is a member of the Italian Society of Neuropsychology, the Italian Association of Psychogeriatrics, the Italian Society of Neurology for Dementia, and the Society for Interdisciplinary Placebo Studies. She was a member of the European Innovation Partnership on Active and Healthy Ageing (EIP AHA), for which she was involved in Action Group A3: Action for Prevention of Functional Decline and Frailty. 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\n
1. Introduction
\n
COPD is a systemic disease associated with extra pulmonary effects such as osteopaenia, muscle wasting, cardiovascular disease and depression [1]. The symptoms of COPD make engagement in physical activity unpleasant. Air trapping and hyperinflation of the lungs cause increased breathlessness due to the resultant inefficient breathing. The breathlessness itself provokes anxiety, which in turn leads to further breathlessness, exacerbations of COPD and episodes of panic. Due to this, activities that involve physical exertion are avoided, leading to muscle deconditioning and a further reduced capacity to engage in physical activity. Pulmonary rehabilitation improves symptoms, quality of life and health-care utilisation in patients with COPD [1, 2].
\n
Pulmonary rehabilitation is defined as “an interdisciplinary programme of care for patients with chronic respiratory impairment that is individually tailored and designed to optimise each patient’s physical and social performance and autonomy. Programmes comprise individualised exercise programmes and education” [3]. Physical inactivity is a key predictor of mortality in COPD and consequently all major guidelines highlight the importance of exercise in the treatment and management of COPD. There is now high quality evidence for improved exercise capacity, health-related quality of life and decreased breathlessness, fatigue and health-care utilisation following pulmonary rehabilitation [1].
\n
Pulmonary rehabilitation is focussed on an interdisciplinary and holistic approach to the management of COPD, emphasising behavioural change as a key component. It fits very well with the concept of integrated care, with its cornerstone being individually tailored exercise training. Patient assessment, education, psychosocial support and nutritional counselling are also included in the standard pulmonary rehabilitation programme. Overall, the focus of a pulmonary rehabilitation programme is to alleviate the physiological effects of the disease process and decrease the psychosocial effects of the illness on the individual.
\n
\n
\n
2. Historical development
\n
The effects of exercise in patients with chronic respiratory diseases have been a subject for study for some time. By the middle of the 20th century, accepted wisdom was that dyspnoea on exertion should be avoided [4]. Dr. Alvan Barach was the first to offer a contrary opinion in the 1950s, with his advice to “remember to cure the patient as well as the disease”. Thomas L. Petty was the first to establish an out-patient programme of pulmonary rehabilitation in the 1960s, despite the conventional wisdom of not exerting patients with respiratory limitations. This programme included individualised instruction, bronchial hygiene, breathing retraining, physical reconditioning and individualised pharmacologic therapy. Rehabilitation programmes were set up throughout the USA, and Petty noted improved exercise tolerance, reduced hospitalisations and a return to gainful employment in the majority of his patients [4]. Subsequently, in the 1980s a view became prevalent that as exercise conditioning did not improve lung function, pulmonary rehabilitation was unlikely to provide physiological benefit to patients. It was felt that if physiological benefit was not demonstrated, the programme design was not particularly important. Finally, in the 1990s, physiologic benefit was proven by using exercise at a higher intensity and the concept of pulmonary rehabilitation was reinvigorated [4, 5].
\n
\n
\n
3. Rationale for pulmonary rehabilitation
\n
Pulmonary rehabilitation is designed to reduce the symptoms of COPD, improve health related quality of life (HRQoL), improve and re-establish functional ability, enhance participation in everyday life and promote patient autonomy. The exercise component of pulmonary rehabilitation increases inspiratory volume and reduces dynamic hyperinflation, both of which reduce dyspnoea when a person is performing tasks. Exercise also increases muscle function, which delays fatigue and results in increased exercise tolerance. The educational component focuses on self-management and behaviour change. Providing information and knowledge, skills such as goal setting, problem solving and decision making, along with action plans to better recognise and manage their disease are all integral parts of the programme. Modifying nutritional intake and smoking patterns, medication adherence and utilising effective energy-saving strategies and breathing techniques are part of the education component [1].
\n
The exercise capacity of patients with COPD is often impaired and limited by dyspnoea. The reasons for this are complex and multifactorial, including defective gas exchange, dynamic hyperinflation, peripheral muscle dysfunction, respiratory muscle dysfunction, the effects of physical deconditioning, the presence of co-morbidities and the natural age-related decline in exercise capacity [6]. Physical exercise in pulmonary rehabilitation is the best method of improving muscle function and skeletal muscle adaption in patients with COPD [5, 7, 8, 9, 10]. The benefits pulmonary rehabilitation produces are explained by improvements in muscle function and the oxidative capacity and efficiency of skeletal muscles, despite the absence of any changes in lung function [11, 12]. Other related improvements include increased motivation, improved mood and improved cardiovascular functioning, which result in ongoing participation in exercise beyond the rehabilitation programme [13].
\n
Even those patients with severe chronic respiratory disease can often sustain the necessary training intensity and duration for skeletal muscle adaptation. Skeletal muscle adaptation following exercise training leads to gains in exercise capacity despite the absence of changes in lung function. In addition, the improved oxidative capacity and efficiency of the skeletal muscles leads to a reduced ventilator requirement for a given submaximal work rate. This could reduce dynamic hyperinflation, adding to the reduction in exertional dyspnoea [6]. Medical therapy should be optimised prior to exercise training beginning and a patient assessment is required prior to beginning an exercise programme.
\n
\n
\n
4. The clinical effectiveness of pulmonary rehabilitation
\n
\n
4.1. Physiological
\n
One of the first studies to show an improvement in exercise tolerance following exercise training in COPD was Casaburi et al. in 1991 [14]. They showed a statistically significant improvement in exercise tolerance and reduced blood lactate and ventilatory requirement post exercise. These findings have been supported by others [5] and a Cochrane review in 2009 [2] showed a statistically significant improvement in exercise capacity in people who underwent a pulmonary rehabilitation programme. Results of a further Cochrane review in 2015 strongly supported the benefits of pulmonary rehabilitation [1]. They found clinically and statistically significant improvements in important domains of health-related quality of life, including dyspnoea, fatigue, emotional function and mastery, as well as the 6 minute walk test: a measure of functional exercise [1]. Also noted was a small but statistically significant improvement in physical activity levels. Physical activity has become more important in COPD management as it has been shown that inactivity is linked with reduced survival, poorer quality of life and increased healthcare utilisation [15].
\n
\n
\n
4.2. Quality of life
\n
The benefits of pulmonary rehabilitation on dyspnoea and health status have been supported by a Cochrane review [1]. The Chronic Respiratory Questionnaire was used in a number of studies and showed an improvement in dyspnoea that was statistically significant and clinically relevant. Improvement was also noted in the other CRQ domains of fatigue, emotional function and patient’s sense of control. The St. Georges Respiratory Questionnaire Scores were also subject to a meta-analysis in the same Cochrane review and found to show significant improvement following pulmonary rehabilitation [16].
\n
\n
\n
4.3. Reduction of healthcare utilisation
\n
Several studies have investigated whether pulmonary rehabilitation leads to a decrease in the number of caregiver or physician visits, hospital days, and medication use [3, 6]. In general, some benefit is shown in this important area. Several randomised studies comparing pulmonary rehabilitation with usual care found a trend towards reduced hospital admissions and hospital days. Studies comparing healthcare use before and after pulmonary rehabilitation show that pulmonary rehabilitation significantly reduced emergency room visits and physician visits [3, 6].
\n
\n
\n
4.4. Psychosocial
\n
In a Cochrane review published in 2015, participants allocated to rehabilitation had significantly greater changes in HRQoL [17]. A Cochrane review in 2009 had previously shown moderate to large effects of rehabilitation on health-related quality of life and exercise capacity [2].
\n
\n
\n
4.5. Self-efficacy
\n
Self-efficacy refers to the level of belief someone has in their ability to complete a chosen task or goal. Overall, self-efficacy scores improve with pulmonary rehabilitation [1].
\n
\n
\n
4.6. Survival
\n
There is limited evidence for increased survival to date, however only one randomised controlled trial has looked at survival: the control group received education and the intervention group received rehabilitation and education. The study was unlikely to be powered to detect mortality [18]. A prospective observational study of 1218 patients showed no mortality benefit from pulmonary rehabilitation [19]; however, another study did show improved mortality in patients where exercise capacity and dyspnoea improved after rehabilitation only [9].
\n
\n
\n
4.7. Nutrition
\n
In an underweight population, some small weight gain was noted following exercise training; however, in general the effect of pulmonary rehabilitation on nutritional status does not appear to be significant. Nutritional outcomes at the start of a rehabilitation programme do not affect outcomes such as exercise capacity or health status [6].
\n
\n
\n
\n
5. Setting up a pulmonary rehabilitation Programme
\n
\n
5.1. Duration
\n
There remains no consensus internationally on the optimum duration of a pulmonary rehabilitation programme. However, pulmonary rehabilitation programmes of 6–12 weeks are recommended and demonstrate a significant benefit in health status, dyspnoea and exercise in patients with chronic respiratory diseases limited by breathlessness. An attendance at a minimum of 12 exercise sessions is recommended to successfully complete the programme. Programmes of less than 6 weeks have been shown to provide some benefits in health status and exercise capacity in individuals with COPD; however, these programmes should be individualised and measures of benefit should be in place prior to the patient concluding the programme. The ongoing benefits of a pulmonary rehabilitation programme of longer than 3 months duration has been shown, including changes in daily physical activity levels, but the cost benefit of these remains unclear [3, 6, 20, 21, 22].
\n
\n
\n
5.2. Frequency
\n
The recommended frequency of exercise classes also differs internationally. The general consensus supports a minimum of two supervised exercise sessions per week, and either a third supervised session or formalised unsupervised session depending on the resources available. This is in contrast with the WHO recommendation of 5 sessions of 30 minutes exercise per week. However, to date the key improvement outcomes in pulmonary rehabilitation are based on at least two supervised sessions per week. Pulmonary rehabilitation programmes should therefore encompass a minimum of twice weekly supervised exercise sessions, a third session of prescribed unsupervised exercise and encouragement of regular physical activity for 30 minutes five days per week in line with standard healthy living advice [3, 6, 20, 21, 22].
\n
\n
\n
5.3. Staffing
\n
There is no consensus on staffing levels for a pulmonary rehabilitation programme. The staffing of the programmes varies globally, with physical therapists coordinating programmes in Australia, South America and Europe, while respiratory therapists coordinate programmes in the United States. There is no one best staffing structure. Optimal staff-patient ratios also differ: the American Association of Cardiovascular and Pulmonary Rehabilitation recommends ratios of 1:4 for exercise training, 1:8 for educational sessions and 1:1 for complex patients; the British Thoracic Society recommends ratios of 1:8 for exercise training and 1:16 for educational sessions. These ratios are not evidence based and are designed based on experience and opinion [3, 6, 20, 21, 22].
\n
It is recommended and accepted that for patients to gain optimum benefit from a pulmonary rehabilitation programme, a multidisciplinary approach should be taken [13, 23]. Availability of resources and staff will dictate the level of input the Multidisciplinary team will have but each member plays an important role in the rehabilitation programme:
\n
Respiratory physician: medical assessment; pharmacological management; referral; screening for oxygen and oxygen prescription.
Physiotherapist: exercise testing, prescription and training; musculoskeletal assessment, treatment and advice; airway clearance education; strategies for the management of dyspnoea; inspiratory muscle training; assessment for ambulatory oxygen requirements.
Respiratory nurse: Disease specific education; development of action plans; inhaler technique training.
Dietician: Nutritional assessment and advice.
Occupational therapist: Assessment and modification of home environment; energy conservation advice.
Pharmacist: advice and education on respiratory education and inhaler use.
Social worker: information and access to support services.
Psychologist: psychosocial assessment and treatment for conditions including panic, anxiety and depression.
\n
\n
\n
5.4. Rolling or cohort programme
\n
Deciding on whether to administer a rolling or a cohort programme is dependent on local considerations, as there is no high-quality evidence to suggest the benefit of one over the other. The characteristics of a rolling and a cohort programme are outlined in Table 1 [3]:
\n
\n
\n
\n
\n\n
\n
\n
Rolling
\n
Cohort
\n
\n\n\n
\n
Nature of programme
\n
Continual cycle of sessions, where patients join when there is a space available and leave after completing the programme of sessions
\n
All patients start and finish the programme at the same time
\n
\n
\n
Waiting list
\n
Patients enter the programme when a space arises, permits fast track access, potentially allows better capacity
\n
An accumulative number of patients wait to start the programme, the waiting list may be distorted
\n
\n
\n
Rehabilitation delivered at different locations by the same team
\n
Not possible as the programme always runs in the same venue
\n
Suitable
\n
\n
\n
Education programme
\n
The order of the talk is individual and governed by the point of entry
\n
Can ‘flow’ in a logical order
\n
\n
\n
Group dynamics
\n
A new patient may be the sole new participant which may be a beneficial or a challenge
\n
Patients all start together which permits group leaning of lifestyle changes
\n
\n
\n
Assessments
\n
Must perform pre and post assessments in parallel to the course
\n
Dedicated assessment slots can be programmed for all subjects pre and post rehabilitation
\n
\n
\n
Duration of programme
\n
Allows lengthening the programme or early graduation as required
\n
Fixed length for each programme
\n
\n\n
Table 1.
Characteristics of Rolling and Cohort programmes.
\n
\n
\n
5.5. Selection criteria for pulmonary rehabilitation programmes
\n
Any person with a chronic lung condition who continues to be limited by breathlessness despite optimal medical management should be considered for a pulmonary rehabilitation programme [22]. Improvements following a pulmonary rehabilitation programme have been shown in patients with COPD irrespective of their age or gender [24, 25, 26] level of functional impairment [27, 28, 29] or disease severity [30, 31]. By promoting self-efficacy and behaviour change, improving exercise tolerance and physical activity and reducing exacerbations, pulmonary rehabilitation at an earlier stage of disease has the potential to markedly change the course of the disease [6]. Frequent reasons for referral to a pulmonary rehabilitation programme include:
Dyspnoea/fatigue and chronic respiratory symptoms.
Impaired health-related quality of life.
Decreased functional status.
Difficulty performing activities of daily living.
Increased use of medical resources (e.g., frequent exacerbations, hospitalizations, emergency room visits).
One of the primary indicators for referral to pulmonary rehabilitation is based on the modified Medical Research Council Breathlessness (mMRC) score (see Table 2) [3]. This scale measures perceived respiratory disability, and allows patients to indicate the extent to which their breathlessness impacts their mobility. It is a 0–4 grade scale used to establish levels of perceived breathlessness [3, 6].
\n
\n
\n
\n\n
\n
Grade
\n
Degree of breathlessness related to activities
\n
\n\n\n
\n
0
\n
Not troubled by breathless except on strenuous exercise
\n
\n
\n
1
\n
Short of breath when hurrying or walking up a slight hill
\n
\n
\n
2
\n
Walks slower than contemporaries on level ground because of breathlessness or has to stop for breath when walking at own pace
\n
\n
\n
3
\n
Stops for breath after walking 100 metres or after a few minutes on level ground
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4
\n
Too breathless to leave the house, or breathless when dressing or undressing
\n
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Table 2.
The modified Medical Research Council Breathlessness (mMRC) score.
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There is very strong evidence that patients with an mMRC dyspnoea score of 2–4 who are functionally limited by breathlessness should be referred for pulmonary rehabilitation. However, patients with an mMRC dyspnoea score of 1 who are functionally limited by breathlessness should also be referred for pulmonary rehabilitation. Patients with COPD who have an mMRC score of 4 but who are able to attend an outpatient pulmonary rehabilitation programme achieve similar benefits from the programme as those with a lower breathlessness score [28].
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5.6. Exclusion criteria
\n
The exclusion criteria for enrolment into a pulmonary rehabilitation programme are minimal, and in some cases participation in the programme by a patient can be facilitated by the attendance and support of a carer or relative. However, general exclusion guidelines would include [3, 6]:
Patients with unstable cardiovascular disease or mobility problems which make exercising safely impossible (for example, severe arthritis, severe peripheral vascular disease, severe orthopaedic conditions).
Patients with significant psychiatric or cognitive impairment who are unable to follow simple instructions safely in a group setting.
Any further excluding factors are based on the assessor’s own objective judgement or with a discussion with the referring physician, for example, a perceived lack of motivation to participate in the programme.
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5.7. Referral process
\n
Once a patient has been deemed suitable to attend a pulmonary rehabilitation programme by the healthcare professional, the referral should be used as an opportunity to educate the patient about the benefits of the programme, to explore their understanding of the programme and to address the patients’ concerns [3]. The programme should be presented to the patient as a core treatment for the management of their condition as opposed to an optional adjunct. Patients should be referred to the programme under the care of a respiratory physician, who should be available to the staff co-ordinating the programme to discuss any medical problems which may arise during the programme and to ensure that potential participants have been medically assessed for suitability for the programme and that their pharmacological management has been optimised [22].
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5.8. Pulmonary rehabilitation post exacerbations of COPD
\n
Exacerbations of COPD result in increased mortality and healthcare use, worsening symptoms and health-related quality of life, as well as impaired exercise capacity, reduced skeletal muscle function of the lower limbs and reduced physical activity levels [3, 6]. Studies have therefore been conducted to explore the merits and the safety of ‘early’ pulmonary rehabilitation both during a hospital admission and within 1 month of hospital discharge for an acute exacerbation of COPD. It is now known that early pulmonary rehabilitation post exacerbation [2]:
Is not associated with any adverse events or increased mortality
Reduces risk of hospital readmissions
Improves health related quality of life
Improves exercise capacity
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It is therefore recommended unequivocally that patients with COPD who are hospitalised for an acute exacerbation should be referred for pulmonary rehabilitation at discharge, and should be enrolled into the pulmonary rehabilitation programme within 1 month of leaving the hospital.
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6. Patient assessment
\n
The initial assessment for the programme is an opportunity to outline a detailed description of the programme to the patient, to assess for co-morbidities, risk factors and contraindications for the programme, and to consider any appropriate onward referrals to maximise the benefit the patient will receive from the programme [3]. The essential information required for pulmonary rehabilitation includes:
Known communication/language barriers.
Current activity levels.
Respiratory diagnosis: spirometry for those with COPD.
Height, weight, BP and oxygen saturations at rest are desirable.
Modified Medical Research Council breathlessness score.
Smoking status (for those who continue to smoke, document details of previous attempts to quit; recent quitters may require support and/or counselling).
Therapies: current list of medication.
Use of oxygen: long-term oxygen therapy, short-burst oxygen therapy, ambulatory; oxygen saturations, use of domiciliary Positive Pressure Ventilation.
Significant and relevant comorbidities (which may affect their ability to participate in the exercise programme or education sessions, including adequacy of literacy and vision).
Transport needs: if applicable to that rehabilitation provider.
Health care utilisation: including number of hospital admissions and length of stay in the previous 12 months.
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6.1. Specific situations at assessment
\n
When deciding on a patient’s suitability for pulmonary rehabilitation, there are certain groups of patient characteristics which need further consideration during assessment for the programme including [3]:
\n
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6.1.1. Smoking status
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There is currently no evidence that smokers benefit any less from pulmonary rehabilitation than non-smokers, and the rehabilitation programme can be an ideal opportunity to support and facilitate these patients in smoking cessation. Smokers should be offered smoking cessation advice and should be referred to smoking cessation programmes.
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6.1.2. Chronic respiratory failure
\n
Patients with chronic respiratory failure (PaO2 < 8 kPa, PO2 > 6 kPa or both) gain much benefit from pulmonary rehabilitation and should not be excluded from the programme for this reason alone. The use of oxygen and non-invasive ventilation for these patients during the programme should be discussed with the referring physician, and the safety of the patient with consideration to the skill mix of the staff in the programme and the programme setting should also be considered when accepting these patients onto the programme.
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6.1.3. Cardiovascular disease
\n
From a safety perspective, patients with unstable cardiovascular disease (e.g. unstable angina, unstable arrhythmias) should not commence a pulmonary rehabilitation programme until their cardiac condition is stabilised. However, patients with stable cardiovascular disease as well as a chronic respiratory disease do benefit from the programme, and should be referred if pulmonary rehabilitation is indicated. Patients with aortic aneurysms <5.5 cm can participate safely in moderate intensity aerobic exercise training as long as their blood pressure is monitored and controlled.
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6.1.4. Anxiety and depression
\n
Patients with symptoms of anxiety and depression also benefit from the pulmonary rehabilitation programme, and should not be excluded from referral to the programme. The pulmonary rehabilitation programme allows an opportunity to detect these conditions and to consider onward referral for optimal management.
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6.1.5. Obese subjects
\n
Pulmonary rehabilitation may be an ideal setting in which to address the needs of obese patients with associated respiratory symptoms, including exercise training, nutritional education, psychological support and onward referral to specialists as required. Obese patients should not be excluded from the pulmonary rehabilitation programme; however, assessments for other cardiac and pulmonary comorbidities may need to be considered prior to commencing the pulmonary rehabilitation programme. Weight limits of equipment should be considered, low impact exercises may be more appropriate and specialised equipment may be required to accommodate these patients [6].
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6.1.6. Co-morbidities
\n
COPD is commonly associated with other medical co-morbidities, which may result from the common risk factors for COPD such as smoking as well as systemic inflammation. These can further impact on the patient’s management, and can include cardiovascular disease (arrhythmias, congestive heart failure, hypertension, and coronary disease), metabolic conditions (diabetes mellitus, osteoarthritis, and hyperlipidaemia), infections, lung cancer, obstructive sleep apnoea, cognitive dysfunction, depression or anxiety. These co-morbidities must be considered in the assessment and management of COPD patients enrolled in a pulmonary rehabilitation programme, as early intervention may influence the course and prognosis of the disease and can have a beneficial effect on both COPD and the relevant co-morbidity. Pulmonary rehabilitation is very important for patients with COPD and co-morbidities as physical activity is well documented to not only benefit COPD but also many other chronic conditions including obesity, diabetes, cardiovascular disease, musculoskeletal disease and peripheral vascular disease [32, 33, 34, 35, 36].
\n
The presence of co-morbidities does not preclude pulmonary rehabilitation in patients with COPD but they should be considered thoroughly when monitoring and prescribing exercise to allow these individuals to exercise safely. For patients with cardiac conditions, the need for pre-rehabilitation investigations (for example, echocardiography or stress testing) should be discussed with the referring physician to define safe exercise parameters. Anaemia, orthopaedic and neurological issues require further consideration of a safe exercise plan and the need for specialised equipment. The patient may also require further onward referrals (for example, dual energy X-ray absorptiometry (DEXA) scan, psychological review, and nutritional review) based on observations during the exercise programme.
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6.2. Exercise testing
\n
Prior to commencing the rehabilitation programme, an exercise assessment is essential to [6]:
Ensure the patient is safe to participate
Rule out cardiovascular morbidities
Assess baseline capacity
Individualise exercise prescription
Assess for the need for supplementary oxygen
Define the factors contributing to exercise limitation
Evaluate the effectiveness of the intervention
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Exercise tests can include field walking tests, or laboratory cycle ergometer or treadmill tests. Field walking tests are most commonly used, and are considered more reflective of daily living; they are low cost and are convenient in most settings. These include the 6-minute walk test (6MWT) and the incremental shuttle walk test (ISWT). The 6MWT is a valid, reliable and reproducible self-paced walk test once the established, recommended and standardised protocol is used. Performed over a minimum of 30 metres, patients are asked to walk as far as possible in 6 minutes along a flat corridor [37]. The ISWT is a symptom limited maximal exercise capacity, externally paced walk test performed over a 10-metre course. It is also valid and reliable. The walk speed continues until the participant can no longer continue, with a maximum duration of 20 minutes. The endurance shuttle walks test (ESWT) is a constant walking speed test performed at a set speed based on the ISWT [6].
\n
The choice of test is usually decided based on objectives, time, cost and availability.
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7. Exercise training in pulmonary rehabilitation
\n
Lower limb weakness is commonly seen in patients with COPD, and is a poor prognostic indicator [12]. The exercise component of pulmonary rehabilitation therefore should primarily be delivered reflecting aerobic exercise and on lower limb endurance and resistance training. The general principles of exercise in COPD are no different than in exercising a healthy population: it must reflect the individuals own capacity, progress as improvement occurs and exceed normal loads encountered in daily life to improve aerobic capacity and muscle strength.
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7.1. Aerobic/endurance training
\n
A target intensity of 60% peak work rate, aiming for an accumulative time of 30–60 minutes of aerobic training per session is recommended, with 30 minutes of continuous aerobic activity [3]. However, both interval and continuous training have been shown to be effective in patients with COPD, and should be selected based on both therapist and patient preference. Endurance exercise, most commonly delivered in the form of walking (treadmill or ground walking) or cycling, three to five times per week at a Borg dyspnoea or fatigue score of 4–6 (moderate to severe) is the recommended target training intensity [6].
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7.2. Resistance training of the lower limbs
\n
Resistance training of all major muscle groups, but particularly the quadriceps, should also be incorporated, not only for the improvements that are well documented for COPD symptoms, but also to reduce falls and to improve or maintain bone mineral density [6]. Resistance training should aim for 2–4 sets of 10–15 repetitions of each exercise, on 2–3 days of the week. The selected weight should be individualised for each patient, aiming for a prescribed weight of 60–70% of 1 repetition maximum for each individual patient. The weight should only have progressed once all sets can be completed with the selected weight [6]. Based on local resources, weight machines, elastic bands or free weights are all acceptable forms of resistance training.
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7.3. Resistance training of the upper limbs
\n
While it is suggested that upper limb training can improve upper limb function in patients with COPD, the optimal prescription of this training remains unclear, as do the improvements gained in broader outcomes for COPD patients. However, upper limb training may be incorporated based on individual needs to improve functional living. It could be assumed that starting loads and progression may follow the same prescription as for lower limb training [20].
\n
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7.4. Flexibility training
\n
While minimal research has been done on flexibility training as part of the pulmonary rehabilitation programme or the optimal duration and intensity of stretching exercises, flexibility of the major upper and lower limb muscle groups on 2–3 days a week can be recommended [38]. Also, improved thoracic mobility and posture may improve vital capacity in COPD patients, and should be assessed and addressed in all COPD patients [6].
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7.5. Generic vs. individualised exercise programmes
\n
Generic exercise training is recommended for the pulmonary rehabilitation classes: all patients in the class should do all the same exercises as opposed to an individualised exercise programme for each patient. However, the prescription of exercise should be individualised to each patient to ensure the correct intensity for that patient. Goal setting should be addressed with each patient on the initial assessment to address any hurdles to exercise and to further address each patient’s specific needs [3].
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8. Education in pulmonary rehabilitation
\n
Education on COPD and its management to both patient and family is an integral component of pulmonary rehabilitation programmes. Several studies show that patients instructed about the nature of their disease and the implications of therapy can better understand, recognise, and treat the symptoms of their disease [39]. The educational component acts as a support to lifestyle and behavioural change, and assists in the development of self-management skills. Patients are empowered to actively participate in their own healthcare, which can promote adherence to therapy and self-efficacy (i.e., the confidence in successfully managing one’s health). The educational needs of each patient should be individualised and identified at the initial assessment and reassessed over the course of the programme. The style of teaching used in pulmonary rehabilitation is changing from traditional didactic lectures to a collaborative self-management approach, which may be more effective [6]. Education should run in conjunction with an exercise programme and should cover relevant topics associated with chronic lung disease. Different aspects should be delivered by different healthcare professionals involved in the programme, with the relevant expertise in that area.
\n
Self-management includes core generic strategies, such as goal setting, problem solving, decision making, adherence to medication, maintaining regular exercise, nutritional advice, breathing techniques, bronchial hygiene and smoking cessation [40, 41]. Behavioural change strategies including the prevention, early recognition and treatment of exacerbations and advanced care directives are additional core educational issues incorporated in collaborative self-management programmes. The development of a patient-specific, collaborative self-management plan for COPD exacerbations including the recognition of symptoms, a personalised action plan and communication with a healthcare provider has been shown to be beneficial [41, 42].
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8.1. Breathing strategies
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Breathing strategies encompasses a range of breathing techniques, including active expiration, pursed lip breathing, diaphragmatic breathing, adapting certain body positions and co-ordinating paced breathing with activities. The aim of these techniques is to improve regional ventilation, gas exchange, respiratory muscle function, dyspnoea, exercise tolerance and quality of life [43].
\n
The breathing strategies are tailored to the individual, with patients adopting the technique most effective in reducing symptoms [44].
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8.2. Bronchial hygiene techniques
\n
Excessive airway secretions secondary to mucus hypersecretion and impaired mucociliary clearance are distinctive features for some patients. Chest physiotherapy is used to aid removal of airway secretions, which involves teaching on importance of daily clearance and training in drainage techniques [45].
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8.3. Smoking cessation
\n
In approximately 90% of cases of COPD, cigarette smoking is the direct cause. The single most important intervention to retard the progression of air-flow limitation and improve survival is smoking cessation. For many patients smoking cessation may be difficult due to strong physiologic and psychological dependence. Long-term quit success rates of up to 25% can be achieved when sufficient reserves and time are dedicated to smoking cessation programmes [46]. The rehabilitation programme provides a forum for education and continued reinforcement, on risks of continued smoking, advice on nicotine replacement therapy and other pharmacotherapy, along with referral to smoking cessation programmes.
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8.4. Advance care planning
\n
The process of advance care planning is often inadequate in chronic respiratory diseases [47]. Anxiety and fear of death is well described in individuals with advanced COPD along with reluctance to discuss it with their treating physician [48]. The pulmonary rehabilitation programme has been identified as an appropriate setting for discussion on advance care planning and end of life care [49].
\n
The idea is to allow both patient and family a unique opportunity to communicate goals of treatment and preferences regarding the use of life-sustaining treatments, such as cardiopulmonary resuscitation, mechanical ventilation, dialysis and feeding tubes, with the health care provider. Ideally, the discussion will facilitate better understanding of certain topics, such as the disease itself and prognosis, process of dying and end-of life care, advance directive documents (e.g. designating a health care proxy or enduring power of attorney).
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8.5. Psychosocial support
\n
Severe COPD is associated with increased risk for anxiety and depression, which can affect motivation levels and result in decreased participation in social activities [6, 46]. Episodes of dyspnoea often trigger fear and anxiety in patients with COPD and result in further anxiety in anticipation of repeat episodes [50]. Depression, feelings of hopelessness and an inability to cope are common in patients with COPD, with an approximate prevalence rate of 45% in patients with moderate to severe disease [51, 52]. Patients with depression have the tendency to withdraw from social interactions which can worsen feelings of isolation and loneliness. Sexual activity can be affected by depression and also the physical restrictions imposed by COPD itself, sexuality should be raised and discussed when necessary and appropriate counselling initiated.
\n
Screening for anxiety and depression should be included at the initial assessment in a pulmonary rehabilitation programme. If possible interviewing and involving the caregiver is beneficial. Promotion of an adequate patient support system is an important component of pulmonary rehabilitation [53]. Psychological and social support provided within the pulmonary rehabilitation setting can facilitate adjustment the physiological impact of the disease by encouraging adaptive thoughts and behaviours. These aid patients in diminishing negative emotions, provides a socially supportive environment and may improve compliance with rehabilitation. Multidisciplinary team members with the appropriate expertise to address these issues are most useful and referral to appropriate professional care may be necessary.
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8.6. Nutrition
\n
Nutrition counselling and education on weight management are particularly important in lung disease. Up to 20–30% of normal weight individuals with COPD show a shift in body composition to muscle wasting and relative increased fat mass, independent of spirometric severity [53]. Typically, underweight status and weight loss are more prevalent in advanced disease and emphysematous phenotype [54], while obesity is more prevalent in mild disease [53]. Patients with COPD are at risk of obesity and muscle wastage due to limitations in physical activity and adverse effects of glucocorticoids given for exacerbations. For patients with COPD there is an association between underweight status and lean muscle loss and increased mortality, again independent of FEV1 [55, 56], in addition underweight patients report a lower HRQoL status then normal weight patients with COPD [57].
\n
Changes in body weight or BMI do not accurately reflect all the changes in body composition that occur in patients with COPD. Body weight is made up of fat mass and fat free mass (FFM), fat free mass consists of water and body cell mass (organ, muscles, bone). Muscle mass constitutes a major part of fat free mass. The loss of FFM is characteristic of chronic lung diseases such as COPD and in severe COPD low FFM and mid-thigh cross sectional area have been shown to be a better predictor of prognosis than BMI [58]. Patients with COPD and low FFM have a lower exercise tolerance and impaired respiratory muscle strength than patients with maintained FFM [59, 60, 61]. FFM can be estimated using skinfold anthrometry, bioimpedance analysis or dual energy X-ray absorptiometry (DEXA).
\n
A comprehensive pulmonary rehabilitation programme should at a minimum include a simple nutritional screening, such as calculating patient’s body mass index or BMI. The aetiology of weight loss and muscle wasting in COPD is complex and a number of different physiologic and pharmacologic interventions have been used to stop or even reverse the process. This includes simple nutritional supplementation with an emphasis on adequate protein intake in order to stimulate protein synthesis to maintain or restore FFM. The increased energy requirements during activity in pulmonary rehabilitation must also be met in both underweight and normal weight individuals. Nutritional supplementation alone has not been successful in achieving significant weight gain. However, a 6 month intervention of dietary counselling along with nutritional supplementation resulted in significant weight gain and maintenance of FFM compared with control group [62].
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9. Post rehabilitation assessment
\n
\n
9.1. Patient-centred outcomes
\n
Patient-centred outcomes are used as outcome measures in pulmonary rehabilitation to measure the change or impact the pulmonary rehabilitation programme has had on the patient’s symptoms and quality of life [6]. Outcomes used during the programme should be valid, reliable and sensitive to change and have descriptions of relevant change, such as the minimally clinical important difference, which indicate a meaningful change of the condition for better or for worse.
\n
Outcome measures used are generally generic or disease specific, and should assess quality of life (health related quality of life, symptoms and functional impairment), depression and anxiety, functional status and breathlessness.
\n
Exacerbation history should also be documented as an outcome measure. The same exercise test used in the pre-rehabilitation assessment (6MWT or ISWT) should also be reassessed on completion of the programme to assess for improvements in exercise capacity. Quality of life measures are used to assess symptoms, physiological functioning, functional impairment and health related quality of life [55, 63, 64]. At least one of these questionnaires is advised and may include, for example, the Chronic Respiratory Disease Questionnaire [65, 66], the St. Georges Respiratory Questionnaire [16], or the COPD Assessment Test [67]. As outlined previously, up to 40% of COPD patients have symptoms of depression and anxiety [68]. All patients should be assessed both before and after the rehabilitation programme using, for example, the Hospital Anxiety and Depression Scale [68, 69], and an onward referral to a mental health professional considered if symptoms persist significantly on completion of the programme.
\n
Patients who are attending pulmonary rehabilitation should have the outcome of their treatment in terms of dyspnoea, health status and exercise capacity measured. Objective measurements of a patient’s baseline function and post-rehabilitation function, and reassessments in the months following completion of the rehabilitation programme allows the co-ordinator to assess the benefit obtained by the individual during the programme, to provide quality assurance for the rehabilitation services and to facilitate ongoing referrals if required. Other measures of outcome, such as muscle strength, nutritional status, physical activity levels and self-efficacy measures) may also be beneficial.
\n
\n
\n
\n
10. Unanswered questions in pulmonary rehabilitation
\n
\n
10.1. Where is the ideal location to carry out rehabilitation?
\n
The ideal location to carry out rehabilitation is currently unclear. The settings for pulmonary rehabilitation programmes vary; most of the research to date has involved outpatient programmes; however pulmonary rehabilitation programmes may also be conducted in an inpatient hospital or home setting. In a recent international survey involving 400 centres in 40 countries, 85% of pulmonary rehabilitation programmes in Europe and North America were using an outpatient model [70]. Outpatient settings include hospital outpatient departments, community facilities and physiotherapy clinics.
\n
Inpatient rehabilitation is offered in hospitals and can provide specialised rehabilitation care for individuals in a stable pulmonary state or after an exacerbation. It certain cases it can be initiated during inpatient acute care including the intensive care unit where ventilator limitations may limit aerobic exercise, but resistive muscle training can be well tolerated and is associated with improved 6-minute walk distance and muscle strength [6, 71]. Potential disadvantages with inpatient rehabilitation include higher costs and lack of coverage by health insurance in certain countries.
\n
Home based rehabilitation is an alternative model, which involves transferring the site of exercise training to the home. This could make the course more convenient and broaden the availability of the service. There is increasing evidence comparing home- and hospital-based programmes, including a recent large randomised equivalence study of home vs. outpatient rehabilitation. This demonstrated that important outcomes such as functional exercise capacity and health related quality of life were equivalent between both groups [72]. Fernandez and colleagues demonstrated that a home-based programme was safe and effective in a group of 50 patients with severe COPD on long-term supplemental oxygen [73]. There has been little uptake in clinical practice, with less than 5% of centres worldwide providing home based rehabilitation [70]. This is likely a result of limitations in some of the current studies, with many being underpowered or failing to provide all of the essential components of pulmonary rehabilitation.
\n
The American Thoracic Society (ATS)/European Respiratory Society (ERS) Policy Statement on Pulmonary Rehabilitation identified the need to increase accessibility of pulmonary rehabilitation as a key priority, which includes investigating novel PR programme models that are more accessible and acceptable to patients [74]. Thus, when choosing a rehabilitation setting characteristics of both a particular healthcare system or setting and the patient as an individual need to be considered. Factors such as transportation, availability of various programme settings as described above and in certain countries, payment considerations and health insurance need also to be considered. In relation to patient specific factors, the severity of their disease is important, as is the haemodynamic stability of a patient often in the context of recent exacerbation, co-morbidities and extent of disability if any. These factors can influence the most appropriate setting and level of supervision a patient needs enrolling in a pulmonary rehabilitation programme.
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\n
\n
10.2. What are the barriers to the uptake of pulmonary rehabilitation?
\n
One key goal of pulmonary rehabilitation is ongoing lifestyle modification to encourage patients to undertake a more active lifestyle in the future. Despite the extensive evidence for its benefits, pulmonary rehabilitation is delivered to fewer than 10% with those with COPD who would benefit [52]. Accessibility is a major factor particularly in rural settings where programmes are not available or appropriate infrastructure to provide them does not exist. However, it has also been shown in metropolitan areas that up to 50% of those who are referred will never attend and of those who do present, up to a third will not complete the programme [75].
\n
A systematic review in 2011 was carried out to identify barriers to uptake and factors affecting pulmonary rehabilitation adherence. The factors that influence whether people choose to attend their initial appointment can be different to the factors that influence programme completion [75]. A number of barriers to enrolment following referral were identified, including:
Disruption to established routine, varying from concerns over missing social activities to work commitments or carer demands such as caring for other family members.
Travel, transport and location, including distance to travel, available transportation or inability to travel independently.
Influence of the referring physician – some patients declined to attend following referral by a doctor they did not know or if the perceived that their doctor did not think the rehabilitation programme would benefit them.
Lack of perceived benefit, as some studies report patients perceiving their disease to be too severe to gain improvement or that the programme lacks guaranteed benefits.
Inconvenient timing of the programme – patient preference on timing of rehabilitation sessions can vary between morning and afternoon, and given the limited capacity and availability not everyone’s preference can be accommodated.
\n
The definition of programme non-adherence varies in the literature from declining to participate in the programme to attending at least one session. A non-adherence rate ranging from 10 to 32% has been described and varies considerably from study to study [75]. Factors associated with non-adherence include illness and co-morbidities, travel, transportation, lack of perceived benefits, smoking, depressive symptoms and lack of support [27, 76]. Cigarette smoking at enrolment was the sole independent risk factor for non-completion of pulmonary rehabilitation, in the systematic review described above [75]. This highlights the importance of the educational component and facilitating behaviour change including programmes for strategies for smoking cessation.
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\n
\n
10.3. How can the benefits of pulmonary rehabilitation be maintained?
\n
Given the nature of COPD as a progressive chronic disease, it frequently results in a progressive loss of function over time. It is therefore reasonable that any benefits obtained from an initial programme are likely to regress over time [3]. The benefits of an initial pulmonary rehabilitation programme have been shown to persist to some degree for at least 12 months, with quality of life maintained better than the increased exercise capacity. Developing strategies to extend the effects of the rehabilitation programme is extremely important. The benefits of ongoing supervised maintenance exercise programmes beyond the completion of the initial cycle remains uncertain [6].
\n
A repeat programme in those whose condition has deteriorated more than 1 year since completing the programme should be considered, and an earlier repeat programme may be warranted in those patients with a profound physiological decline within the initial 12 months of completing the programme. The benefits of a repeat programme of a patient who failed to benefit from the original programme are questionable. Ongoing exercise upon completing the programme should be encouraged in all patients, and opportunities for exercise upon completion of the programme should be provided to all patients.
\n
Implementation of a home exercise programme at least twice a week at an early stage during the rehabilitation programme encourages the participant to exercise independently during the programme, but also improves adherence to regular exercise once the programme has been completed. Written material with an individualised description and prescription of each exercise, resembling those undertaken in the supervised classes should be provided to each participant. The programme coordinator should monitor the patients home exercise diary throughout the programme, and any barriers to exercise that the patient is experiencing should be addressed. Precautions and advice on exercise should also be addressed [20].
\n
On completion of the programme, patients should be provided with a written, individualised, structured plan for ongoing exercise maintenance to encourage ongoing exercise. It should include aerobic and strength exercises, and information on local exercise amenities. Patients should be asked to reflect on the effect the programme has had on their daily physical activity and on their symptoms. Strategies to maintain their improvements and adherence to an ongoing exercise programme should be discussed. Regular assessments following completion of the initial programme can assist in maintaining the gains achieved during the programme [22].
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\n
\n
10.4. Is there a role for new technology?
\n
Pulmonary rehabilitation has rapidly established itself as a cornerstone in the comprehensive management of patients with COPD. As previously stated, a recent joint policy statement by the ATS and ERS has identified improved access and delivery of pulmonary rehabilitation to suitable patients as a priority in need of further research and development. As popularity and lack of capacity increase demand, other settings for effective rehabilitation will need to be found. These new settings would ideally maintain the quality and effectiveness of conventional programmes but be more convenient to patients [6].
\n
New technology may play a part in improving services by telemonitoring or provision of remote rehabilitation to inaccessible regions. Telemedicine is the use of telecommunication and information technology to provide clinical health care from a distance. Telerehabilitation is the delivery of rehabilitation services over telecommunication networks and the internet, allowing point-to-point video conferencing between a central control unit and a patient at home. This is a promising way of delivering health services to individuals who may live in isolated areas without adequate access to transportation or have a level of disability which limits their ability to travel. A study carried out in 2008 used mobile phone based systems to remotely monitor an endurance exercise programme at home [77]. This programme provided a music component with an appropriate tempo to facilitate the correct intensity of training; adherence could also be monitored and appropriate feedback and support delivered. The study demonstrated good compliance and significant improvement, and was also associated with fewer exacerbations and hospitalisations [78].
\n
There has also been evidence to support the delivery of a pulmonary rehabilitation programme from a large expert centre to smaller regional centres via videoconferencing [78]. In a controlled trial, there were equivalent outcomes for exercise capacity and quality of life. One other small trial in individuals with moderate to severe COPD, who had completed at least 12 sessions of outpatient pulmonary rehabilitation, found that telemonitoring by health care professionals reduced primary care contacts for respiratory issues compared with usual care [79]. Neither demonstrated any differences between groups and hospital admissions, days in hospital or contact with COPD nurse specialists in the community.
\n
Education, psychosocial support and counselling are components of a pulmonary rehabilitation programme which are critical to its success. A study in 2006 demonstrated that the combination of exercise counselling, stimulation of lifestyle change or adaption and the use of a pedometer is feasible and may improve outcome and maintenance of rehabilitation results [80]. Results of a systematic review comparing home telemonitoring with usual care showed that home telehealth (home telemonitoring and telephone support) decreased rates of hospitalisation and emergency department visits, whereas findings for hospital days varied between studies. There is a great deal of variability between studies in terms of interventions and approach [81].
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11. Conclusion
\n
Pulmonary rehabilitation is one of the most cost-effective therapies for individuals with chronic respiratory disease. Despite this, many programmes are not funded adequately due to a lack of knowledge and awareness of the benefits of pulmonary rehabilitation. Healthcare professionals in clinical practice are often not familiar with the benefits, science and process of pulmonary rehabilitation, and therefore do not offer it to suitable patients. The need for standardised formal training in pulmonary rehabilitation is clear. Interestingly, even when referred, uptake of pulmonary rehabilitation by suitable patients remains poor. This may be due to a perception of pulmonary rehabilitation as being difficult or frightening. Therefore, equally important is patient education regarding the proven benefits of pulmonary rehabilitation and the processes by which those benefits are attained. Given that pulmonary rehabilitation is an evidence-based, widely-accepted gold standard treatment for many respiratory patients, the disparity in access and availability results in unacceptable inequality of healthcare [82].
\n
\n\n',keywords:"pulmonary rehabilitation, COPD, exercise, physical activity",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/57506.pdf",chapterXML:"https://mts.intechopen.com/source/xml/57506.xml",downloadPdfUrl:"/chapter/pdf-download/57506",previewPdfUrl:"/chapter/pdf-preview/57506",totalDownloads:1890,totalViews:1012,totalCrossrefCites:2,totalDimensionsCites:6,totalAltmetricsMentions:0,impactScore:3,impactScorePercentile:85,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"April 3rd 2017",dateReviewed:"September 25th 2017",datePrePublished:"December 20th 2017",datePublished:"February 21st 2018",dateFinished:"November 7th 2017",readingETA:"0",abstract:"This chapter will review the rationale for and the need for pulmonary rehabilitation in patients with Chronic Obstructive Pulmonary Disease (COPD). Its clinical effectiveness will be considered, including the evidence supporting a role for rehabilitation in improving exercise tolerance in COPD as measured. While the influence of pulmonary rehabilitation on dyspnoea, exercise tolerance and quality-of-life is clear, evidence for the benefits of rehabilitation on reducing healthcare utilisation such as admission to hospital or attendance at out-of-hours services is limited. The chapter will provide guidance on the setting up of a pulmonary rehabilitation programme and clinical staff required and the suitability of patients to enter such programmes will be outlined. There will be discussion on the key components of a programme including education, nutritional advice and the management of dyspnoea. Exercise is the central component of pulmonary rehabilitation. Assessment of the patient and prescription of an exercise programme will be outlined as will assessing a patient’s improvement. One key goal of pulmonary rehabilitation is ongoing lifestyle modification to encourage patients to undertake a more active lifestyle in the future. Ways of activating patients to do this will be discussed and the evidence for the use of telehealth in this area will be reviewed.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/57506",risUrl:"/chapter/ris/57506",book:{id:"6097",slug:"copd-an-update-in-pathogenesis-and-clinical-management"},signatures:"Michelle Casey, Amy Mulkerns, Cliona O’Donnell and Tim\nMcDonnell",authors:[{id:"208279",title:"Prof.",name:"Tim",middleName:null,surname:"McDonnell",fullName:"Tim McDonnell",slug:"tim-mcdonnell",email:"timothy.mcdonnell@ucd.ie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"University College Dublin",institutionURL:null,country:{name:"Ireland"}}},{id:"208280",title:"Dr.",name:"Michelle",middleName:null,surname:"Casey",fullName:"Michelle Casey",slug:"michelle-casey",email:"m.casey8@icloud.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"208281",title:"Dr.",name:"Cliona",middleName:null,surname:"O'Donnell",fullName:"Cliona O'Donnell",slug:"cliona-o'donnell",email:"clionapodonnell@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"208282",title:"Ms.",name:"Amy",middleName:null,surname:"Mulkerns",fullName:"Amy Mulkerns",slug:"amy-mulkerns",email:"A.Mulkerns@stmichaels.ie",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Historical development",level:"1"},{id:"sec_3",title:"3. Rationale for pulmonary rehabilitation",level:"1"},{id:"sec_4",title:"4. The clinical effectiveness of pulmonary rehabilitation",level:"1"},{id:"sec_4_2",title:"4.1. Physiological",level:"2"},{id:"sec_5_2",title:"4.2. Quality of life",level:"2"},{id:"sec_6_2",title:"4.3. Reduction of healthcare utilisation",level:"2"},{id:"sec_7_2",title:"4.4. Psychosocial",level:"2"},{id:"sec_8_2",title:"4.5. Self-efficacy",level:"2"},{id:"sec_9_2",title:"4.6. Survival",level:"2"},{id:"sec_10_2",title:"4.7. Nutrition",level:"2"},{id:"sec_12",title:"5. Setting up a pulmonary rehabilitation Programme",level:"1"},{id:"sec_12_2",title:"5.1. Duration",level:"2"},{id:"sec_13_2",title:"5.2. Frequency",level:"2"},{id:"sec_14_2",title:"5.3. Staffing",level:"2"},{id:"sec_15_2",title:"5.4. Rolling or cohort programme",level:"2"},{id:"sec_16_2",title:"5.5. Selection criteria for pulmonary rehabilitation programmes",level:"2"},{id:"sec_17_2",title:"5.6. Exclusion criteria",level:"2"},{id:"sec_18_2",title:"5.7. Referral process",level:"2"},{id:"sec_19_2",title:"5.8. Pulmonary rehabilitation post exacerbations of COPD",level:"2"},{id:"sec_21",title:"6. Patient assessment",level:"1"},{id:"sec_21_2",title:"6.1. Specific situations at assessment",level:"2"},{id:"sec_21_3",title:"6.1.1. Smoking status",level:"3"},{id:"sec_22_3",title:"6.1.2. Chronic respiratory failure",level:"3"},{id:"sec_23_3",title:"6.1.3. Cardiovascular disease",level:"3"},{id:"sec_24_3",title:"6.1.4. Anxiety and depression",level:"3"},{id:"sec_25_3",title:"6.1.5. Obese subjects",level:"3"},{id:"sec_26_3",title:"6.1.6. Co-morbidities",level:"3"},{id:"sec_28_2",title:"6.2. Exercise testing",level:"2"},{id:"sec_30",title:"7. Exercise training in pulmonary rehabilitation",level:"1"},{id:"sec_30_2",title:"7.1. Aerobic/endurance training",level:"2"},{id:"sec_31_2",title:"7.2. Resistance training of the lower limbs",level:"2"},{id:"sec_32_2",title:"7.3. Resistance training of the upper limbs",level:"2"},{id:"sec_33_2",title:"7.4. Flexibility training",level:"2"},{id:"sec_34_2",title:"7.5. Generic vs. individualised exercise programmes",level:"2"},{id:"sec_36",title:"8. Education in pulmonary rehabilitation",level:"1"},{id:"sec_36_2",title:"8.1. Breathing strategies",level:"2"},{id:"sec_37_2",title:"8.2. Bronchial hygiene techniques",level:"2"},{id:"sec_38_2",title:"8.3. Smoking cessation",level:"2"},{id:"sec_39_2",title:"8.4. Advance care planning",level:"2"},{id:"sec_40_2",title:"8.5. Psychosocial support",level:"2"},{id:"sec_41_2",title:"8.6. Nutrition",level:"2"},{id:"sec_43",title:"9. Post rehabilitation assessment",level:"1"},{id:"sec_43_2",title:"9.1. Patient-centred outcomes",level:"2"},{id:"sec_45",title:"10. Unanswered questions in pulmonary rehabilitation",level:"1"},{id:"sec_45_2",title:"10.1. Where is the ideal location to carry out rehabilitation?",level:"2"},{id:"sec_46_2",title:"10.2. What are the barriers to the uptake of pulmonary rehabilitation?",level:"2"},{id:"sec_47_2",title:"10.3. How can the benefits of pulmonary rehabilitation be maintained?",level:"2"},{id:"sec_48_2",title:"10.4. Is there a role for new technology?",level:"2"},{id:"sec_50",title:"11. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'McCarthy B, et al. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2015 Feb 23;(2):CD003793. DOI: 10.1002/14651858.CD003793.pub3\n'},{id:"B2",body:'Puhan M, et al. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2009 Jan 21;(1):CD005305. DOI: 10.1002/14651858.CD005305.pub2\n'},{id:"B3",body:'Bolton CE, et al. British Thoracic Society guideline on pulmonary rehabilitation in adults. 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A review of the clinical evidence for exercise in osteoarthritis of the hip and knee. Journal of Science and Medicine in Sport. 2011;14(1):4-9\n'},{id:"B35",body:'O\'Gorman DJ, Krook A. Exercise and the treatment of diabetes and obesity. Medical Clinics of North America. 2011;95(5):953-969\n'},{id:"B36",body:'Rees K, et al. Exercise based rehabilitation for heart failure. Cochrane Database of Systematic Reviews. 2010 Apr 14;(4):CD003331. DOI: 10.1002/14651858.CD003331.pub3\n'},{id:"B37",body:'Redelmeier DA, et al. Interpreting small differences in functional status: The six minute walk test in chronic lung disease patients. American Journal of Respiratory and Critical Care Medicine. 1997;155(4):1278-1282\n'},{id:"B38",body:'Munro PE, et al. Pulmonary rehabilitation following lung transplantation. Transplantation Proceedings. 2009;41(1):292-295\n'},{id:"B39",body:'Make B. Collaborative self-management strategies for patients with respiratory disease. 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Bronchopulmonary hygiene physical therapy for chronic obstructive pulmonary disease and bronchiectasis. Cochrane Database of Systematic Reviews. 2000;(2):CD000045\n'},{id:"B46",body:'From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. www.goldcopd.org (cited July 2017)\n'},{id:"B47",body:'Spruit MA, et al. Rehabilitation and palliative care in lung fibrosis. Respirology. 2009;14(6):781-787\n'},{id:"B48",body:'Janssen DJA, et al. A call for high-quality advance care planning in outpatients with severe COPD or chronic heart failure. Chest. 2011;139(5):1081-1088\n'},{id:"B49",body:'Heffner JE. Advance care planning in chronic obstructive pulmonary disease: Barriers and opportunities. Current Opinion in Pulmonary Medicine. 2011;17(2):103-109\n'},{id:"B50",body:'Heim E, Blaser A, Waidelich E. Dyspnea: Psychophysiologic relationships. 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Thorax. 1987;42(10):773-778\n'},{id:"B66",body:'Williams JEA, et al. Health status measurement: Sensitivity of the self-reported chronic respiratory questionnaire (CRQ-SR) in pulmonary rehabilitation. Thorax. 2003;58(6):515\n'},{id:"B67",body:'Jones PW, et al. Development and first validation of the COPD assessment test. European Respiratory Journal. 2009;34(3):648\n'},{id:"B68",body:'Coventry PA. Does pulmonary rehabilitation reduce anxiety and depression in chronic obstructive pulmonary disease? Current Opinion in Pulmonary Medicine. 2009;15(2):143-149\n'},{id:"B69",body:'Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatrica Scandinavica. 1983;67(6):361-370\n'},{id:"B70",body:'Spruit MA, et al. Differences in content and organisational aspects of pulmonary rehabilitation programmes. European Respiratory Journal. 2014;43(5):1326-1337\n'},{id:"B71",body:'Troosters T, et al. Resistance training prevents deterioration in quadriceps muscle function during acute exacerbations of chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine. 2010;181(10):1072-1077\n'},{id:"B72",body:'Holland AE, et al. Home-based rehabilitation for COPD using minimal resources: A randomised, controlled equivalence trial. Thorax. 2016\n'},{id:"B73",body:'Fernandez AM, et al. Home-based pulmonary rehabilitation in very severe COPD: Is it safe and useful? Journal of Cardiopulmonary Rehabilitation and Prevention. 2009;29(5):325-331\n'},{id:"B74",body:'Rochester CL. An official American Thoracic Society/European Respiratory Society policy statement: Enhancing implementation, use, and delivery of pulmonary rehabilitation. Am J Respir Crit Care Med. 2015;192(11):1373-1386\n'},{id:"B75",body:'Keating A, Lee A, Holland AE. What prevents people with chronic obstructive pulmonary disease from attending pulmonary rehabilitation? A systematic review. Chronic Respiratory Disease. 2011;8(2):89-99\n'},{id:"B76",body:'Hogg L, et al. Effectiveness, attendance, and completion of an integrated, system-wide pulmonary rehabilitation service for COPD: Prospective observational study. Chronic Obstructive Pulmonary Disease. 2012;9(5):546-554\n'},{id:"B77",body:'Liu WT, et al. Efficacy of a cell phone-based exercise programme for COPD. The European Respiratory Journal. 2008;32(3):651-659\n'},{id:"B78",body:'Stickland M, et al. Using Telehealth technology to deliver pulmonary rehabilitation in chronic obstructive pulmonary disease patients. Canadian Respiratory Journal. 2011;18(4):216-220\n'},{id:"B79",body:'Lewis KE, et al. Does home telemonitoring after pulmonary rehabilitation reduce healthcare use in optimized COPD? A pilot randomized trial. Chronic Obstructive Pulmonary Disease. 2010;7(1):44-50\n'},{id:"B80",body:'de Blok BM, et al. The effects of a lifestyle physical activity counseling program with feedback of a pedometer during pulmonary rehabilitation in patients with COPD: A pilot study. Patient Education and Counseling. 2006;61(1):48-55\n'},{id:"B81",body:'Polisena J, et al. Home telehealth for chronic obstructive pulmonary disease: A systematic review and meta-analysis. Journal of Telemedicine and Telecare. 2010;16(3):120-127\n'},{id:"B82",body:'Vogiatzis I, et al. American Journal of Respiratory and Critical Care Medicine\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Michelle Casey",address:null,affiliation:'
Department of Respiratory Medicine, St. Michaels Hospital and St. Vincent’s University Hospital, Ireland
Department of Respiratory Medicine, St. Michaels Hospital and St. Vincent’s University Hospital, Ireland
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1. Introduction
The preoperative imaging diagnosis of rectal cancer lies at the heart of oncological staging and has a crucial influence on patient management and therapy planning. Computer tomography (CT) with intravenous contrast medium is the standard method to exclude metastases in the liver and lungs. However, the current state-of-the-art modality for local staging of the tumor is magnetic resonance imaging (MRI). Its new development, 3D MRI, seems to bring additional valuable possibilities for the surgery planning of rectal cancer.
1.1 Multidisciplinary management team (MDT) in rectal MRI
Due to the multitude of treatment options available today for the treatment of rectal cancer, it became an international standard (e.g. in [1]) that a multidisciplinary team (MDT) discusses each patient situation pre-therapeutically in a tumor conference. This procedure ensures that all therapeutic options are considered as necessary for the patient’s benefit. The basis for these discussions and decisions of the MDT is in most cases the imaging findings. Magnetic resonance imaging (MRI) of the pelvis has become of central importance in recent years, as it can best depict the relationship of the tumor to the mesorectal fascia and the other structures of the pelvis.
In order to make good therapeutic decisions, an MRI must not only be carried out in a technically adequate manner, but must also be interpreted and presented accordingly. Moreover, the radiologist should also have a basic understanding of the various available therapy options. In particular, it is important to understand the surgery relevant aspects in order to have a target-oriented interdisciplinary discussion. Similarly, the treatment partners should also have basic knowledge of the findings and interpretation of MRI in order to be able to understand the findings of the radiologist.
2. Magnetic resonance imaging (MRI) basics
2.1 Useful MRI sequences
T1 weighted sequences (T1w) are highly sensitive to fat, marrow and gadolinium contrast media, which are able to detect a high intensity signal, so they appear light in T1w images. On the other hand, water retrieves a low intensity signal, so it appears dark. Therefore, you recognize T1w images by the dark gray representation of water, e.g. urine in the bladder, and by the almost white representation of fat, like in the bone marrow. T1w sequences are important particularly for the examination of the pelvic lymph nodes and the bone marrow.
T2 weighted sequences (T2w) are the most important sequences for MRI pelvic imaging. They provide high-resolution anatomical images that allow an accurate representation of the rectal carcinoma and its relationship to surrounding structures. It depicts the mesorectal fascia (CRM) as a thin line of low T2-signal intensity. You may easily recognize the T2w-images by their parameters: the signal-rich representation of water, e.g. urine in the bladder, and the signal-rich representation of fat. T2-weighted (T2w) sequences are water-sensitive, so water is signal-rich (light), whereas fibrotic tissue with low water content is signal-poor (dark). Paradoxically, fat also appears signal-rich (light) in T2w-images, which makes it difficult to distinguish from water in individual cases. A specific suppression of the fat signal might help here. However, since fat suppression techniques (FS) all lead to a loss of signal and thus either to increased image noise or to limited spatial resolution, they are not recommended for pelvic imaging - only after intravenous administration of gadolinium chelates contrast agent. In addition, FS techniques reduce the contrast between the low-signal rectal carcinoma in the T2 weighting and the signal-rich mesorectal fat tissue, which has a negative impact on the exact spread of the disease.
Diffusion weighted imaging (DWI) is achieved using diffusion-sensitive gradients in fast T2w sequences. DWI, in contrast to T1 and T2 measurement (excellent for morphological properties) is an in vivo measurement and shows the mobility of water molecules in different tissues (normal, tumorous, or fibrotic tissue). The limited diffusion in malignant tissue leads to a higher signal (bright) on the DW images. Tumors therefore usually appear bright on DWI images, while their lower diffusivity then leads to a low signal on ADC maps. DW sequences have the lowest spatial resolution of all sequences used in routine clinical protocols due to limitations in the signal-to-noise ratio, and they are susceptible to artifacts and distortion. These distortions are particularly pronounced at air-tissue boundaries (e.g. intestine) and OP clips. Moreover, the DWI technique necessarily requires fat saturation, so that fat presents itself with little or no signal. For spatial orientation, we always take corresponding anatomical images using T2w sequences.
Diffusion-weighted sequences are optional for the primary staging of rectal carcinoma, but we strongly recommend including them into the standard MRI protocol, as they can significantly facilitate the localization of the tumor and lymph nodes, and later restaging. MRI examinations for restaging of the rectal carcinoma after neoadjuvant therapy should contain a DWI sequence in order to be able to detect or exclude vital tumor remnants.
2.2 Patient preparation
2.2.1 Bad diagnosis always begins with bad patient preparation
Contrary to what is still being claimed, preparation of the bowel by means of enema (clyster or micro clyster) immediately prior to the examination is extremely important. We want to perform a high-precision examination similar to colonoscopy in a clean medium and not in a contaminated organ. The patient will always be informed in detail about the exact procedure of the examination, and this ensures active cooperation in most cases. This way, we minimize restlessness and movement artifacts. After flushing with Microlax Rectal Solution, the rectum is filled with warm tap water. Water is an excellent contrast medium without risking distension of the intestinal wall. In our department, we only use ultrasound gel for MRI defaecography, but not for tumor diagnosis, as the expansion of the rectum due to compression may restrict the assessment of the mesorectal space. Water as contrast medium allows an exact detection of even small flat lesions, which may be the case after RCT. Another advantage is the elimination of air besides stool residues. This procedure also creates perfect conditions for high quality DWI, which plays a particularly important role in restaging. Air is an enemy and real falsificator of DWI measurements! Last but not least, we prepare an infusion for administration of butylscopolamine to reduce intestinal motility, and for administration of contrast agent, if necessary.
Having this done, specially trained medical-technical staff accompanied by doctors trained in rectal MRI perform the actual MRI examination. They always follow a standardized protocol with particular attention to angulation. The main axial layers must always be orthogonal to the tumor. Only in this way can the MRI results correspond with histology in terms of local tumor staging, and measurement of infiltration depth and distance to the mesorectal fascia. Furthermore, it is important to ensure that the restaging examination is always performed with the same equipment as the primary staging examination was done. Our experience has shown that different devices (e.g. Siemens vs. Phillips) deliver different DWI, which can make precise restaging difficult. These organizational challenges can only be overcome if we are all aware of them.
2.3 Examination protocol
Rectal MRI can be performed routinely on a 1.5 T or 3 T system and takes about 25 minutes. However, our surgery department prefers 3 T systems because of their clearly higher resolution, shorter examination time, and the possibility of performing 3D imaging. A limited FOV (“field of view”) is recommended, as it allows both accurate local tumor diagnosis, and excellent imaging of the mesorectum and adjacent organs.
We begin with a sagittal T2-weighted turbo spin echo (TSE) sequence, which serves as the planning sequence for the second axial thin-layer (3 mm) T2 TSE sequence and is the decisive sequence of the rectal protocol. Axial in this context always means perpendicular to the carcinoma, so that depending on the extent and location of the tumor, paraaxial, axial or paracorononary layers result!
The mandatory and most important measurements, done in mm, such as tumor infiltration depth into the mesorectum and the tumor distance to the mesorectal fascia, are performed based on these paraaxial images. If the radiological department performs accurately, then the measured values and the tumor staging correspond to the histological results. Radiologists achieve this performance only after a relatively long learning curve. We always correlate our results with the pathology results during the tumor board.
Tips for the high resolution T2 axial sequence
Must be angled perpendicular to the tumor. The invasive center (the part of the tumor extending the most within the mesorectal fat) of the tumor must be detected on the sagittal plane. It is at this level where the sequence must be angled perpendicularly to the tumor.
Sometimes, it may be necessary to obtain more than one sequence angulation for optimal assessment in bulky tumor masses.
A slice thickness of 3 mm or less is recommended.
As mentioned above, in deep carcinomas (lower third of the rectum) a coronary T2w TSE sequence is obligatory in order to detect or exclude infiltration of the muscle levator ani (T4 stage) or to diagnose infiltration of the anal canal. For deep carcinomas, we recommend to perform a Gd-enhanced T1 weighted axial and coronal gradient echo sequence with fat saturation (GRE fs) as standard. These sequences depict the infiltration of the anal canal more accurately than with the native T2 sequence alone, Figure 1A and B.
Figure 1.
A. Paracoronal T2WI, no enhancement, shows a lower rectal T2 stage tumor without infiltration of the mesorectum, levator ani or anal canal. B. Gd enhanced paracoronal T1FS, anal canal. C. Gd-enhanced axial T1 FS. Markings: Yellow arrow: Levator ani; Yellow star: end of mesorectum; Green arrow: FMR = CRM; Red star: tumor; Red dashed arrow: muscularis propria; Red plain arrow: internal anal sphincter (IAS); Blue plain arrow: external anal sphincter (EAS)’Purple double arrow: anal canal; and Yellow dashed arrow: intersphincteric plane (ISP). Source: F. Bauer, Radiology Kaufbeuren.
Another important part of the MRI rectal protocol is the preparation of diffusion-weighted sequences (DWI-MRI) including the quantitative measurement of ADC values (apparent diffusion coefficient), which in particular provides valuable additional information for the evaluation of therapy response after neoadjuvant radiochemotherapy. DWI is also very helpful for detection of lymph nodes (Figure 2), but it is not suitable for determining their benignity or malignancy, because in both cases the lymph nodes have a high cellularity [2].
Figure 2.
Axial DWI-T2W image of a rectal cancer. Note the good demarcation of the tumor (red arrow) and of some irregular intramesorectal lymph nodes (yellow arrows) with the same signal intensity as the tumor. DWI is good in nodal detection, but has no value in assessing nodal malignancy. Source: F. Bauer, Radiology Kaufbeuren.
Since about 12 months, we included the 3D volume measurement into the standard protocol, when using modern 3 T systems with newest hardware and software. This supplementary measurement takes about 5 minutes.
2.4 Clinically relevant embryology of rectum and anal canal
Rectum and anal canal emerge from the part of the endodermal intestinal tract known as the hindgut. At the ventrocaudal end (approx. 5th week of development) this has a sack-shaped dilatation, cloaca, which is closed to the outside by the cloacal membrane. The cloaca lined with endoderm provides not only the epithelial lining for the rectum and anal canal, but also for the bladder and urethra. Through growth or proliferation of the urorectal septum in the direction of the cloacal membrane (approx. 7th week of development), the cloaca is divided into the ventrally located urogenital sinus and the dorsally located anorectum. The cloacal membrane, which consists of epithelial cell clusters, disappears by apoptosis (rupture of the cloacal membrane), so that the urethral and anal canals are each open to the outside. The tip of the urorectal septum has now reached the body surface and forms the future perineum. Through the use of refined methods it has been disproved for decades that the cloacal membrane is the place where the endoderm and ectoderm meet.
Proliferating epithelial cell clusters, so-called anal membrane, temporarily displace the anal opening. This lies at the level of the linea pectinata, which can already be detected at this point by the different immunohistochemical behavior of the surface epithelia. The epithelial closure disappears in the 8th week of development. In the following 9th week of development, the different epithelia proliferate and differentiate and the columnae and sinus anales are formed, thus not only the linea dentata is clearly marked, but the epithelial border between high-prismatic (cubic) epithelium and squamous epithelium becomes clear. In the mesenchyme around the anorectum, the smooth inner ring muscle layer differentiated, reaching with a thickened end in the 8th week of development to the level of the Linea pectinata. The outer longitudinal muscle layer differentiates with a time delay in craniocaudal direction [3].
Conclusion: Only the rectum part above the linia anorectalis emerges from the endoderm, similarly to the colon. The anal canal emerges from the ectoderm, and for this reason, some authors do not consider it as belonging to the rectum.
3. Normal anorectal anatomy in MRI and the fasciae
In MRI, we can divide the rectum into three sections based on its three lateral curvatures (in analogy to the Houston valves inside).
The upper two thirds are surrounded anterolaterally (upper third) and anteriorly (middle third) by the visceral peritoneum. This forms the anterior peritoneal fold approximately at the level of the middle curve (in the area of the so-called Kohlrausch’s fold) and thus delimits the upper two thirds of the rectum from the extraperitoneally located wide lumen rectal ampulla.
The anterior peritoneal fold has a specific shape in axial stratification, which resembles the appearance of a seagull, hence the name “seagull sign” (Figure 3C).
Figure 3.
Normal rectal wall in high-resolution MRI. A. Paraaxial T2WI depicts well layers of the rectal wall around the high-intensity intestinal lumen (filled with water): low intensity muscularis propria (red arrow) and high intensity mesorectal fat (yellow star) including lymph nodes and vessels. MRF (green arrow) is shown as a very thin line of low intensity surrounding the mesorectum. This line is crucial for surgery planning, as it represents the CRM (MRF=CRM). B. Paracoronal T2WI depicts additionally the low intensity mucosa (blue arrow), followed by the high intensity submucosa (yellow arrow) followed by again a low intensity structure, the muscularis propria. C. Paraaxial T2WI depicts the anterior peritoneal fold “Seagull sign” (yellow arrow). Source: F. Bauer, Radiology Kaufbeuren.
As mentioned in 2.3, T2-weighted sequences optimally depict the individual wall layers of the rectum:
Submucosa, represented as an inner layer of high intensity. Appropriate examination parameters (see below), allow even to differentiate between mucosa and submucosa. In this case, the mucosa stands out as a fine low intensity line against both the positively contrasted intestinal lumen and the high intensity submucosa;
Muscularis propria, represented as a further adjacent layer of intermediate to low signal intensity.
Mesorectal fat, the natural barrier to tumor spread, represented as an outer layer of high intensity.
The mesorectal fascia (MRF) represents an important boundary structure for the description of the tumor extension and is well recognizable in T2-weighted sequences as a thin linear structure of low signal intensity.
The mesorectal fascia encases the perirectal (so-called mesorectal) fat including lymph nodes and vessels and represents an important natural barrier to tumor spread [4]. It corresponds to the so-called circumferential resection margin (CRM), which determines the extent of surgical resection in the context of total mesorectal excision (TME) [5], as seen in Figure 3A and B. At the level of the anterior peritoneal fold, the MRF fuses with the peritoneum. From this point on, the proportion of mesorectal fat decreases continuously until neither fat nor fascia are visible in imaging at the level of the anorectal transition. Inferiorly, the rectum fuses with the anal sphincter complex (Sphincter ani externus and internus).
The external sphincter consists of striated muscles, can be defined as a hypointense structure in all sequences in the MRI and only slightly accumulates contrast medium after gadolinium administration (a typical feature of striated muscles).
The boundary between the rectum and the anal canal can be easily recognized in MRI by the complex of the muscle levator ani at the upper end of the anal canal, which fuses with the muscle layer of the inferior rectum [5]. The internal sphincter represents a sort of expansion of the circular muscle layer of the Muscularis propria of the rectum and consists of smooth muscle. In both T1-weighted and T2-weighted sequences it has an intermediate signal intensity. We use Gd-enhanced MRI with i.v. administration of the contrast agent to highlight the internal sphincter, Figure 1B and C.
4. Tumor morphology with MRI
By far the most common rectal adenocarcinoma, up to 90%, in MRI may appear as solid, polypoid or flat lesions within the intestinal wall, whereas the aspect of an annular or semiannular mass and growing with varying degrees of stenosis is the most frequent image.
Less rectal tumors, up to 10%, may contain mucin, and mucinous tumors have a poor prognosis and a high risk of spillage during surgery [6]. MRI depicts these tumors well on T2w as well delimited high intensity masses, Figure 4.
Figure 4.
A. Axial T2w image shows a low-lying mucinous tumor of high signal (red star) disrupting the mesorectal fascia (green arrows) and extending into the dorsal bladder wall (yellow arrow). B. The very large mucinos adenocarcinoma (signet-ring) with a central scar situated in the middle third of the rectum with complete infiltration of the mesorectum, and of the dorsal bladder wall at 12 o’clock. Stage: T4, CRM+, N0, EMVI. Histology confirmed this result. Source: F. Bauer, Radiology Kaufbeuren.
As described above, T2-weighted sequences under optimal conditions can differentiate the wall layers of the rectum. The vast majority of carcinomas have a higher signal than the hypointense (not always controllable) mucosa, but a lower signal than the clearly hyperintense submucosa. Exceptions to this are, on the one hand, mucinous carcinoma and on the other hand, sigmoid ring cell carcinoma [7].
After administration of contrast medium, the entire rectal wall is clearly hyperintense and the individual wall layers can no longer be differentiated from each other. Therefore, the native T2-weighted sequences should be used for the primary diagnosis of the T category.
5. Local staging with MRI
The assessment of the findings obtained with MRI should be based on the TNM system. However, the MRI also provides other essential information, such as the distance of the tumor to the circumferential resection margin (CRM), and the tumoral invasion of the venous structures beyond the muscularis propria (EMVI). This additional information must be included in the report as well.
Multiple studies have proved the added value of structured reporting in rectal cancer [8, 9, 10], and resulted in many proforma available online. The diagnosis is ideally carried out using a structured report (SR) like our Structured Report (see Appendix at end of this chapter) for Primary Staging of Rectal Carcinoma at our Imaging Center (www.radiologie-kaufbeuren.de).
The report should include both the appearance of the tumor (e.g. ulcerative growth), as well as its minimum distance from anus. In addition, the craniocaudal tumor extent and the positional relationship of the tumor to the peritoneal fold should be reported. Furthermore, the radius of the carcinoma in the intestinal wall according to lithotomy position (SSL), whether the muscularis propria is infiltrated or whether extramural growth is already present should be reported.
5.1 T-staging
Rectal cancer staging is based on the TNM (tumor, nodes, and metastases) system. In this context, a stage T1 disease passes through the mucosa and submucosa but does not infiltrate the muscularis propria.
A stage T2 (Figure 5A) disease infiltrates additionally the muscularis propria.
The more advanced stage T3 (Figures 5B,6, and 7) disease infiltrates the muscularis propria and goes beyond into the mesorectum. This stage T3 has been further split into substages a, b, c, and d to categorize the depth of extramural invasion, as follows: < 1 mm = T3a; 1–5 mm = T3b; > 5–15 mm = T3c, and > 15 mm = T3d (Figures 6 and 7).
Figure 5.
A. Paraaxial T2w image shows a rectal tumor which invades the muscularis propria (red arrow) but does not penetrate its external margin. Note the fine spiculations towards the mesorectum (yellow star), and the irregular heterogeneous nodes of same signal intensity as the tumor, indicating potential nodal involvement (yellow arrow). Diagnosis: T2, N1, CRM-, EMVI-, which was confirmed by histology (T2 with “desmoplastic reaction” and nodal metastasis). B. Rectal tumor stage T3a. Note the similarity to A: tumor extensions (yellow arrow) into the mesorectal fat (yellow star). Source: F. Bauer, Radiology Kaufbeuren.
Figure 6.
Short axis axial high-spatial-resolution T2w images of different sub-classifications of T3 tumors with extramural spread (arrow): A. T3a (<1 mm), B. T3b (1-5 mm), C. T3c (>5-15 mm). Markings: mesorectal involvement (yellow arrow), muscularis propria (red dashed line), and CRM = FMR (green arrow). Source: F. Bauer, Radiology Kaufbeuren.
Figure 7.
Axial T2wi shows a rectal tumor (yellow star) staged: T3d (>15 mm), CRM+, EMVI+, N1). The extramural spread is measured from the level of the supposed muscularis propria (red dashed line) to the maximal point of mesorectal involvement (red arrow). Notice also the invasion of the venous structures (EMVI, blue arrow) and the extramesorectal metastatic node (yellow arrow). This node group will not be removed in a regular TME! CRM = FMR (green arrow). Source: F. Bauer, Radiology Kaufbeuren.
The last stage, T4, also divides into two subclasses, a, and b. Substage T4a is diagnosed when the tumor involves visceral peritoneum or anterior peritoneal reflection, while T4b is diagnosed when the tumor invades at least one adjacent organ, see Figure 8.
Figure 8.
A. Stage T4a tumor involves visceral peritoneum or anterior peritoneal reflection (green arrow). B. Stage T4b tumor involves an adjacent organ, uterus (yellow arrow), and the mesorectum (yellow star). Source: F. Bauer, Radiology Kaufbeuren.
Several histopathologic studies have shown that T3 tumors with more than 5 mm mesorectal invasion have a cancer-specific 5-year survival rate of approximately 54% [11]. On the other hand, for tumors of 5 mm or less in diameter, the cancer-specific survival exceeds 85% [12, 13]. Therefore, it is crucial to report the depth of extramural spread in detail, with the precise substage T3a, b, c or d. The overall reported accuracy for T staging using a pelvic phased-array coil ranges from 59% to 95% [12, 13]. Differences in T2 signal intensity between the tumor, submucosa, muscular layer, and mesorectum play the main role while detecting and staging rectal cancers using MRI.
T stage must be assessed on planes strictly perpendicular to the tumor. Incorrect prescription of the acquisition plane leads to blurring of the muscularis propria and may lead to overstaging. When the tumor is not visible on sagittal T2 WI: obtaining high-resolution images of the entire length of the rectum and adding DWI may help localize the mass. The depth of extramural spread must be measured in millimeters beyond the outer edge of the longitudinal muscular layer [13], as depicted in Figures 5,6 and 7.
Al-Sukhni et al. [9] published a meta-analysis (21 studies between 2000 and 2011) on the diagnostic accuracy of MRI and found a high overall accuracy in the assessment of the T-stage with a sensitivity of 87% and a specificity of 75%.
5.1.1 Challenges for T-staging
Differentiation between T2 and borderline T3 lesions is still challenging today. The main issue is to distinguish true mesorectal tumor invasion from desmoplastic reactions [14]. In this case, the inflammatory accompanying reaction in the adjacent mesorectal fat masks the actual tumor spread. In particular, fine spicular extensions in the mesorectum should be evaluated carefully - if these are mistakenly interpreted as a tumor (T3 instead of T2), overstaging and thus overtherapy may occur.
One often error source is the use of thicker sections and lower resolution techniques. Therefore, using fine sections in T2WI should help clarifying such cases. Indeed, desmoplasia associated with ulcerating tumors at the invasive border is typically seen as fine low-signal-intensity spicules on T2WI. These spicules do not show restricted diffusion. Tumor extension into the mesorectum, on the other hand, forms thicker, intermediate signal- intensity nodular bands with restricted diffusion and disruption of muscularis propria [15].
From the therapeutic point of view, the differentiation between T2 and T3a, b stages is not important since the treatment of these lesions is identical: TME alone or short term RCT followed by TME.
5.1.2 Specific issues related to low-lying tumors
Low-rectal tumors are associated with higher rates of positive resection margins, higher local recurrence rates, and poorer survival [16]. This is largely due to anatomic considerations and the fact that the mesorectal envelope tapers and narrows at this level. These rates can be improved by using CRT in locally advanced low-rectal tumors. The results show a good response with higher sphincter preservation rates and disease-free survival [15]. In consequence, a tumor that would have previously required an abdominoperineal excision may instead be treated with ultralow resection and coloanal anastomosis.
Our experience has shown that, particularly in the case of low-lying tumors, the primary surgical concept changed relatively often after CRT and restaging. Consequently, tumors that had required abdominoperineal excision before CRT only needed ultralow resection and coloanal anastomosis after CRT.
All these require a very good quality MRI beforehand, to define the location of the tumor relative to the sphincter complex precisely, so that we select correctly the patients who will profit from preoperative CRT.
For the assessment of the anal canal, T1w lipid-saturated T1FS sequences with contrast medium are superior to T2w-sequences, since m. levator ani and m. sphincter ani externus are reliably separated from m. sphincter ani internus due to their signal and contrast medium behavior.
Rectal carcinoma usually shows low signal intensity compared to the normal intestinal wall and sphincters. Stage T3 implies the infiltration of the external sphincter. At stage T4, the tumor infiltrates also of the m. levator ani. As a matter of fact, as soon as a rectal carcinoma crosses the mesorectal fascia and infiltrates the visceral peritoneum, the diagnosis is T4. Here, it must be differentiated whether adjacent organs (vagina, uterus, ovaries, prostate, seminal vesicles, bladder and ureter) are reached by the tumor (T4b) or whether only the visceral peritoneum (T4a) is infiltrated (Figure 8A and B). The contact of the tumor with surrounding organs (without a preserved fat layer adjacent to the organ) automatically requires classification as T4 in the findings report, even if the adhesion later turns out histopathologically to be a peritumorous inflammation.
Tips for T-staging of low-lying tumors with MRI
Protocol of choice: High-spatial-resolution T2W and T1 FS coronal imaging after i.v. administration of Gd, because it depicts optimally the tumor relationship with the levator and puborectal muscles, sphincter complex, and intersphincteric plane, as depicted in Figure 1A, and B.
First focus on the location of the lower edge of the tumor in relation to the puborectalis sling:
If tumor is located above the puborectalis sling: sphincter involvement can be easily excluded.
If the tumor extends below the puborectalis sling, 3 areas have to be evaluated and reported on, Figure 1B, and C (see Appendix on structured reporting).
The internal sphincter (IAS)
The intersphincteric plane (ISP)
The external sphincter (EAS)
In case of stage T4: Levator and puborectalis muscles or external sphincter are involved.
5.2 Mesorectal fascia (MRF) = Circumferential resection margin (CRM)
A central component of preoperative local staging is the assessment of the distance of the tumor from the mesorectal fascia (MRF) and thus from to the circumferential resection margin (CRM). CRM infestation is an important prognostic indicator for the occurrence of local recurrences [5].
In the case of MRI-based surgery of the rectum, we deliberately equated fascia mesorectalis (MRF) with Circumferential Resection Margin (CRM) in the MDT conference, which naturally led to a need for clarification at the beginning of the discussions. In the meantime, this discussion has been clarified, if one considers the following anatomical and surgical conditions.
The CRM is the non-peritoneal surgical resection plane that is prepared during surgery and has no direct anatomical correlate in the MRI, as it is de facto only determined by the surgeon during the procedure. In practice, however, the surgeon orients himself or herself on the MRF, so that the MRF serves as the most important anatomical landmark in preoperative staging and is practically equated with the surgical resection plane. Accordingly, the visceral peritoneum or peritoneal flap are not part of the CRM, as they cannot be influenced by the surgeon. Consequently, the CRM is only “circumferential” in the lower third of the rectum and thus strongly dependent on the height of the respective rectal section, since in the middle third, the rectum is already covered anteriorly by peritoneum, and the CRM accordingly only exists laterally and posteriorly. In the upper third of the rectum, the CRM is only present on the dorsal side, since the rectum is predominantly peritoneal at this height. The distance between the rectal carcinoma and the circumferential resection margin (CRM) is the most important risk factor for a local tumor recurrence, therefore special importance must be attached to the CRM.
The CRM is considered positive (MRI predicted “cut edge positivity”) if the distance between the rectal carcinoma and the mesorectal fascia is 1 mm or less (= CRM positivity), see Figure 7.
Therefore, we need to document the minimum distance to the MRF in millimeters in the findings. There is no general consensus regarding the evaluation of the lymphatic of extramural vascular infiltration if these are closer to the MRF than the primary tumor. In our clinic, we consider clear lymph node metastases and clear extramural vascular infiltration a CRM positive criteria, when the shortest distance to the MRF is lower than or equals 1 mm.
The lower third of the rectum poses a particular challenge for the assessment of CRM due to its anatomical situation. Therefore, the best possible image quality is essential here, including the exact angulation of the layers with respect to the anal canal. The mesorectal fascia fuses in the lower third of the rectum on the levator ani and ends at the upper edge of the sphincter complex. CRM positivity here depends in particular on the surgical procedure. In this context, the intersphincterian fat lamella is an important anatomical guiding structure in addition to the m. levator ani. If the m. sphincter ani internus is infiltrated, but there is a distance between the tumor and the intersphincterian fat lamella or m. levator ani of more than 1 mm, the CRM for an intersphincterian resection is negative. If, on the other hand, the intersphincterian fat lamella or the m. levator ani is infiltrated, an extended resection must be performed, otherwise CRM positivity would be present.
5.3 Extramural venous invasion (EMVI)
EMVI is defined as tumoral invasion of large vessels, typically veins, in close proximity to the muscularis propria. It represents an important criterion for the individual prognosis, as positive EMVI leads significantly more often to local tumor recurrence and metastases (both local and distant). The probability of metastasis increases with the caliber of the infiltrated vessel, whereas larger vessels with a caliber of ≥3 mm greatly increase the probability of metastasis. On the other hand, smaller vessels are difficult to differentiate from lymph vessels, which have a somewhat better prognosis. This distinction is difficult even for histopathology, where it may be achieved using special staining. EMVI indicates at least stage T3, since EMVI expands per continuitatem and represents a tumor infiltration through the muscularis propria.
MRI has shown an increasing sensitivity for the detection of EMVI with the increasing use of 3 T systems. The infiltration can be detected much easier using a higher resolution, where it is shown as an intravascular substrate having an identical T2w signal intensity as the primary tumor. At the same time, no flow signal can be detected inside the vessel (Figure 7).
The MRI-EMVI point score system recommended by Smith and Brown in 2008 was not practical for us, and with the increasing use of 3 T equipment, we are now increasingly successful in directly detecting vascular infiltration.
5.4 Lymph node staging
All radiological imaging procedures, including MRI, have limited sensitivity and specificity in assessing lymph node metastasis, but we can significantly improve this result by consistently applying the DLC system, as depicted in Figure 9 [2]:
D – Detection using axial DWI (number of lymph nodes), see also Table 1;
Figure 9.
Nodal staging using the DLC system. D = Detection using DWI, L = Localization using T2w, and C = Characterization using high resolution systems with 3 T. Red arrow: intramesorectal nodes. Yellow arrow: extramesorectal nodes. Green arrow: fascia mesorectalis (CRM). Blue dashed arrow: characterization (inhomogeneity, round-oval with spiculae). Red star: tumor. Source: F. Bauer, Radiology Kaufbeuren.
Class
Interpretation
Nx
Regional lymph nodes cannot be assessed
N0
No involved regional lymph nodes
N1
a
1 involved regional lymph node
b
2-3 regional lymph nodes involved
c
No involved regional lymph nodes, but tumor deposits in subserosa, mesentery or non-peritonealized pericolic or perirectal/mesorectal tissues
N2
a
4-6 regional lymph nodes involved
b
> = 7 lymph nodes involved
Table 1.
Extended N-classification for rectal cancer.
L – Localization of lymph nodes (no. of intra and extra mesorectal) using T2w high resolution multiplanar imaging using a 3 T system (axial, coronal, and sagittal planes);
C – Characterization using T2w high resolution imaging using a 3 T system: tumor size in mm and morphological criteria like inhomogeneity, round-oval with spiculae, etc.
We can answer all therapeutically relevant questions using this scheme. In addition, the increase use of 3 T devices has significantly improved the resolution. Our experience shows that many lymph nodes previously considered round and smooth show distinct spiculae in high resolution images, which is a clear criterion for malignancy. We have also previously seen this correlation between focal findings and resolution in mammography. A good resolution is the key to a correct morphological assessment of the lymph nodes. Currently, the morphology of lymph nodes is becoming more important than their size!
The mesorectal fatty tissue offers a unique and excellent opportunity for a very clear demarcation of lymph nodes. In signal-rich fatty tissue (light), the signal-poor lymph nodes (dark) can be excellently demarcated and characterized (see Figure 10). Unfortunately, we do not have this unique situation everywhere in the abdomen!
Figure 10.
Lymph nodes of same size (4 mm) but with totally different morphology in MRI. A. Lymph node metastasis in a patient with rectal cancer. Note the typical aspect of malign lymph nodes: inhomogeneous signal; irregular border with spikes (red arrow). B. Benign (reactive) nodes (arrows), characterized by homogeneous signal and well-defined borders on the background of anal fistula (no cancer!). Source: F. Bauer, Radiology Kaufbeuren.
In general, we have no problems with the assessment of the larger lymph nodes over 5 mm near the tumor or proximal to the primarius, which are usually always positive. We only have problems with smaller lymph nodes below 4 mm, which as we know can contain micrometastases. Here, morphology with good resolution and powerful 3 T devices provides a valuable help, as shown in Figure 10.
In our tumor conference, we focus on the localization of lymph nodes, because it is crucial to assess the presence of potentially malignant extramesorectal lymph nodes. While intramesorectal lymph nodes are standardly removed in TME, extramesorectal/obturator lymph nodes are usually left out. If the latter ones present malignancy aspects in MRI, the surgical procedure may change to a D3 lymphadenectomy removing extramesorectal lymph nodes (depending on the surgical strategy).
We recommend the consistent use of structured reporting (see template in Appendix) for primary MRI staging of rectal cancer. This report includes all therapeutically and diagnostically important points.
Nodal metastases must be detected and characterized preoperatively, as they are critical for surgical planning, prognosis, and the decision to administer adjuvant/neoadjuvant chemoradiation.
6. MRI and the newer 3D technology
As in all areas of life, knowledge and experience are also the key to success in dealing with technology. One of these new technologies that deserves application and experience is “high resolution 3D imaging”. Perhaps, it will even change the way we scan in MRI in the future.
3D imaging does not mean, as the term might suggest, image representation in spatial form, but rather the generation of images by means of 3-dimensional data sets.
3D imaging provides numerous benefits for experienced surgeons, from the facilitated planning of complex operations to the use of realistic models. The latter provides effective solutions for one of the greatest challenges in any academic surgical department: training young surgeons in practical techniques without the negative impact of the learning curve on the patient.
Since 2019, radiologists working in MRI have been using extremely fast, high-resolution 3D data sets. These make even the smallest lesions visible and allow viewing from a variety of perspectives. The “isotropic resolution” (less than 1 mm) ensures excellent display of the tumor’s characteristics and its relation to the surroundings and neighboring organs – and in the shortest possible time. A relevant surgical area can often be measured in only 5 minutes, which saves time and reduces movement artifacts. The “3D high-resolution compressed SENSE pelvic program” converts layered 2D measurements into a single 3D volume scan (Figure 11), plane by plane. It allows easily reformatting of isotropic 3D volume data in the range below 0.5 mm in any plane, without gaps, and with the same resolution as the “native” plane. The SNR-rich, ultra-thin 3D volume allows visualization of even subtle lesions without the partial volume averaging effect. Moreover, tissue structures that are best seen in oblique view can be viewed easily.
Figure 11.
A 3D volume of pelvis acquires contiguous, sub-millimeter, isotropic 3D data sets that can be easily reformatted into any plane, without losing its resolution. The SNR-rich, ultra-thin slices can provide help to visualize even small and subtle lesions without partial volume averaging effect. This will change the way we scan in the future. Muscularis propria with rectal tumor (red dashed line), mesorectum (yellow arrow), FMR = CRM (green arrow). Source: F. Bauer, Radiology, Kaufbeuren.
The new, self-calibrating technique with parallel imaging and compressed scanning significantly speeds up the MRI examination. As a result, scanning times can be reduced by up to 50% compared with those of conventional examination without “compressed SENSE” – all while providing exquisite tissue contrast.
The advantage of 3D imaging in surgical and radiotherapy planning is obvious: multiplanar images with excellent soft tissue contrast. This allows exact delineation of the tumor and healthy tissue, which is of decisive importance for RCT planning.
Furthermore, during follow-up, e.g. after RCT, changes in anatomy and tumor biology can be better visualized, thus permitting improved adaptation of treatment plans.
Our own experience shows that high resolution in 3D has clear advantages with regard to the assessment of the mesorectal fascia. 3D volume scans allow very clear and seamless visualization of the MRF/CRM at any desired level — even in critical areas, such as ventrally or around the junctional zone, where there is very little to no fat tissue.
Another advantage we see is in the use of arbitrary angulation (adapted to the tumor level) in real time, which permits any possibly unfavorable 2D angulation to be checked quickly and, if necessary, to be corrected accordingly.
Our current results contradict our own older experience as well as the common opinion in the literature regarding the reliability of 3D MRI. The new technology is very stable and can be implemented quickly if given the prerequisite of using 3 T systems with the latest hardware and software technology. Localization certainly plays an important role here. In the small pelvis we have no respiratory or pulsation artifacts and the intestinal peristalsis can be exposed very effectively with Buscopan. Of course, we do not have all these unique local conditions in the area of the parenchymatous upper abdominal organs. I can only encourage every user to include this 3D measurement of the pelvis (if 3 T devices are available) in the standard protocol of the rectal examination.
The surgical department has particularly appreciated this 3-dimensional, high quality, multiplanar real-time imaging. We, radiologists, we are especially pleased that the correct orthogonal planning to the tumor can be done very accurately and now in real time, but retrospectively. In the past, incorrect angulation has often produced incorrect readings, resulting in over or underestimation to the distance to the mesorectal fascia. If our measurements are to agree with the histological result, this evaluation must be extremely precise. We see a further advantage in tumors with a strong curvature or in double carcinomas, where multiple angulation is required for precise axial layers. We can now perform all these transformations from one acquired 3D data set. We see no real argument against this 3D volume measurement of the pelvis, which supplements the current standard protocol with an additional 5-minute measurement.
7. Other imaging modalities
7.1 MRI vs. CT
CT cannot be recommended for the local staging of rectal cancer.
The decisive advantage of MRI over CT is that it displays much better the morphology of the tumor and its topographical relationship to the border lamella of the mesorectum and to neighboring structures (prostate, seminal vesicle, vagina, uterus, os sacrum and os coccygeum as well as bladder and sphincter apparatus). As we have shown above, the relationship of the tumor to the neighboring structures is just as important as the TNM classification scheme [17, 18]. In addition, the lymph node prediction accuracy of CT is lower than with MRI.
For the detection of distant metastases, however, contrast-enhanced CT (CECT) is currently the method of choice due to its high availability and supported by current guidelines [19]. In most cases, it consists of a combined examination of the thorax and abdomen, which is a routine protocol both preoperatively for staging and in follow-up.
7.2 MRI vs. PET-CT
We do not routinely use PET-CT in our center for primary staging, nor for restaging after CRT, as complete remission can be evaluated much better with MRI. In fact, although PET-CT can address the question of tumor response, it cannot determine the presence of complete remission.
However, we do apply PET-CT in particular cases for metastasis detection and evaluation on the background of high CEA values.
7.3 MRI vs. EUS
For the detection, characterization and staging of rectal tumors, MRI is being considered the imaging modality of choice alongside endoscopic ultrasound (EUS), which offers particular advantages for early tumor stages T1 and T2. Without radiation exposure, it enables excellent soft tissue imaging and offers the possibility of multiplanar image acquisition and reconstruction, which is the current standard for the preoperative imaging of rectal tumors [20].
Currently, MRI increasingly being replacing EUS in the local staging for rectal cancer. Both modalities are equivalent for assessment of tumor spread beyond the muscularis propria (i.e., T2 versus T3 status). However, MRI holds several advantages over EUS in case of locally advanced rectal cancers (LARC), because it allows to better characterize lesion size, morphology, tumor margin and other helpful details for surgical planning. In addition, this modality offers a precise characterization of important aspects that may impact therapeutic decisions, such as proximity of the tumor to the mesorectal fascia, presence of extramural vascular invasion (EMVI), presence of extramesorectal pelvic lymph nodes, and involvement of the peritoneum/anterior peritoneal reflection, as well as the assessment of the R0 resectability.
Many of these findings are either difficult to assess, or are beyond the scope of EUS. Because of these advantages, MRI has become the preferred modality in the initial staging of rectal cancer, particularly as part of an interdisciplinary approach [15].
7.4 Endorectal sonography (ERUS) and its evaluation in the MDT tumor conference
At our clinic, our colleagues from gastroenterology apply ERUS routinely for the preoperative local diagnosis of rectal carcinoma and for restaging. The obtained images are then loaded together with colposcopy images into PACS, so that the obtained information is available to all involved personnel, including radiologists. The examination protocol is well defined and observed: clinical examination at first, followed by colposcopy with biopsy, and then by ERUS. After this series of examination, and after delivery of the histological finding, we do MRI. At the end, we discuss the results together with all involved departments in the MDT tumor conference.
ERUS is particularly well suited for the preoperative diagnosis of small tumors T1, T2, T3a, and b. However, ERUS has difficulties with large tumors, especially if they are high-set or stenosing carcinomas; likewise, the limited FOV (field of view) of large T3 and T4 tumors can push ERUS to its limits - MRI is superior here. Most of the misdiagnoses in MRI occur during differentiation between T1 and T2 tumors, mostly because of an inadequate representation of the submucosa. In conclusion, ERUS is slightly better suited for the preoperative diagnosis of small low-lying tumors than MRI.
The assessment of the mesorectal fascia (MRF) remains a domain of MRI; especially after neoadjuvant radiochemotherapy, endosonography can neither assess the distance of the tumor to the potential circumferential resection margin (CRM), nor does it offer sufficient sensitivity/specificity to assess the primarius.
ERUS and MRI should not be considered as competing procedures, but rather as complementary imaging modalities. Additionally, we must consider that, especially for endorectal ultrasound, there is a steep learning curve, which possibly also contributes to the lower overall accuracy of ERUS in large multi-center studies. In the hands of an experienced investigator, however, ERUS has proven to be a cost-effective and reliable method for the preoperative diagnosis of rectal cancer.
8. Imaging modalities for restaging
At our Imaging Center we evaluated in the past 5 years (2015-2020) 135 patients with rectal carcinoma using MRI (4 devices of 1.5 T, 2 devices of 3 T).
In the first 2 years, we almost exclusively performed primary diagnoses, the question of restaging being very low. On the one hand, this was due to our surgeons, who did not want to reconsider their original operation planning after completing CRT; on the other hand, it was due to us, because we were still very busy delivering high quality MRI diagnoses. When our image diagnostic results matched the histology, we finally got an adequate appreciation. This required a long learning curve. Today, restaging is as obligatory in our institute as preoperative MRI diagnostics. Restaging is a very demanding examination and can only work if the primary staging is performed with constant high quality. At this point, at the latest, the standardized examination protocol with DWI pays off.
While restaging, MRI imager after nCRT are correlated with MRI images before nCRT in all elements evaluated in primary staging. This requires post therapeutic image acquisition under nearly identical protocol parameters and levels. Essential points at this stage are position, extent and signal intensity of the tumor. These features are compared in the MRI images before and after nCRT. Care is also taken to ensure that restaging or follow up is always performed with the same device, because of the decisive diffusion-weighted images. As already mentioned, different devices (e.g. Siemens vs. Philips) provide different diffusion values, which are not always comparable.
Restaging is not for beginners and requires a long learning curve, similar to MRI of the mamma or MRI of the prostate. A minimum of 50 histologically confirmed cases/examinations are necessary to achieve a good performance.
The difficulties of restaging are obvious: Neoadjuvant therapy leads to profound changes in tumor tissue and surrounding structures, such as excessive fibrosis, deep stoma aging, wall thickening, characteristic muscle remodeling, tumor necrosis, calcification and inflammatory infiltration. As a result, the diagnostic accuracy of the imaging procedures decreases significantly with respect to restaging. Accordingly, the local tumor extent can be over- or underestimated.
These challenges can best handled using MRI with diffusion images. The accuracy of clinical examinations using endorectal ultrasound (EUS), computed tomography (CT) and 18F-FDG protrusion emission tomography with CT (18F-FDG-PET/CT), is very low both for the assessment of mesorectal invasion and for the evaluation of lymph node metastases and is therefore not used at our clinic for restaging as the sole examination.
Our restaging strategy includes digital rectal examination, endoscopy/EUS, and finally MRT (DWI). Care is always taken to ensure that this examination sequence is followed. This is where the multidisciplinary team meeting between surgeons, gastroenterologists and radiologists plays a special role (Figure 12). The decisive images are introduced into the PACS system and are available to everyone. When the radiologist starts restaging, these important staging examinations are already available to everyone.
Figure 12.
Response assessment with MRI T2w, DWI, and EUS. Pre RCT imaging shows a rectal cancer stage T2 (yellow arrow) with low to moderate signal in T2w (A, B) and high signal in DWI, C. Reporting: T2, N0, EMVI-, CRM-. Post RCT imaging shows complete remission, stage mrTRG-1. Note the tumor has completely regressed and was replaced by fibrosis (green arrows show fibrotic wall thickening with no evidence of tumor remnants) D, E. F. There is no focal high signal in DWI anymore, no diffusion restriction F. G T2wi shows a typical endoluminal white scar. Reporting: yT0, yN0, yEMVI-, CRM-. Therapy strategy: wait-and-see with no tumor recurrence within the following 2.8 years. Source: F. Bauer, Radiology Kaufbeuren.
Almost 90% of our patients have received the internationally recommended standard of care for adenocarcinoma of the lower to middle third of the rectum with a tumor stage T3/4 and/or cN+ and neoadjuvant radiochemotherapy (nRCT).
In addition to the generally known findings such as reduction of the local recurrence rate and improvement of the tumor-free interval, we try to identify the group of patients who would benefit from a non-surgical treatment strategy. The surgical community was initially very reticent towards the watch-and-wait strategy. In fact, it requires a high accuracy MRI examination to identify patients with full remission (CR: ypToN0). Own experience, good interdisciplinary cooperation and evaluation of all diagnostic tests are the prerequisite for reliable diagnostics.
The reference standard for CRT was histopathology or the recurrent free interval of >12 months in watch-and-wait approaches. After a long learning curve, our diagnostic accuracy has improved steadily. In about 24% (33 patients) of the cases we could show a full response, here interestingly also in some patients where chemotherapy had to be discontinued due to cardiac side effects. In almost all CRT cases, the initial stage was a T2 and/or T 3a, b, or c tumor stage. During a follow-up period of 2 years, we could see that almost always a small fibrosis limited to the intestinal wall took place and that this fibrosis was almost always unchanged in the course of the treatment. If a complete remission (CRT) occurred after radiotherapy, a high percentage of patients remained tumor-free.
Restaging remains particularly difficult for initially advanced tumor stages, like T3d with CRM+ or T4. Here, the strong hypointense mass fibrosis of the tumor bed and irregular fibrotic mass or wall thickening with irregular margins and/or spicules makes reliable diagnosis very difficult. In these cases, surgical resection, mostly TME, has always been recommended and performed. In case of low rectal tumors, the anal canal must be assessed.
In fact, our standardized protocol must answer the following questions for surgery:
Are there vital tumor remnants inside the fibrosis?
Is the tumor limited to the rectal wall?
Is the mesorectal fascia (CRM) tumor-free?
Are there still metastatic lymph nodes?
Has the tumor withdraws from the anal canal?
In some cases, we have seen that the tumor has actually retreated from the anal canal, thus opening the way for sphincter-preserving surgery and a life without an artificial exit.
The restaging of the lymph nodes often turned out to be surprisingly simple. In the vast majority of cases, where there was a very good or good response to radiochemotherapy, the mesorectum showed complete remission of the lymph nodes. In some cases, the morphological assessment with regard to spicules and inhomogeneity is particularly difficult due to the extensive fibrosis within the lymph nodes. In such cases, we use the significant reduction in size of the lymph nodes for assessment. Consequently, we consider negative small, star-shaped lymph nodes below 3 mm. However, these lymph nodes must be monitored particularly closely during follow-up.
The time interval to restaging was about 6-8 weeks after the end of CRT. In uncertain cases, where we suspected an almost complete remission, a follow-up examination in about 4 weeks was recommended, because persistent inflammatory reactions and/or a short-term reduction in tumor metabolism can cause an inaccurate result.
The key to success in MR diagnostics and especially in restaging is the unique combination of morphological T2 imaging with in vivo functional (diffusion weighted measurements, DWI) imaging. High-resolution T2 imaging can detect very accurately the extent of fibrosis and mucoid degeneration within fibrosis. Only diffusion-weighted images can assess whether vital tumor tissue is still present within the fibrosis and only MRI is able to combine morphology and functional imaging uniformly within one examination in only 25 minutes (Figure 12). Perhaps the mnemonic can help: MRI with DW is a kind of “PET- CT” of the poor man. There is another functional MRI imaging and that is DCE-MRI (Dynamic Contrast Enhanced), which we know very well from prostate diagnostics. We are also experimenting with these sequences. Although we apply here our experience from prostate diagnostics, we currently cannot recommend this examination for routine practice.
Recording the size of the tumor must be paid attention to during restaging and in cases of poor response. A reduction in tumor size can be effectively measured by 3-dimensional MR volumetry and shows a good correlation with the ypT stage after neoadjuvant therapy [21].
Good tumor regression rate in the pathological examination correlates with a tumor volume reduction of more than 70% after nCRT [21, 22] and a higher disease-free survival [21]. Moreover, a volume reduction of more than 75% is significantly associated with pCR [21, 23]. mrTRG can be used to effectively assess the response of rectal carcinomas to CRT. This classification is easy, effective and practice-oriented. According to our experience, a good agreement in histology can be achieved even with minimal training. Again, the focus should be on facilitating the identification of good responders (see Table 2 for tumor regression stages).
Grade
Response
MRI Finding
mrTRG-1
Complete response
No tumor signal, nor evidence of relapse.
mrTRG-2
Good response
Dense fibrosis, no detectable tumor signal.
mrTRG-3
Moderate response
>50% fibrosis or mucin lakes; detectable tumor signal.
mrTRG-4
Poor response
Predominance of tumor signal over fibrosis and mucin lakes.
mrTRG-5
No response
No change in tumor signal after therapy.
Table 2.
MRI based tumor regression grading.
9. Conclusion
Magnetic resonance imaging plays a key role in planning rectal cancer treatment, as it not only accurately depicts the local extent of the cancer and its anatomical positional relationship to the key structures, but can also generate relevant information for prognoses and thus can directly influence the choice of the optimal therapeutic procedure for each individual patient.
To exploit the full potential of MRI, the following must also be reported in addition to the T-stage, including the respective T3 sub-classifications:
the distance to the circumferential resection margin (CRM),
presence of extramural vascular infiltration (EMVI), and
the lymph node status, under consideration of the methodological limitations of MRI.
Endosonography (EUS) is a very important complementary method, especially for determining tumor stage T1 versus T2. A CT thorax/abdomen is routinely used to assess the M status. A PET-CT does not play a significant role in local primary diagnosis and restaging. In this context, the expertise of the radiologist plays an important role, especially in more difficult restaging. We expressly encourage everyone to include 3D volumetry in the standard protocol, because this new technique is already playing an increasingly important role in precise, preoperative surgery planning.
Due to the multitude of therapeutic options available for the treatment of rectal cancer today, it has become an international standard to discuss each patient’s findings pre-therapeutically in a tumor board comprising a multidisciplinary team (MDTmeetings). This procedure ensures that all therapeutic options are considered for the benefit of the patient, according to need.
\n',keywords:"rectal cancer, staging, MRI, protocol, reporting, 3D imaging",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73481.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73481.xml",downloadPdfUrl:"/chapter/pdf-download/73481",previewPdfUrl:"/chapter/pdf-preview/73481",totalDownloads:776,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 31st 2020",dateReviewed:"September 3rd 2020",datePrePublished:"October 20th 2020",datePublished:"July 14th 2021",dateFinished:"October 6th 2020",readingETA:"0",abstract:"The preoperative imaging diagnosis of rectal cancer lies at the heart of oncological staging and has a crucial influence on patient management and therapy planning. Rectal cancer is common, and accurate preoperative staging of tumors using high-resolution magnetic resonance imaging (MRI) is a crucial part of modern multidisciplinary team management (MDT). Indeed, rectal MRI has the ability to accurately evaluate a number of important findings that maBay impact patient management, including distance of the tumor to the mesorectal fascia, presence of lymph nodes, presence of extramural vascular invasion (EMVI), and involvement of the anterior peritoneal reflection/peritoneum and the sphincter complex. Many of these findings are difficult to assess in non-expert hands. In this chapter, we present currently used staging modalities with focus on MRI, including optimization of imaging techniques, tumor staging, interpretation help as well as essentials for reporting.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73481",risUrl:"/chapter/ris/73481",signatures:"Ferdinand Bauer",book:{id:"9788",type:"book",title:"Colorectal Cancer",subtitle:null,fullTitle:"Colorectal Cancer",slug:"colorectal-cancer",publishedDate:"July 14th 2021",bookSignature:"Alberto Vannelli",coverURL:"https://cdn.intechopen.com/books/images_new/9788.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83881-103-7",printIsbn:"978-1-83881-102-0",pdfIsbn:"978-1-83881-117-4",isAvailableForWebshopOrdering:!0,editors:[{id:"34524",title:"Dr.",name:"Alberto",middleName:null,surname:"Vannelli",slug:"alberto-vannelli",fullName:"Alberto Vannelli"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"220870",title:"Dr.",name:"Ferdinand",middleName:null,surname:"Bauer",fullName:"Ferdinand Bauer",slug:"ferdinand-bauer",email:"bauer.ferdinand@t-online.de",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Multidisciplinary management team (MDT) in rectal MRI",level:"2"},{id:"sec_3",title:"2. Magnetic resonance imaging (MRI) basics",level:"1"},{id:"sec_3_2",title:"2.1 Useful MRI sequences",level:"2"},{id:"sec_4_2",title:"2.2 Patient preparation",level:"2"},{id:"sec_4_3",title:"2.2.1 Bad diagnosis always begins with bad patient preparation",level:"3"},{id:"sec_6_2",title:"2.3 Examination protocol",level:"2"},{id:"sec_7_2",title:"2.4 Clinically relevant embryology of rectum and anal canal",level:"2"},{id:"sec_9",title:"3. Normal anorectal anatomy in MRI and the fasciae",level:"1"},{id:"sec_10",title:"4. Tumor morphology with MRI",level:"1"},{id:"sec_11",title:"5. Local staging with MRI",level:"1"},{id:"sec_11_2",title:"5.1 T-staging",level:"2"},{id:"sec_11_3",title:"5.1.1 Challenges for T-staging",level:"3"},{id:"sec_12_3",title:"5.1.2 Specific issues related to low-lying tumors",level:"3"},{id:"sec_14_2",title:"5.2 Mesorectal fascia (MRF) = Circumferential resection margin (CRM)",level:"2"},{id:"sec_15_2",title:"5.3 Extramural venous invasion (EMVI)",level:"2"},{id:"sec_16_2",title:"5.4 Lymph node staging",level:"2"},{id:"sec_18",title:"6. MRI and the newer 3D technology",level:"1"},{id:"sec_19",title:"7. Other imaging modalities",level:"1"},{id:"sec_19_2",title:"7.1 MRI vs. CT",level:"2"},{id:"sec_20_2",title:"7.2 MRI vs. PET-CT",level:"2"},{id:"sec_21_2",title:"7.3 MRI vs. EUS",level:"2"},{id:"sec_22_2",title:"7.4 Endorectal sonography (ERUS) and its evaluation in the MDT tumor conference",level:"2"},{id:"sec_24",title:"8. Imaging modalities for restaging",level:"1"},{id:"sec_25",title:"9. Conclusion",level:"1"},{id:"sec_27",title:"",level:"1"}],chapterReferences:[{id:"B1",body:'NAPRC (2020) Commision on Cancer. National Accreditation Program for Rectal Cancer. Optimal Resources for Rectal Cancer Care. 2020 Standards Am Coll Surg pp. 1-60. https://www.facs.org/quality-programs/cancer/naprc/standards/2020'},{id:"B2",body:'Bauer F (2016) The Importance of Preoperative Staging of Rectal Cancer Using ultiparametric MRI Part II: TNM Cancer Staging. Chirurgia Vol. 111(6): 463-475'},{id:"B3",body:'Fritsch H, Lienemann A, Brenner E et al (2004) Clinical anatomy of the pelvic floor. Adv Anat Embryol Cell Biol 175:1-64'},{id:"B4",body:'Laghi A, Iafrate F, Paolantonio P et al (2002) Magnetic resonance imaging of the anal canal using high resolution sequences and phased array coil: visualization of anal sphincter complex. Radiol Med 103:353-9'},{id:"B5",body:'Iafrate F, Laghi A, Paolantonio P et al (2006) Pre-operative staging of rectal cancer with MR imaging: correlation with surgical and histopathologic findings. Radiographics 26:701-714'},{id:"B6",body:'McCawley N, Clancy C, O’Neill BD, Deasy J, McNamara DA, Burke JP (2016) Mucinous Rectal Adenocarcinoma Is Associated with a Poor Response to Neoadjuvant Chemoradiotherapy: A Systematic Review and Meta-analysis. Dis Colon Rectum 59: 1200-1208'},{id:"B7",body:'Schäfer AO, Langer M, Baumann T (2012) Bedeutung der Schnittbildverfahren für das Staging des Rektumkarzinoms [The role of cross-sectional imaging in staging of rectal cancer]. Chirurg. 83(5):439-447'},{id:"B8",body:'Taylor FG, Quirke P, Heald RJ et al (2011) MERCURY study group. One millimetre is the safe cut-off for magnetic resonance imaging prediction of surgical margin status in rectal cancer. Br J Surg 98(6):872-879'},{id:"B9",body:'Al-Sukhni E, Milot L, Fruitman M et al. (2012) Diagnostic accuracy of MRI for assessment of T category, lymph node metastases, and circumferential resection margin involvement in patients with rectal cancer: a systematic review and meta-analysis. Ann Surg Oncol 19(7):2212-2223'},{id:"B10",body:'Beets Tan RG, Lambregts DM, Maas M et al (2018) Magnetic resonance imaging for clinical management of rectal cancer: Updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting, Eur Radiol 28(4): 1465-1475'},{id:"B11",body:'Rao SX, Zeng MS, Xu JM et al (2007) Assessment of T staging and mesorectal fascia status using high-resolution MRI in rectal cancer with rectal distention. World J Gestroenterol 13:4141-4146'},{id:"B12",body:'Maas M, Lambregts DM, Lahaye MJ et al (2012) T-staging of rectal cancer: accuracy of 3.0 Tesla MRI compared with 1.5 Tesla. Abdom Imaging 37:475-481'},{id:"B13",body:'Smith N, Brown G (2008) Preoperative staging of rectal cancer. Acta Oncol 47: 20-31'},{id:"B14",body:'Lambregts DM, Beets-Tan RG. Optimal imaging staging of rectal cancer. EJC Suppl. 2013;11(2):38-44. DOI: 10.1016/j.ejcsup.2013.07.031'},{id:"B15",body:'Nougaret S, Jhaveri K, Kassam Z, Lall C, Kim DH (2019) Rectal cancer MR staging: pearls and pitfalls at baseline examination. Abdom Radiol 44:3536-3548'},{id:"B16",body:'Shihab OC, Brown G, Daniels IR, Heald RJ, Quirke P, Moran BJ (2010) Patients with low rectal cancer treated by abdominoperineal excision have worse tumors and higher involved margin rates compared with patients treated by anterior resection. Dis Colon Rectum 53:53-56'},{id:"B17",body:'Bernini A, Deen Kl, Madoff RD et al (1996) Preoperative adjuvant radiation with chemotherapy for rectal cancer: its impact on stage of disease and the role of endorectal ultrasound. Ann Surg Oncol 3(2):131-135'},{id:"B18",body:'Gerard JP, Ayzac L, Coquard R et al (1996) Endocavitary irradiation for early rectal carcinomas Tl (T2). A series of 101 patients treated with the Papillon\'s technique. Int J Radiat Oncol Biol Phys 34(4):775-783'},{id:"B19",body:'S3 Guideline colorectal cancer version 1.0 - June 2013 AWMF registry number: 021/0070L. http://www.awmf.org/uploads/tx_szleitlinien/021_007OLI_S3_KRK_14062013.pdf'},{id:"B20",body:'Raghunathan G, Mortele KJ (2009) MR imaging of anorectal neoplasms. Clin Gastroenterol Hepatol 7(4):379-388'},{id:"B21",body:'Nougaret S, Reinhold C, Mikhael HW et al (2013) The use of MR imaging in treatment planning for patients with rectal carcinoma: have you checked the “DISTANCE”? Radiology 268(2):330-344'},{id:"B22",body:'Barbaro B, Fiorucci C, Tebala C et al (2009) Locally advanced rectal cancer: MR imaging in prediction of response after preoperative chemotherapy and radiation therapy. Radiology 250(3):730-739'},{id:"B23",body:'Kang JH, Kim YC, Kim H et al (2010) Tumor volume changes assessed by three-dimensional magnetic resonance volumetry in rectal cancer patients after preoperative chemoradiation: the impact of the volume reduction ratio on the prediction of pathologic complete response. Int J Radiat Oncol Biol Phys 76(4):1018-1025'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ferdinand Bauer",address:"ferdinand.bauer@radiologie-kaufbeuren.de",affiliation:'
KLF Radiologie und Nuklearmedizin, Kaufbeuren, Germany
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Seventy-two animals were used by group. Goats were older than 3 months, seronegative to brucellosis, not vaccinated previously, and kept within positive flocks. Vaccinated animals received 2 mL of product subcutaneously in the neck region. The first block was injected with Rev-1; the second received RB51, and the third group was injected with RB51-SOD. Follow-up sampling was performed at 30, 60, 90, and 365 days postvaccination. The general prevalence of brucellosis for the three groups was 1.2% (95%CI:0.5–2.7). The seroconversion rate by day 30 after vaccination was 77.7% (95%CI:61.9–88.2) for goats vaccinated with Rev-1. At 365 days post vaccination, the percentage of seropositive goats declined to 13.8% (95%CI:6.0–28.6). At day 365 after vaccination, 2.7% (95%CI:0.4–14.1) and 5.5% (95%CI:1.5–18.1) of animals vaccinated with RB51 and RB51-SOD, respectively, became positive. Results show that the seroconversion induced by Brucella abortus RB51 and RB51-SOD vaccines is lower than that by Brucella melitensis Rev-1.",signatures:"Baldomero Molina-Sánchez, David I. Martínez-Herrera, Violeta T. Pardío-Sedas, Ricardo Flores-Castro, José F. Morales-Álvarez and José A. 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The Open Access model is applied to all of our publications and is designed to eliminate subscriptions and pay-per-view fees. This approach ensures free, immediate access to full text versions of your research.
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
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850 GBP Journal Article (Across Portfolio)
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Services included are:
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Open Access Funding
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Added Value of Publishing with IntechOpen
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Indexing and listing across major repositories, see details ...
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Dissemination and Promotion
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Proven world leader in Open Access book publishing with over 10 years experience
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The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
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1,400 GBP Chapter - Edited Volume
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10,000 GBP Monograph - Long Form
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850 GBP Journal Article (Across Portfolio)
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During the launching phase journals do not charge an APC, rather they will be funded by IntechOpen.
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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Services included are:
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An online manuscript tracking system to facilitate your work
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Assurance that your manuscript meets the highest publishing standards
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\n\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Discoverability - electronic citation and linking via DOI
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Permanent and unrestricted online access to your work
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What isn't covered by the Open Access Publishing Fee?
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If your manuscript:
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If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
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Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
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Open Access Funding
\n\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\n
Added Value of Publishing with IntechOpen
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Choosing to publish with IntechOpen ensures the following benefits:
\n\n
\n\t
Indexing and listing across major repositories, see details ...
\n\t
Long-term archiving
\n\t
Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
\n\t
Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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Proven world leader in Open Access book publishing with over 10 years experience
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+5,700 OA books published
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Most competitive prices in the market
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Optimized processes that assure your research is made available to the scientific community without delay
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Personal support during every step of the publication process
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+184,650 citations in Web of Science databases
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Currently strongest OA platform with over 175 million downloads
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In addition, we will present the methods that can be used for the evaluation of HER2 status at different levels (protein, RNA, and DNA level) in clinical practice.",book:{id:"6813",slug:"cancer-prognosis",title:"Cancer Prognosis",fullTitle:"Cancer Prognosis"},signatures:"Daniela Furrer, Claudie Paquet, Simon Jacob and Caroline Diorio",authors:null},{id:"67964",doi:"10.5772/intechopen.87963",title:"Protein Tyrosine Phosphatases in Tumor Progression and Metastasis: Promoter or Protection?",slug:"protein-tyrosine-phosphatases-in-tumor-progression-and-metastasis-promoter-or-protection-",totalDownloads:897,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"Reversible phosphorylation of proteins, executed by kinases and phosphatases, is the major posttranslational protein modification in eukaryotic cells, causing them to become activated or deactivated. This intracellular event represents a critical regulatory mechanism of several signaling pathways and can be related to a broad number of diseases, including cancer. Few decades ago, protein tyrosine phosphatases (PTPs) were considered as tumor suppressors. However, nowadays, accumulating evidence demonstrates that a misregulation of PTP activities plays a crucial and decisive role in cancer progression and metastasis. In this chapter, we will focus on the molecular aspects that support the crucial role of PTPs in cancer and in turn make them promising for prediction, monitoring, and rational appropriate therapy selection of individual patients.",book:{id:"8002",slug:"tumor-progression-and-metastasis",title:"Tumor Progression and Metastasis",fullTitle:"Tumor Progression and Metastasis"},signatures:"Carmen V. Ferreira-Halder, Stefano Piatto Clerici, Alessandra V. Sousa Faria, Patrícia Fernandes de Souza Oliveira, Helon Guimarães Cordeiro and Erica Akagi",authors:[{id:"61709",title:"Prof.",name:"Carmen",middleName:null,surname:"Ferreira",slug:"carmen-ferreira",fullName:"Carmen Ferreira"},{id:"307647",title:"MSc.",name:"Stefano",middleName:null,surname:"Piatto Clerici",slug:"stefano-piatto-clerici",fullName:"Stefano Piatto Clerici"},{id:"307648",title:"Ph.D. Student",name:"Alessandra",middleName:"V. S.",surname:"Faria",slug:"alessandra-faria",fullName:"Alessandra Faria"},{id:"307649",title:"MSc.",name:"Patrícia",middleName:null,surname:"Oliveira",slug:"patricia-oliveira",fullName:"Patrícia Oliveira"},{id:"307650",title:"MSc.",name:"Helon",middleName:null,surname:"Cordeiro",slug:"helon-cordeiro",fullName:"Helon Cordeiro"},{id:"307651",title:"Dr.",name:"Erica",middleName:null,surname:"Akagi",slug:"erica-akagi",fullName:"Erica Akagi"}]},{id:"55760",doi:"10.5772/intechopen.69397",title:"Exosomes and Their Role in Viral Infections",slug:"exosomes-and-their-role-in-viral-infections",totalDownloads:2360,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"Exosomes are excretory nano-vesicles that are formed by the cell’s endocytic system and shed from the surface of almost all types of cells. These tiny extracellular vesicles, once thought to be “garbage bags for cells,” carry a wide variety of molecules of cellular origin, including proteins, lipids, and RNAs, that are selectively incorporated during the formation of exosomes. Exosomes are now known to play a central role in several important biological processes such as cellular communication, intercellular transfer of bioactive molecules, and immune modulation. Recent advances in the field have shown that a number of animal viruses can exploit the exosomal pathway by incorporating specific cellular or viral factors within exosomes, in order to modulate the cellular microenvironment and influence downstream processes such as host immunity and virus spread. In this chapter, we provide an overview of our current understanding of exosome biogenesis and how this normal physiological process is hijacked by some pathogenic viruses. Viral components that appear to be selectively incorporated into exosomes and the potential role of these exosomes in viral pathogenesis are discussed. Identifying viral signatures in exosomes and their mode of action is fundamental for any future diagnostic and therapeutic strategies for viral infections.",book:{id:"5793",slug:"novel-implications-of-exosomes-in-diagnosis-and-treatment-of-cancer-and-infectious-diseases",title:"Novel Implications of Exosomes in Diagnosis and Treatment of Cancer and Infectious Diseases",fullTitle:"Novel Implications of Exosomes in Diagnosis and Treatment of Cancer and Infectious Diseases"},signatures:"Gulfaraz Khan, Waqar Ahmed and Pretty S. Philip",authors:[{id:"199889",title:"Prof.",name:"Gulfaraz",middleName:null,surname:"Khan",slug:"gulfaraz-khan",fullName:"Gulfaraz Khan"},{id:"201764",title:"Mr.",name:"Waqar",middleName:null,surname:"Ahmed",slug:"waqar-ahmed",fullName:"Waqar Ahmed"},{id:"201766",title:"Ms.",name:"Pretty",middleName:null,surname:"Philip",slug:"pretty-philip",fullName:"Pretty Philip"}]}],mostDownloadedChaptersLast30Days:[{id:"60895",title:"An Overview of Cancer Treatment Modalities",slug:"an-overview-of-cancer-treatment-modalities",totalDownloads:2983,totalCrossrefCites:28,totalDimensionsCites:50,abstract:"Cancer is a global issue majorly affecting developing countries. According to a survey, 63% of deaths due to cancer are reported from developing countries. There are different conventional treatment modalities that are available to treat and manage cancer. However, new cancer treatment options are being explored continuously as over 60% of all current experimental trials worldwide are focusing on tumor cure. The success of treatment depends upon the type of cancer, locality of tumor, and its stage of progression. Surgery, radiation-based surgical knives, chemotherapy, and radiotherapy are some of the traditional and most widely used treatment options. Some of the modern modalities include hormone-based therapy, anti-angiogenic modalities, stem cell therapies, and dendritic cell-based immunotherapy. This chapter discusses different traditional and novel treatment modalities to combat different types of cancer.",book:{id:"6313",slug:"neoplasm",title:"Neoplasm",fullTitle:"Neoplasm"},signatures:"Zaigham Abbas and Sakina Rehman",authors:[{id:"214546",title:"Dr.",name:"Zaigham",middleName:null,surname:"Abbas",slug:"zaigham-abbas",fullName:"Zaigham Abbas"}]},{id:"64178",title:"Zebrafish (Danio rerio) as a Model Organism",slug:"zebrafish-em-danio-rerio-em-as-a-model-organism",totalDownloads:2722,totalCrossrefCites:4,totalDimensionsCites:24,abstract:"Animals as model organisms, the silent sentinels, stand watch over the environmental health of the world. These are non-human animal species which can be used to understand specific biological processes and to obtain informations which can provide an insight into working of other organisms. Among the model organisms, the zebrafish (Danio rerio) is one of the best leading models to study developmental biology, cancer, toxicology, drug discovery, and molecular genetics. In addition, the zebrafish is increasingly used as a genetic model organism for aquaculture species and in toxicogenomics and also to generate zebrafish disease models for application in human biomedicines. This tiny fish is a versatile model organism for many fields of research because of its easy maintenance, breeding, and transparent body during early development.",book:{id:"7054",slug:"current-trends-in-cancer-management",title:"Current Trends in Cancer Management",fullTitle:"Current Trends in Cancer Management"},signatures:"Farmanur Rahman Khan and Saleh Sulaiman Alhewairini",authors:[{id:"221847",title:"Dr.",name:"Saleh",middleName:null,surname:"Alhewairini",slug:"saleh-alhewairini",fullName:"Saleh Alhewairini"},{id:"258210",title:"Dr.",name:"Farmanur Rahman",middleName:null,surname:"Khan",slug:"farmanur-rahman-khan",fullName:"Farmanur Rahman Khan"}]},{id:"70898",title:"MicroRNA: A Signature for Cancer Diagnostics",slug:"microrna-a-signature-for-cancer-diagnostics",totalDownloads:942,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Various tools and techniques are being used for the diagnosis of cancer, but not a sole technique provides powerful result at the very early stages of cancer. This provides the need for type of tools which could detect cancer at early stages so that survival rate could be augmented. There are various diagnostic ways to identify cancer, but in each case, there are always circumstances to compromise on the sensitivity. In this framework, a new and more advanced approach of diagnosis for cancer is microRNA (miRNA). miRNAs are conserved regions among humans and animals, and their synthesis takes place in the nucleus and cytoplasm. There are several types of microRNAs that could be upregulated and downregulated in various cancers. A cancer cell could be identified by measurement of the expression pattern of miRNA. By examining the expression level for different types of cancers, miRNA can be used as biomarker for early detection of cancer in human beings.",book:{id:"9172",slug:"current-cancer-treatment",title:"Current Cancer Treatment",fullTitle:"Current Cancer Treatment"},signatures:"Ayesha Siddiqua, Sumaira Kousar, Amer Jamil, Riaz Tabassum, Tariq Mehmood and Nusrat Shafiq",authors:null},{id:"63685",title:"A Molecular Link between the Circadian Clock, DNA Damage Responses, and Oncogene Activation",slug:"a-molecular-link-between-the-circadian-clock-dna-damage-responses-and-oncogene-activation",totalDownloads:1376,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Circadian clocks enhance the efficiency and survival of living things by organizing their behavior and body functions. There has been a long history of research seeking a link between circadian clock and tumorigenesis. Studies of animal models and human tumor samples have revealed that the dysregulation of circadian clocks is an important endogenous factor causing mammalian cancer development. The core circadian clock regulators have been implicated in the control of both the cell cycle and DNA damage responses (DDR). Conversely, several intracellular signaling cascades that play important roles in regulation of the cell cycle and the DDR also contribute to circadian clock regulation. This review describes selected regulatory aspects of circadian clocks, providing evidence of a molecular link of the circadian clocks with cellular DDR.",book:{id:"7281",slug:"oncogenes-and-carcinogenesis",title:"Oncogenes and Carcinogenesis",fullTitle:"Oncogenes and Carcinogenesis"},signatures:"Yoshimi Okamoto-Uchida, Junko Izawa and Jun Hirayama",authors:[{id:"246364",title:"Prof.",name:"Jun",middleName:null,surname:"Hirayama",slug:"jun-hirayama",fullName:"Jun Hirayama"}]},{id:"67447",title:"Molecular Pathogenesis of Oral Squamous Cell Carcinoma",slug:"molecular-pathogenesis-of-oral-squamous-cell-carcinoma",totalDownloads:3737,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Oral carcinogenesis is a molecular and histological multistage process featuring genetic and phenotypic molecular markers which involves enhanced function of several protooncogenes, oncogenes and/or the deactivation of tumor suppressor genes, resulting in the over activity of growth factors and its cell surface receptors, which could enhance messenger signaling intracellularly, and/or leads to the increased production of transcription factors. Alone oncogenes are not responsible for carcinogenesis, genes having tumor suppressor activity, leads to a phenotypic change in cell which is responsible for increased cell proliferation, loss of cellular cohesion, and the ability to infiltrate local tissue and spread to distant sites. Understanding the molecular interplay of both onco and tumor genes will allow more accurate diagnosis and assessment of prognosis, which might lead the way for novel approaches to treatment.",book:{id:"8211",slug:"squamous-cell-carcinoma-hallmark-and-treatment-modalities",title:"Squamous Cell Carcinoma",fullTitle:"Squamous Cell Carcinoma - Hallmark and Treatment Modalities"},signatures:"Anshi Jain",authors:[{id:"280692",title:"Dr.",name:"Anshi",middleName:null,surname:"Jain",slug:"anshi-jain",fullName:"Anshi Jain"}]}],onlineFirstChaptersFilter:{topicId:"428",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:99,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:289,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"6",title:"Infectious Diseases",doi:"10.5772/intechopen.71852",issn:"2631-6188",scope:"This series will provide a comprehensive overview of recent research trends in various Infectious Diseases (as per the most recent Baltimore classification). Topics will include general overviews of infections, immunopathology, diagnosis, treatment, epidemiology, etiology, and current clinical recommendations for managing infectious diseases. Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"May 26th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",isOpenForSubmission:!1,editor:null,editorTwo:null,editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",isOpenForSubmission:!0,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:5,paginationItems:[{id:"81972",title:"The Submicroscopic Plasmodium falciparum Malaria in Sub-Saharan Africa; Current Understanding of the Host Immune System and New Perspectives",doi:"10.5772/intechopen.105086",signatures:"Kwame Kumi Asare",slug:"the-submicroscopic-plasmodium-falciparum-malaria-in-sub-saharan-africa-current-understanding-of-the-",totalDownloads:0,totalCrossrefCites:null,totalDimensionsCites:null,authors:null,book:{title:"Malaria - Recent Advances, and New Perspectives",coverURL:"https://cdn.intechopen.com/books/images_new/11576.jpg",subseries:{id:"5",title:"Parasitic Infectious Diseases"}}},{id:"81821",title:"Pneumococcal Carriage in Jordanian Children and the Importance of Vaccination",doi:"10.5772/intechopen.104999",signatures:"Adnan Al-Lahham",slug:"pneumococcal-carriage-in-jordanian-children-and-the-importance-of-vaccination",totalDownloads:1,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Streptococcal Infections",coverURL:"https://cdn.intechopen.com/books/images_new/10828.jpg",subseries:{id:"3",title:"Bacterial Infectious Diseases"}}},{id:"81813",title:"Schistosomiasis: Discovery of New Molecules for Disease Treatment and Vaccine Development",doi:"10.5772/intechopen.104738",signatures:"Andressa Barban do Patrocinio",slug:"schistosomiasis-discovery-of-new-molecules-for-disease-treatment-and-vaccine-development",totalDownloads:10,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"New Horizons for Schistosomiasis Research",coverURL:"https://cdn.intechopen.com/books/images_new/10829.jpg",subseries:{id:"5",title:"Parasitic Infectious Diseases"}}},{id:"81644",title:"Perspective Chapter: Ethics of Using Placebo Controlled Trials for Covid-19 Vaccine Development in Vulnerable Populations",doi:"10.5772/intechopen.104776",signatures:"Lesley Burgess, Jurie Jordaan and Matthew Wilson",slug:"perspective-chapter-ethics-of-using-placebo-controlled-trials-for-covid-19-vaccine-development-in-vu",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"SARS-CoV-2 Variants - Two Years After",coverURL:"https://cdn.intechopen.com/books/images_new/11573.jpg",subseries:{id:"6",title:"Viral Infectious Diseases"}}}]},overviewPagePublishedBooks:{paginationCount:13,paginationItems:[{type:"book",id:"6667",title:"Influenza",subtitle:"Therapeutics and Challenges",coverURL:"https://cdn.intechopen.com/books/images_new/6667.jpg",slug:"influenza-therapeutics-and-challenges",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Shailendra K. 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He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. 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