Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\n
Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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At the root of empowerment is power and this power works to shape the experiences of every individual within the school institution. While teachers may not have the ability to control some aspects of how power is operationalized within the school institution, teachers do have control over how they perceive and operationalize power in the classroom. As such, it is argued that the effective and conscious operationalization of this power is a key aspect of the professional development of teachers. This chapter explores the concepts of power and empowerment, their various conceptualizations and their implications on classroom teaching and learning processes. 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Teachers can improve their professional abilities through principals’ instructional supervision and their own knowledge-management (KM) behaviors to benefit students. Thus, this chapter analyzes the relationship among principals’ instructional supervision, teachers’ KM, and teachers’ professional development. The author believes that principals’ instructional supervision and effective KM can facilitate the professional development of teachers. 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\r\n\tThe continuous growth in the development of electronic devices, cellular wireless communication systems, and medical electronic devices over the last twenty years resulted in most of the world’s population owning smartphones, smartwatches, tablets, and other similar devices. As a result, the number of unwanted electronic devices is growing at a rapid rate. With this huge number of devices being produced and discarded, a new environmental disaster strikes our planet. Electronic waste and discarded old electronics are filling up landfills at an alarming rate. These electric devices contain hazardous and toxic materials that endanger the environment and the health of local communities, increasing environmental pollution. Furthermore, the consumption of electrical energy is in rapid growth. Traditional energy sources such as fuel and coal significantly increase environmental pollution. Green technologies, as well as recycling electronic waste, old batteries, plastic waste, and bottles, are employed to decrease environmental pollution. Renewable energy is also a major factor in decreasing environmental pollution. This book's main objective is to present innovation in green electronic technologies and devices, enabling engineers, students, and scientists from all areas to follow and understand the topics presented in the book.
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1. Introduction
Physicians responsible for patient care focus on readily available clinical and trending laboratory data to help direct the patient’s clinical course and evaluate efficacy of therapy. Most clinicians fail to incorporate newer parameters of tumor response such as tumor growth rate when evaluating patient treatment response. Available now, is a wealth of dynamic growth parameters that shed new light on tumor biology and should be used in clinical decision-making.
What follows is in part a review of former paradigms of prostate tumor growth. Later, focus is directed to newer techniques to assist in evaluating targeted drug effects on the kinetics of prostate and other cancers. The discussion introduces the concept of tumor or marker specific growth rate (SGR) and challenges historical results obtained by use of the classic tumor or marker doubling time (PSA-DT).
As we proceed with this discussion, a mobile device App for hand-held computers including the iPhone, iPad, or iPod is presented. This conveniently facilitates a more sophisticated tumor and marker analysis at the bedside or in the clinic.
2. Historical perspective of tumor growth kinetics, exponential and Gompertzian kinetics
Though there is occasional homage paid to Gompertzian tumor growth, for practical purposes, when we care for patients, tumors are frequently undergoing exponential expansion. In the absence of tumor mutation or perturbation by therapy the growth rate of exponentially growing tumors is constant. Rarely, there may be periods of interrupted growth.
Gompertzian growth [1, 2, 3] is best described by a sigmoid-shaped curve. At tumor initiation growth is occult, slow and remains subclinical for several years. A second phase is the rapid, clinically apparent exponential phase lasting for a few years followed by the slower terminal growth phase as the tumor approaches 35-40 doublings representing a volume approaching 1000 cc or a tumor diameter of 10 cm Figure 1. The duration of tumor growth from inception is several years and for three quarters of that period the tumor is clinically undetectable. At the time of discovery, the oncologist is attending to the last quarter of tumor growth.
Figure 1.
Note the differences between the exponential and Gompertzian growth curves. The lethal burden of tumor is approximately 1000 cc or ~35-40 doublings. In the clinic when tumors reach 0.5-1 cm in diameter (30 doublings or 109 cells) they are measurable and follow the exponential growth curve, the steeper the slope the larger the tumor specific growth rate (SGR). Nonetheless, many feel that when looking at the entire lifespan of malignant tumors (over several years) tumor growth may better be described by Gompertzian kinetics [3].
3. Exponential growth
In 1934 Mottram [4, 5] reported work on the rat tar wart. Tar warts are tar-carcinogen induced neoplasms of the skin starting 75-100 days after the continuous painting of the rat’s neck with tar. Histologically, some warts appear benign while others are clearly malignant.
Using the tar wart tumor growth model, Mottram was the first to describe tumor expansion as exponential. Exponentially growing tumors graphically produce straight lines by plotting linear time on the x-axis versus the log (at any base) of either tumor area, tumor cell number, tumor volume or tumor diameter on the y-axis see Figure 2.
Figure 2.
Friberg, Collins, Spratt, Steel, Schwartz affirmed that in the clinic, an exponential growth pattern adequately described tumor growth for most patients. A semi-log plot of tumor diameter vs. time illustrates the linear relationship characteristic of exponential growth.
Figure 3.
Von Fournier et al. confirm a straight-line (by semi-log plot) relationship for patients with breast tumors supporting the model of exponential growth model.
Twenty years later Laird [6, 7] reported on the growth of transplanted tumors in the rat. Under her specific laboratory conditions, most tumor growth could be described in terms of the Gompertzian model. Her experiments lead her to accept that for her laboratory model; most transplantable, rapidly growing tumors could be described in Gompertzian terms.
Studies of tumor growth in clinic patients have been described in terms of both exponential and Gompertzian models. Nevertheless, several investigators reported data that was inconsistent with the Gompertzian model for the majority of their patients. These authors engaged routine imaging of both metastatic and primary pulmonary lesions in an attempt to resolve whether exponential growth could be confirmed in the clinic. Friberg, Collins, Spratt, Steel, Schwartz [8, 9, 10, 11, 12,13] affirmed that in the clinic, an exponential growth pattern adequately described tumor growth for most patients Figures 2, 3.
4. The tumor marker as a surrogate for tumor growth exemplified by PSA and prostate cancer
4.1. PSA Velocity (PSA-V)
PSA-V is the rate of change in serum PSA over time. PSA-V = 1/2 ((PSA2-PSA1/t1 in years) + (PSA3 – PSA2/t2 in years)), where PSA1 is the first, PSA2 the second and PSA3 the third PSA measurement. Time represents the interval (in years) between PSA measurements. It is recommended that three PSA measurements obtained over 24 months yields optimal accuracy. A PSA-V exceeding 0.75 ng/ml/year is highly predictive of prostate cancer. PSA-V is more useful than PSA doubling time (PSA-DT) in the pretreatment setting to help identify those men with life-threatening disease [14].
Studies confirm that the PSA tumor marker reflects prostate tumor growth and PSA dynamic changes are useful for predicting clinical outcome in several situations such as tumor recurrence and overall survival [15].
Klotz [16] reviewed the value of PSA as a tumor marker in patients with prostate cancer. He noted that use of a single serum value of PSA is inadequate for predicting patient survival. However, the PSA-V as ng/ml/yr. was a marker of disease biology. D’Amico [17] included preoperative PSA-V in determining subsequent risk of death from prostate cancer in 1095 men with clinically localized prostate cancer that underwent prostatectomy and radiation therapy [18]. A PSA-V >2 ng/ml/yr the year before prostatectomy, was associated with lymph node metastases, an advanced pathologic stage, and high-grade disease. This threshold level of PSA-V was associated with a significantly shortened time to recurrence, death from prostate cancer, and death from any cause. Strikingly, men with a PSA rise of >2.0 ng/ml had prostate cancer-specific mortality rates nine times those with a PSA-V <2 ng/ml.
4.2. Tumor marker Doubling Time (DT)
Miyamoto [19] studied the growth of hepatic metastases in colorectal cancer patients. He established that a tumor marker could accurately reflect tumor volume and its changes. Using the CEA tumor marker he reported an almost equal and parallel correlation between CEA doubling time and hepatic tumor volume doubling time.
PSA-DT Figure 4 is the time it takes for the serum PSA to double. Evidence indicates PSA-DT closely mirrors prostate tumor volume doubling time. Kato et al. in 2008 [20] undertook an attempt to correlate prostate tumor volume to serum PSA level. Kato’s group calculated that for each ng/ml increment of serum PSA, there was a 0.302 cc increase in total tumor volume and a 0.7% increase in relative tumor volume. Total tumor volume in cc was given as V(cc) = 3.476 + 0.302 X PSA (ng/ml) while the percent tumor volume Volume(%) = 11.331 + 0.704 X PSA (ng/ml).
Babaian et. al. [21] reported that multivariate regression analysis of tumor volume as a function of PSA, grade and stage demonstrated that log PSA had the strongest association with tumor volume. Tanaka [22] reported that among significant preoperative and postoperative parameters, calculated cancer volume remained an independent predictive parameter in multivariate analysis (P <0.01). Tumor volume, as calculated by preoperative parameters, was an independent predictor of biochemical recurrence in patients who had undergone radical prostatectomy. Vollmer et al. [23] used a compartmental model and first order kinetics to develop the calculation necessary to relate serum PSA to tumor volume. They found that the resulting model was a good fit to the observed kinetic data of PSA measured after biopsy or prostatectomy. The model also predicted a linear relationship between PSA and the sum of volumes of benign and malignant tissues.
Until evidence to the contrary, it is assumed that similar to colorectal tumors and CEA, there is a reasonable relationship between serum PSA and its kinetics allowing its use as a predictor of changes of prostate tumor volume and growth kinetics.
An important point when using serum PSA in calculations is that an exact interval for testing remains controversial, some investigators stress that the interval between PSA-DT determinations should approach 3-6 months [24] to limit error due to random variation of PSA values. Using a third generation highly sensitive PSA assay, our laboratory changes in PSA are precise to the third decimal point and allow educated decision-making based on monthly determinations.
Historically, PSA kinetics for watchful waiters included PSA-DT. A PSA-DT of >10 yr. can be considered favorable; a PSA-DT of <3-4 yr. suggests a change in biology and consideration should be given to an alternative therapy [25]. PSA kinetics should always be combined with other diagnostics such as endorectal ultrasound; endorectal MRI, digital rectal exam and repeat prostate biopsies approximately every 6-12 months.
Figure 4.
This figure is a semi-log plot of logs PSA (y-axis) vs. time (x-axis) [26]. Note the linear relationship, indicating that the rise of PSA values follows an exponential expansion of PSA.
4.3. PSA-DT as a surrogate for drug activity
PSA is one of the major androgen receptor-dependent target genes [27], and clinical monitoring is used to detect early stage disease as well as the emergence of recurrent tumor after therapy [28, 29, 30] and changes mirror changes in tumor bulk and indicate response to drugs. The graphic representation of PSA-DT is illustrated and its formula is given in Figure 4 [26].
Kelloff et al. [31], reviewed the use of PSA-DT as a surrogate for tumor response to drugs in patients with prostate cancer. They concluded that protocols that demonstrate significant changes in PSA-DT might be used to support accelerated approval of newer therapies. There is data to suggest PSA-DT in castrate resistant patients is predictive of outcome after chemotherapy [32]. An important caveat is expressed by Newling’s review [33] of the subject which concluded that though dynamic changes in the PSA such as PSA-DT are commonly used in clinical trials of new drug therapies, PSA-DT might be affected by other factors including assay variations and false elevations of serum PSA caused by irritation of bladder catheters, prostatitis and cystitis. A substantial incidence of transient elevations of PSA (55%) was reported following combined external beam radiation and brachytherapy for prostate cancer [34]. These complicating issues should always be considered before PSA-DT is used to modify therapy.
Most recently, newer targeted and immunotherapies were found to produce paradoxical effects on PSA kinetics. Newling [33] argues that PSA should therefore be used as a secondary end point while overall survival still remains the gold standard in evaluating therapeutic efficacy for patients with hormone refractory disease.
5. Defining PSA response
Investigators participating in new prostate cancer drug trials commonly define PSA response according to the Bubley guidelines [35] for phase II clinical trials in androgen-independent prostate cancer. The guidelines qualify the following categories of PSA: PSA normalization, PSA <=0.2 ng/ml; PSA decrease, PSA decline ≥50%, confirmed by a second PSA value 4 or more weeks later; PSA progression, PSA ≥25% increase over the baseline (and an increase in the absolute value PSA level by at least 5 ng/mL). Though useful for evaluating clinical trials, these PSA changes lack sensitivity when evaluating subtle drug effects vs. prostate tumor growth [36,37, 38].
Therasse [39, 40], in his thesis reports on MRI and PSA as tools in a RECIST evaluation used to define tumor response in prostate cancer patients with measurable soft tissue lesions. When comparing MRI soft tissue responses to serum PSA changes, the correlation of PSA and MRI showed agreement in 14 of the 20 (70%) patients.
6. PSA-DT and Survival of prostate cancer patients
The importance of PSA-DT in predicting survival is illustrated by Freedland et al. [41] Figure 5. This chart presents data for a group of patients experiencing biochemical recurrence of PSA after prostatectomy. Under these circumstances, PSA-DT clearly defined prostate cancer survival into four groups: 1) PSA-DT >=15 months, 2) PSA-DT 9-14 months 3) PSA-DT 3-8.9 months, 4) PSA-DT <3 months. For this study, PSA-DT is clearly a surrogate for prostate cancer-specific survival.
Figure 5.
7. PSA in the era of biologic and targeted therapy
A wealth of data establishes PSA as a marker of tumor aggressiveness, tumor stage, drug response and survival. Controversy and concern persists regarding PSA’s role as a marker of disease stabilization and response induced by cytostatic and immunotherapies when compared to cytolytic therapies. An evaluation of the difficulties surrounding PSA interpretation has been addressed [42].
Two vaccine trials, Sipuleucel-T (Provenge) [43, 44, 45] and the TRICOM PROSTVAC [46, 47] demonstrated a significant overall survival benefit without any consistent decline in PSA, raising questions about the value of PSA response for non-hormonal, non-cytotoxic therapies. In addition, wide fluctuations have been observed in PSA values due to a transient effect of some drugs on PSA production seemingly independent of cell proliferation. The independent, non-proliferative effect of drugs on PSA expression should be considered when interpreting PSA response data. These aberrant PSA effects must be considered together with imaging results and clinical evaluation of the patient. Nevertheless, it has been consistent that post therapy a >50% PSA decline in pre-treatment PSA carries a significant overall survival advantage [48, 35].
Kelly [48] reported on 110 assessable patients treated on seven sequential protocols at Memorial Sloan-Kettering Cancer Center for hormone-refractory prostate cancer a statistically significant survival advantage in 110 patients with >50% PSA decline (>25 months survival) versus those without a 50% PSA decline (8.6 months survival). These results suggest that post therapy PSA declines can be used as a surrogate end point to evaluate new agents in hormone-refractory prostate cancer and criteria for response need prospective validation for phase III trials. Smith et al. [49] showed that a PSA decline > 50% for at least 8 weeks resulted in a longer mean survival time of 91 weeks versus 38 weeks for patients showing a smaller PSA reduction. An improved PSA response was associated with prolonged survival in the TAX 327 study (Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer), with a median survival of 33 months when the PSA was normalized (<4 ng/mL) versus 15.8 months for an abnormal PSA [50, 51].
Heidenreich [52], the chair of the European Association of Urology oversaw the EAU 2012 Prostate Cancer Guidelines. He acknowledged that the PSA has been validated to be the most clinically useful tumor marker of treatment failure following local therapy and of tumor response as well as of tumor progression following hormonal treatment.
8. Assessment of molecularly targeted, cytostatic or anti-angiogenic agents
Bellmunt [53] and others expressed concern that PSA response criteria are not established to properly evaluate molecularly targeted cytostatic or anti-angiogenic agents [54]; therefore, certain drug-specific limitations may exist when using PSA or PSA-DT as an indicator of progression or response. One clear example was noted in a study of sorafenib (Nexavar) in castrate resistant prostate cancer, in which two patients with PSA progression were found to have dramatic resolution of bony disease [55]. Therapy-associated PSA “surge” has been described after effective chemotherapy. PSA surge occurs with Samarium153 radiotherapy, androgen deprivation and chemotherapy and is generally transient. The surge may be due to rapid lysis of prostate cancer cells thus spilling intracellular contents into the intravascular space [56]. Similarly, 10 of 16 patients who discontinued sorafenib and did not receive other therapy demonstrated post-discontinuation PSA declines of 7–52% [57]. The review by Bellmunt [58, 59] notes that several targeted therapies caused prolongation of the PSA-DT as well as significant suppression of PSA levels. The era of targeted therapy for prostate cancer is just beginning and will require changes in how we interpret PSA kinetics.
9. Considerations in evaluating tumor growth effects of targeted therapies
Newer targeted therapies are often cytostatic or cytolentic (slowing proliferation) [60], resulting in disease stabilization, improved quality of life and extended survival. Examples of such drugs include sorefinib (Nexavar) [61], axitinib (Inlyta) for renal cell carcinoma [62], and mTOR inhibitors (everolimus (Afinitor) [63] and temsirolimus (Torisel)). Dasitinib (Sprycel) and sorefinib (Nexavar) are active in prostate cancer. Dasatinib is active in chronic granulocytic leukemia and GIST, inhibits BCR/ABL tyrosine kinase, KIT, PDGFR and Src tyrosine kinase amongst other targets. The Src tyrosine kinase is instrumental in driving hormone-independent prostate cancers [64]. Dasatinib is active in castrate resistant prostate cancer and may be administered safely with docetaxel [65, 66].
These newer therapies target not only the tumor cell but also modify the supporting stroma and microvasculature. The cytostatic/cytolentic effects may leave the tumor dimensionally intact, stable on imaging studies but with slower or absent growth for extended periods of time. Some imaging techniques such as PET and MRI [67], able to quantify such metabolic effects, may enhance clinical evaluation while CT images appear unchanged.
There is mounting evidence that stabilization of tumor growth significantly prolongs overall survival to a degree similar to patients experiencing an objective response judged by RECIST or RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). This raises concern and new calls for modification of current RECIST categories to include new definitions for targeted responses [68].
Simple reductions in PSA levels as defined by Bubley [35] have not yet been validated as a surrogate end point for use in clinical trials of agents with novel mechanisms of action. As indicated, cytotoxic chemotherapy alone, in combination with molecular-targeted agents, or the sole use of targeted therapies, produces different and at times transient and paradoxical changes in serum PSA and further studies are needed to further define this issue.
As questions have emerged concerning the utility of PSA levels as a surrogate end point, the Prostate Cancer Clinical Trials Working Group reviewed the criteria for outcome measures in clinical trials that evaluate systemic treatment for patients with progressive prostate cancer. Recommendations conclude that PSA responses may be delayed in trials of non-cytotoxic agents, and rising PSA levels in the absence of other signs of progression should not lead to discontinuation of trials. This recommendation might lead to much consternation between the patient and doctor where discussion of the latest PSA value is often the primary subject during follow-up visits.
10. Projected tumor size and projected PSA uncover hidden drug activity
Now that surrogacy of static values of PSA and PSA-DT is being questioned for targeted therapies, new techniques of response evaluation are under study. One attempt to quantitate treatment efficacy redirects attention from PSA-DT to PSA-specific growth rate (PSA-SGR) [69, 70, 71]. Generally ignored, projected tumor and marker value play a particularly important role in uncovering and quantifying hidden, cytostatic or cytolentic drug effects. Projected tumor volume or marker value is calculated prior to the initiation of therapy and based on the specific growth rate constant (SGR) before the start of therapy. The projected value is illustrated in Figure 7. This growth projection captures the inherent tumor SGR before therapy and predicts what the outcome (projected tumor or marker volume/value) would be at any future date in the absence of treatment or tumor mutation. Older cytotoxic drugs, when effective, inhibit innate growth by programmed cell death and apoptosis resulting in autophagy and tumor cell lysis [60, 72]. This results in a measurable reduction of tumor size. Interestingly, these drugs are often in part cytostatic or cytolentic and depending on dose may result in stable disease. Keep in mind that prolongation of cytostatic or cytolentic suppression by any drug may eventually induce cytotoxicity and cell lysis [60] Figure 6.
Different combinations of static/lytic drug activity may result in reduced tumor/marker size or complete tumor growth inhibition without clinically detectable change in tumor size. Under these circumstances, use of projected growth uncovers hidden suppression of proliferation. A common clinical scenario occurs when during treatment, a tumor increases in size but much less than projected. Unless the clinician calculates what the projected tumor size should be, the true degree of tumor suppression is not appreciated Figure 7.
10.1. Mathematical relationships of exponentially growing tumors and projected tumor marker or tumor size/volume
The mathematical expression for exponential expansion of growth is: Vt = V0eαt where the tumor volume at time Vt is predictable and is the product of the starting tumor volume [V0] and [e = 2.71828, the base of the natural logarithm raised to the product of the specific growth rate constant α or (SGR) and the duration of growth Δt or (t1-t0)].
This is given as Vt = V0eSGR *∆t and mathematical rearrangement yields SGR=ln(V2V1)t2−t1
Inhibitory drug effects slow SGR and are precisely quantifiable by calculating changes of SGR and the tumor size before and after therapy. Tumor size after therapy should be compared to the projected tumor size the same time after therapy. The current standard for clinical oncologists is comparison of tumor size before and after therapy while neglecting comparison with the projected tumor size. Differences between post therapy tumor size and the post therapy projected tumor size are the clue to hidden responses that are almost never evaluated by the clinical oncologist. These often-subtle differences between projected and post therapy tumor sizes may reveal hidden growth stimulation (mutation or idiosyncratic drug effect) as well as subtle growth inhibition, which may lead to prolonged clinical stability.
The following relationships, extracted from Mehrara’s analysis [69,70,71] define projected tumor volume: ∫tit△SGR(t)*dt=ln(VnVi)−ln(VtVi)where Vn = projected tumor volume, Vt = volume of tumor at the time of response evaluation and Vi is the volume at the initiation of therapy. The tumor response or TR = - ln(Vt/Vn) where Vt is the volume of treated tumor and Vn is the hypothetical or projected tumor volume, both evaluated at the time of efficacy assessment. These relationships are the model for the growth kinetics of exponentially growing tumors and generally require the use of at least a handheld computer to facilitate evaluation in the clinic. This is further discussed in the appendix.
Picture a 4.0 cm diameter (14.1 cc) pulmonary metastasis. At the time of discovery two months before the start of therapy the tumor was 3 cm (33.5 cc). The pre-therapy SGR for this tumor = 1.46%/d (tumor volume was expanding by 1.46%/d). Sixty-one days of therapy was administered and the tumor grew to 4.5 cm (47.7 cc). SGR decreased from 1.46%/d to 1%/d. Clinicians unaware of SGR and the projected tumor volume at this point might declare drug resistance however; the projected tumor volume was actually 80.6 cc and the tumor reached only 47.7 cc. Even though the tumor grew, therapy was significantly effective in slowing growth (59% of intrinsic tumor growth was inhibited)! The parameter for treatment efficacy, TR was +0.5. A positive value for TR means that therapy had some inhibitory activity against the tumor, the larger the value the better. A negative value means therapy was associated with growth stimulation. The value of TR is useful as an objective standard comparator to help evaluate efficacy between different treatments.
Figure 6.
In vitro and in vivo, a clear distinction between cytostatic and cytolytic drugs does not exist. Low-dose cytolytic chemotherapy may exert cytostasis or so-called cytolentic slowing of cell proliferation leading to cell lysis, while targeted therapy’s prolonged cytostatic metabolic effects (or large doses of targeted therapy) may induce cytolysis and autophagy (autophagocytosis). Regardless of mechanism of cell inhibition, the SGR and the TR (treatment response) calculations clearly and objectively define and quantitate drug efficacy (TR value).
Figure 7.
Tumor size (volume) or Marker (PSA, PAP) Time Line
Figure 7 illustrates potential tumor responses to drug treatment. Some of the responses such as positive and negative deviation from the projected\n\t\t\t\t\tPSA value or projected\n\t\t\t\t\ttumor volume are routinely overlooked in the clinic because projected sizes for these parameters must be calculated in advance (projected volume is illustrated by the largest b-b green circle at t2). SGR is calculated based on tumor or PSA growth between t0 and t1. Deviations from projected values reveal subtle drug-tumor interactions. In the appendix we discuss straightforward evaluation of all five-treatment outcome scenarios illustrated above by a hand-held computer.
Until now, most attempts to capture drug effects vs. prostate tumors employed changes of PSA-DT. However, Mehrara [70] presented newer assessments of PSA-DT compared to PSA-SGR that cast doubt on the validity of that historic collection of work.
What follows is a general listing of consequences of drug-tumor interaction. These potential tumor or marker responses Figures 6, 7 are important to understand because subtle changes in tumor proliferation may be the only drug-induced tumor response and may go unnoticed when evaluating targeted therapy by RECIST/RECIST 1.1 response criteria.
10.2. Targeted therapies might require SGR calculations to evaluate the full spectrum of tumor response
Figures 6, 7 display tumor responses evaluable in the clinic. RESIST 1.1 criteria follow for comparison.
Disease stabilization (complete inhibition of pre-therapy SGR)
The marker or tumor’s inherent growth rate is inhibited causing it or its surrogate marker value to remain unchanged during therapy.
Uninterrupted growth
The tumor or marker continues its calculated pre-therapy growth rate without change during therapy. The growth noted in the surrogate marker or tumor after therapy is predictable and equal to the projected tumor growth based on the calculated SGR before the start of therapy.
Tumor “response” of varied degree (note: at the time of response evaluation the tumor may be larger than the pre-therapy value)
Tumor or marker growth is inhibited and at post-therapy response evaluation the tumor or its surrogate marker is less than the projected value. This response may be difficult to identify since the tumor or its marker may have reached a size greater than before the start of therapy however, tumor or marker post therapy is not as large as projected based on the pre-therapy SGR Figure 7. A computer calculation comparing pre- and post-therapy SGR is required to accurately quantify this response category. TR (treatment response) is easily calculable and offers an objective and continuous value for the degree of response. TR is used as either a “tumor response” or “tumor marker response”, to quantitate the effect of therapy. This continuous variable is useful to directly compare treatment efficacy between differing therapies.
Mehrara [71] defined some limitations for the current use of treatment response including: 1) PR and CR as defined in RECIST and other methods are no longer of value for quantifying responses to cytostatic/cytolentic drugs. Combinations of cytolytic and cytostatic/cytolentic therapies add further difficulty to response interpretation. A further problem arises when drugs are used at the extremes of dosing where tumor-killing activity may change from cytostatic/cytolentic to cytolytic and vise versa. 2) Classically, no consideration is given to the persistence of tumor SGR and or its inhibition during the course of therapy. Clinically, this is a trap for the oncologist if response is based solely in terms of whether the tumor marker or size is decreased at the end of therapy 3) The advantage of TR as a continuous variable (as opposed to a discrete variable used to compartmentalize responses such as CR, PR, SD) is that TR is a measurement of inhibitory (+TR) as well as accelerating (-TR) drug effects and is directly comparable between therapies and independent of mechanism of drug action.
A simple statement that the marker or tumor is larger post therapy is no longer adequate to evaluate tumor responses.
The size of the tumor or its surrogate marker decreases after therapy.
This may be a partial or complete return to normal, manifest by partial or complete disappearance of tumor/marker abnormality.
Tumor acceleration and deceleration
Tumor acceleration occurs when the tumor or marker growth rate (SGR) after therapy is greater than the pre-therapy or baseline SGR and SGR = (SGR after Rx − SGR before Rx) / (t2−t1) is a negative value. Tumor growth rate acceleration is positive and may indicate the presence of a tumor-accelerating mutation or an unexpected untoward drug effect.
Tumor deceleration occurs when SGR before therapy is greater than SGR after therapy and is expressed as: SGR deceleration = (SGR after Rx −SGR before Rx) / (t2−t1) this is a negative value.
The rate of change calculations are based on the pre-therapy calculated SGR and its rate of change is calculated at the end of therapy and is expressed as: Acceleration or deceleration of the SGR: ΔSGR/Δt. Or EDITOR use (SGR2-SGR1)/(T2-T1).
Note: In the presence of multiple tumor targets the sum of tumor diameters or volumes is used as an approximation. Clonal heterogeneity (a mosaic of tumors growing at different growth rates and or demonstrating a mixed response) may make some tumors inadequate for analysis.
In 1999 an attempt to write a specific dogma evaluating tumor response resulted in the RECIST 1.0 criteria, later updated 2009 as RECIST 1.1 [73]. Note the absence of drug-response based on the concept of projected tumor growth.
RECIST 1.1 criteria
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Weber noted that the RECIST 1.1 disease stabilization category does not differentiate between a drug that slows tumor growth and the complete lack of drug effect Figure 8. The RECIST 1.1 definition for disease progression is >5 mm absolute increase in size in addition to >20% increase compared with the nadir. In this figure, though all three tumors do not meet the progressive disease criteria and thus would be termed stable, the growth of the third was slowed by therapy. Though all three are termed stable, note the subtle difference between the two tumors showing a continued and uninterrupted pre-therapy growth rate (SGR), compared to the slowed growth rate of the tumor depicted by the red line. Surely there is a drug effect vs. the red tumor. This active drug could be overlooked in spite of its potential to increase survival if maintained for a sufficient period of time.
Figure 8.
Weber [74] reveals the difficulty of classifying real growth inhibition within the RECIST1.1 criteria of stable disease. Real or suppressed tumor growth is illustrated by the pink growth curve only.
In a review of a group of patients treated with targeted therapies, Tourneau [75] revealed clinical evidence where investigators overlooked subtle cytostatic/cytolentic (slowing of SGR) drug activity Figure 6, 8. The group analyzed 50 patient participants in 18 targeted therapy drug trials. Among the 44 patients who withdrew from study because of disease progression according to the investigators’ assessment, 18 patients (41%) demonstrated a favorable slowing trend in tumor specific growth rate. Among the 18, 5 had disease progression according to RECIST 1.1 according to retrospective reassessment of on-study imaging and occurrence of no new lesion during study treatment. Their preliminary evaluation concluded that a substantial proportion of patients treated with targeted agents were removed from protocol in spite of possibly benefitting from therapy.
Ferte et al. [76] studied metastatic renal cell carcinoma patients treated with sorafenib (Nexavar) and everolimus (Afinitor). Analysis of tumor SGR clearly revealed drug effects that would have been missed had RECIST response criteria been applied. Tumor response was assessed before, during, at the time of tumor progression and after drug discontinuation. Tumor growth rate was computed by dividing tumor shrinkage by the time between two related evaluations (% RECIST x 100 /day).
In two different patient populations (IGR and TARGET) tumor growth rate significantly decreased following sorafenib (-23.6 vs. 20 (IGR) and -19 vs. 22 (TARGET)) and everolimus (-5.2 vs. 30 (IGR)). The great majority of patients (IGR) had a decrease in the tumor growth rate during vs. before therapy, regardless of the RECIST evaluation, both with sorafenib (28/29) or everolimus (36/37). Growth rate after sorafenib or everolimus interruption was significantly higher than at the time of progression in both settings (IGR) (14.6 vs. 31 and 17.9 vs. 32.1 respectively). No significant difference was observed between growth rate before or after therapy for either sorafenib or everolimus (IGR). They concluded that SGR evaluation revealed: 1) better evaluation of tumor response, regardless of RECIST criteria, 2) had independent prognostic value, 3) the possibility that continuation of sorafenib or everolimus after disease progression might be beneficial to patients by sustaining a continued suppression of tumor growth.
Figure 9.
Following a patient’s tumor size often reveals subtle changes in the slope of the tumor measurement or marker growth curve as revealed above. These subtle changes in growth rate are not associated with a significant decrease of tumor size or marker value. As Le Tourneau et al. and Ferte et al. demonstrate, subtle changes in tumor growth rate are not evaluated as a response when applying RECIST 1.1 criteria nevertheless, they do represent a true cytostatic effect of targeted therapies that may translate into a meaningful prolonged survival.
The following section presents a model of tumor growth rate expressed as an executable algorithm in the form of an Apple App that quantitates subtle changes of tumor specific growth rate (SGR).
11. SGR is a useful tool to identify subtle drug-associated tumor or marker kinetic changes of tumors
Mehrara, as part of his PhD thesis at the Department of Radiation Physics, University of Gothenburg, Goteborg, Sweden presented an analysis of tumor growth kinetics based on the tumor specific growth rate constant (SGR). The analysis assumes that for most practical purposes clinically observable tumor growth follows exponential growth. Additionally, this is true for the surrogate PSA tumor marker. SGR is rapidly calculable by hand-held mobile devices and facilitates the rapid identification of tumor responses easily overlooked in the clinic, many of which are not readily apparent without computer analysis. Occasionally, changes of SGR uncover subtle tumor stimulation.
Construction of the exponential growth curve, similar in shape to the mid portion of the Gompertzian curve Figure 1, requires just two different measurements of tumor volume (or diameter, area, cell number) or a surrogate marker at two different times to satisfy the exponential growth equation:Vt=V0eat. Here “α” is the exponential growth constant, and Vt and V0 are the tumor volume at times t and t0, respectively. This model implies that tumor volume can increase indefinitely and the growth rate of a tumor is proportional to its volume and dV/dt =aV .
SGR is the relative change in tumor volume per unit time calculable as percent increase or decrease of tumor volume per unit time. Excluding mutations, for exponentially growing tumors, SGR is constant, i.e., SGR or α is independent of tumor volume or age. Faster growing tumors have higher SGR values, SGR=0 represents non-growing tumors; a negative SGR represents tumor regression. In 1956 Collins et al. [9] graphically introduced the concept of tumor doubling time. The DT formulation was proposed in 1961 [10]: DT = (t2-t1) * ln(2) / [ln(V2/V1)]. Other relationships of importance include the specific growth rate, SGR = ln(V2/V1)/(t2-t1) and DT = ln(2)/SGR. These equations are descendants of the primary exponential growth equation, Vt = V0eat
Mehrara expresses concerns based on his mathematical treatment of SGR and DT suggesting that for clinical studies, SGR is the best indicator of tumor growth. Tumor growth rate, especially but not limited to urology circles, is usually quantified as DT i.e. PSA-DT. Because of the subtle mathematical relationship between SGR and DT, use of DT alone to evaluate therapeutic effects may give erroneous results.
Mehrara’s studies revealed that DT has several drawbacks when used to describe tumor or tumor marker growth rates. The shortfalls include 1) for brief measurement time intervals, or high volume and very small measurement uncertainties the mean DT can either overestimate or underestimate the average growth rate; 2) DT approaches infinity for very slow growing tumors and is mathematically limited while SGR is a continuous variable no mater the speed and 3) the non normal frequency distribution of DT values restricts use of parametric statistics thus reducing use of more discriminatory statistics especially when studying small samples [77]. Unlike DT, SGR is definable for all tumor volume changes no matter how small, and it is Gaussian (normally) distributed allowing use of parametric statistics. SGR is more accurate to use when considering growth fraction, cell loss rate, and tumor growth rate heterogeneity. For these reasons, Mehrara opines that SGR be used instead of DT, to quantify tumor growth rate.
Accuracy and clinical outcome analysis comparing SGR and DT would be a valuable area of research in light of the cytostatic changes leading to subtle changes of growth rate characteristic of targeted therapies. Later, an in depth illustration of the differences between DT and SGR will help illuminate this issue.
Collins and Schwartz [9, 10] both analyzed several tumors in patients as they defined the use of tumor volume doubling time. Note that for bronchogenic lung cancers a semi-logarithmic plot of tumor diameter (y-axis) versus a linear time period (x-axis) produces a near straight line Figure 2.
12. Measuring tumor growth
It is imperative to depend on sensitive and precise marker assays. Guess [38] tried to address this problem by use of splines or line segments to average all PSA-DT values in an attempt to better detect therapy-induced changes of PSA-DT. Unfortunately, this computerized technique is cumbrous for most to apply.
The accurate and reproducible measurement of tumor diameters from imaging studies is critical. Keep in mind that occasionally plain radiographs of larger lesions are preferred because CT imaging may slice through a lesion at variable levels producing aberrant results for elliptical lesions.
A closer look at differences between DT and SGR.
The mathematical relationship between DT and SGR as revealed by the exponential growth model is important because as displayed in Figure 10, sole use of tumor volume doubling time (TV-DT) or tumor marker doubling time (PSA-DT) rather than tumor or marker specific growth rate as a measure of treatment outcome may be destined for failure depending on the magnitude of differences in the clinical study. Applying the exponential model of tumor growth to published studies reporting only DT as displayed here Table 1,2 and Figures 11,12 reveals discordant conclusions from those using SGR. Note that the DT is mathematically logarithmically related to the inverse of the exponential growth constant (SGR): SGR = ln(2)/DT.
The opposite results using SGR compared to those obtained with DT are critical since prostate cancer research is steeped in the use of the PSA-DT to predict survival, tumor dissemination, relapse, and tumor response to drugs and hormones and to radiation efficacy. In the prostate cancer literature use of DT as a parameter of response is established canon.
Mehrara reveals that DT is not normally symmetrically distributed (non-Gaussian distribution) and its use as an indicator of treatment response could yield inaccurate conclusions. Changes in DT over-predict drug effects in slow growing tumors while they under-predict in rapidly growing tumors and DT is essentially of no value for tumor volumes (or markers) that show no change in value (stable disease) where DT approaches infinity see Figure 10.
Work by others confirms the importance of the tumor or marker-specific growth rate. Stein et al. [46] studied a combination of equations that simultaneously modeled both tumor/ PSA regression and tumor/PSA exponential growth. They found that only the exponential growth equation with its specific growth rate constant (PSA-SGR) predicted a statistically significant high mortality hazard ratio of 5.14 (95% confidence interval, 3.10 - 8.52) in his study group of patients with prostate cancer. The disease regression formula was unable to predict patient mortality.
13. Why PSA-SGR is more useful than PSA-DT
As noted in Figure 10, when SGR is fast and increases 1% from 4 to 5%/day, the doubling time changes 1.3-fold from 4 to 3 days (a slight change). However, when the SGR is slower and increases 1% from 12%/d, doubling time changes four-fold from 69 to 17 days (a large change). A DT of 1-day does not represent the same growth rate when the tumor is slowing as when the tumor is rapidly growing. As the absolute value of SGR approaches zero, DT approaches infinity and is of no practical use other than to say the tumor or marker is stable. Because of the DT-SGR relationship at the extremes of tumor or marker growth, therapy-induced changes in doubling times at the extremes of SGR do not accurately represent the magnitude of the impact of therapy.
Figure 10.
This figure, modified from Mehrara [70], displays the variation of tumor volume doubling time or tumor marker doubling time (DT) per unit change of tumor specific growth rate (SGR) based on:.
14. Clinical application of DT and SGR: Discordant results
Mehrara retrieved data from two previously published clinical studies [70]. The first by Guess et al. [38] Table 1 who studied the effect of modified citrus pectin (MCP) on PSA-DT of 12 prostate cancer patients. Mehrara extracted data and analyzed for both PSA-DT and PSA-SGR before and after therapy. The difference between PSA-DT before and after treatment was not found to be statistically significant by the paired t-test (p = 0.27). Nevertheless, when transforming PSA-DT to PSA-SGR the difference before and after MCP treatment is statistically significant by the paired t-test (p = 0.003) and nonparametric Wilcoxon matched pairs signed rank test: p = 0.002. Thus, a therapy initially deemed ineffective by PSA-DT analysis, when analyzed for a group of patients based on PSA-SGR proved to be highly significant Table 1.
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tEffect of modified citrus pectin (MCP) on PSA-DT and PSA-SGR\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tPatient\n\t\t\t
\n\t\t\t
Before RxPSA-DT(mo)
\n\t\t\t
After RxPSA-DT(mo)
\n\t\t\t
Before RxPSA-SGR (%/mo)
\n\t\t\t
After RxPSA-SGR (%/mo)
\n\t\t
\n\t\t
\n\t\t\t
A
\n\t\t\t
3.97
\n\t\t\t
13.34
\n\t\t\t
17.46
\n\t\t\t
5.16
\n\t\t
\n\t\t
\n\t\t\t
B
\n\t\t\t
5.67
\n\t\t\t
10.11
\n\t\t\t
12.22
\n\t\t\t
6.86
\n\t\t
\n\t\t
\n\t\t\t
C
\n\t\t\t
1.14
\n\t\t\t
2.91
\n\t\t\t
60.80
\n\t\t\t
23.82
\n\t\t
\n\t\t
\n\t\t\t
D
\n\t\t\t
3.37
\n\t\t\t
7.71
\n\t\t\t
20.57
\n\t\t\t
8.99
\n\t\t
\n\t\t
\n\t\t\t
E
\n\t\t\t
1.58
\n\t\t\t
16.49
\n\t\t\t
43.87
\n\t\t\t
4.20
\n\t\t
\n\t\t
\n\t\t\t
F
\n\t\t\t
10.5
\n\t\t\t
7.97
\n\t\t\t
6.60
\n\t\t\t
8.70
\n\t\t
\n\t\t
\n\t\t\t
G
\n\t\t\t
2.66
\n\t\t\t
11.95
\n\t\t\t
26.06
\n\t\t\t
5.80
\n\t\t
\n\t\t
\n\t\t\t
H
\n\t\t\t
3.64
\n\t\t\t
3.27
\n\t\t\t
19.04
\n\t\t\t
21.20
\n\t\t
\n\t\t
\n\t\t\t
I
\n\t\t\t
2.04
\n\t\t\t
4.96
\n\t\t\t
33.98
\n\t\t\t
13.97
\n\t\t
\n\t\t
\n\t\t\t
J
\n\t\t\t
2.33
\n\t\t\t
3.24
\n\t\t\t
29.75
\n\t\t\t
21.39
\n\t\t
\n\t\t
\n\t\t\t
K
\n\t\t\t
6.29
\n\t\t\t
-155.49
\n\t\t\t
11.02
\n\t\t\t
-0.45
\n\t\t
\n\t\t
\n\t\t\t
L
\n\t\t\t
5.12
\n\t\t\t
-645.51
\n\t\t\t
13.54
\n\t\t\t
-0.11
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
Nonparametric Wilcoxon matched pairs signed rank: p = 0.42 Parametric Paired t-test p = 0.2704
\n\t\t\t
Nonparametric Wilcoxon matched pairs signed rank: p = 0.002 Parametric Paired t-test p = 0.0027
\n\t\t
\n\t
Table 1.
Guess et al. [38] studied the effect of modified citrus pectin (MCP) on PSA-DT of 12 prostate cancer patients. Mehrara extracted that data and analyzed both PSA-DT and PSA-SGR before and after therapy. The difference between PSA-DT before and after treatment was not statistically significant by the paired t-test (p = 0.27). Nevertheless, when transforming PSA-DT to PSA-SGR the difference before and after MCP treatment is statistically significant by the paired t-test (p = 0.003) and nonparametric Wilcoxon matched pairs signed rank test: p = 0.002.
A second analysis of original data by Nishida et al. (1999) [78] was based on a study of the correlation of tumor volume and the CA19-9 tumor marker of pancreatic cancer patients Table 2. The correlation between CA19-9-DT and tumor volume-DT was statistically significant (p<0.0001). However, after converting tumor-volume-DT to TV-SGR and CA19-9-DT to CA19-9-SGR, correlation between CA19-9-SGR and TV-SGR was no longer statistically significant (p>0.3). Since SGR is the preferred parameter, the initial analysis of Nishida may benefit from a second look.
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
Relationship between CA19-9-DT and TV-DT vs. CA19-9-SGR and TV-SGR
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tPatient\n\t\t\t
\n\t\t\t
CA19-9 DT(Days)
\n\t\t\t
Tumor-DT(Days)
\n\t\t\t
CA19-9-SGR%/day
\n\t\t\t
Tumor-SGR%/day
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
A
\n\t\t\t
8.3
\n\t\t\t
34.8
\n\t\t\t
8.4
\n\t\t\t
2
\n\t\t
\n\t\t
\n\t\t\t
B
\n\t\t\t
39.7
\n\t\t\t
44.6
\n\t\t\t
1.7
\n\t\t\t
1.6
\n\t\t
\n\t\t
\n\t\t\t
C
\n\t\t\t
46.3
\n\t\t\t
34.5
\n\t\t\t
1.5
\n\t\t\t
2
\n\t\t
\n\t\t
\n\t\t\t
D
\n\t\t\t
36.5
\n\t\t\t
21.2
\n\t\t\t
1.9
\n\t\t\t
3.3
\n\t\t
\n\t\t
\n\t\t\t
E
\n\t\t\t
30.4
\n\t\t\t
47.7
\n\t\t\t
2.3
\n\t\t\t
1.5
\n\t\t
\n\t\t
\n\t\t\t
F
\n\t\t\t
67.1
\n\t\t\t
112.8
\n\t\t\t
1
\n\t\t\t
0.6
\n\t\t
\n\t\t
\n\t\t\t
G
\n\t\t\t
44.7
\n\t\t\t
70.6
\n\t\t\t
1.6
\n\t\t\t
1
\n\t\t
\n\t\t
\n\t\t\t
H
\n\t\t\t
24.7
\n\t\t\t
18.4
\n\t\t\t
2.8
\n\t\t\t
3.8
\n\t\t
\n\t\t
\n\t\t\t
I
\n\t\t\t
42.7
\n\t\t\t
50.6
\n\t\t\t
1.6
\n\t\t\t
1.4
\n\t\t
\n\t\t
\n\t\t\t
J
\n\t\t\t
137.5
\n\t\t\t
231.6
\n\t\t\t
0.5
\n\t\t\t
0.3
\n\t\t
\n\t\t
\n\t\t\t
K
\n\t\t\t
42.3
\n\t\t\t
39.3
\n\t\t\t
1.6
\n\t\t\t
1.8
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
Linear regression: r2 = 0.89 p < 0.0001
\n\t\t\t
Linear regression: r2 = 0.09 p = 0.37
\n\t\t
\n\t
Table 2.
This table displays the extracted data from Nishida’s study [78] of the correlation of tumor volume and the CA19-9 tumor marker of pancreatic cancer patients. The correlation between CA19-9-DT and tumor volume-DT was statistically significant (p<0.0001). However, after converting tumor-volume-DT to TV-SGR and CA19-9-DT to CA19-9-SGR, correlation between CA19-9-SGR and TV-SGR was no longer statistically significant (p>0.3).
Most prostate cancer studies employ changes in the PSA-DT. PSA-DT values are not normally distributed and thus not readily subject to more sensitive parametric statistical analysis. However, PSA-specific growth rate is normally distributed and parametric statistics can be applied. Nonparametric statistical methods lose discriminatory power especially for clinical studies of smaller groups of patients [77].
During a cursory review of the literature we found two additional studies, one dealing with the effects of celecoxib on PSA-DT Figure 11 and the other investigating the effects of a combination of calcitriol and naproxin on PSA-DT of prostate cancer patients Figure 12.
Smith et al. [79] Figure 11 studied the biologic activity of celecoxib, a selective cyclooxygenase-2 inhibitor, in men with recurrent prostate cancer using change in PSA-DT as the primary outcome variable. We carefully extracted the data from his graphic report. We applied the Wilcoxon matched-pairs signed rank test [two tailed] (for nonparametric distribution of PSA-DT) to the data. PSA-DT before versus after celecoxib was highly significant: p = 0.0006. After transformation of PSA-DT to PSA-SGR, the Paired t-test [two tailed] for parametric distribution of PSA-SGR suggests that the celecoxib effect lacked statistical significance p = 0.213!
A second study by Srinivas [80] Figure 12 evaluated naproxen in combination with calcitriol in patients with early recurrent prostate cancer. All patients received 45 μg of calcitriol (DN101, Novacea, South San Francisco, CA, USA) orally once a week with naproxen 375 mg twice a day and were evaluated for a biochemical PSA response and a change in PSA doubling time (PSA-DT). Testing the efficacy of the combination therapy using changes of PSA-DT by the non-parametric Wilcoxon matched-pairs signed rank test [two tailed] p = 0.037 a significant difference. However, after transforming PSA-DT to PSA-SGR (SGRPSA = ln(2)/DTPSA), analysis with the parametric Paired t-test [2-tailed] indicate naproxen plus calcitriol was not effective in slowing tumor growth, p = 0.213.
Figure 11.
Smith et al. [79] studied the biologic activity of celecoxib, a selective cyclooxygenase-2 inhibitor, in men with recurrent prostate cancer using change in PSA-DT as the primary outcome variable. We retrieved their graphic data for our own analysis. A histogram of the PSA-DT paired differences for before and after celecoxib appears normally distributed. Applying the parametric Paired t-test statistic for significance of the difference yields p = 0.0002. Next, we transformed the same (before-after celecoxib PSA-DT data with to PSA-SGR before and after pairs and applied the paired t-test. Contrary to the statistical analysis for celecoxib induced change of PSA-DT, changes of PSA-SGR revealed that the celecoxib difference was no longer significant, p = 0.213!
Figure 12.
Sinivras and Feldman [80] evaluated naproxen in combination with calcitriol in patients with early recurrent prostate cancer. All patients received 45 μg of calcitriol (DN101, Novacea, South San Francisco, CA, USA) orally once a week with naproxen 375 mg twice a day and were evaluated for a biochemical PSA response and a change in PSA doubling time (PSA-DT). Applying the paired t-test for statistical significance (before PSA-DT and after PSA-DT) resulted in p = 0.034. Nevertheless, after transforming PSA-DT to PSA-SGR (PSA-SGR = ln(2)/PSA-DT), analysis with the paired t-test [2-tailed] suggested naproxen plus calcitriol was not effective in slowing tumor growth, p = 0.213.
The non-linear relationship between the SGR and DT may be responsible for erroneous interpretations of treatment effects reported in prior prostate cancer trials that published results solely in terms of changes in PSA-DT Figure 10.
15. Evaluation of tumor and surrogate marker drug responses, rate of change of response:SGR acceleration = (SGR after Rx −SGR before Rx) / (t2−t1); A positive number
The dynamic of PSA change was used as an early predictor of overall survival after a short exposure to docetaxel therapy (4 doses). Knowledge that a drug may extend survival after just a short exposure would minimize toxicity from ineffective drugs. Hannenin‘s work [81] found that a rapid rate of PSA decline expressed as PSA half-life <70 days was associated with a longer overall-survival Figure 13. This result was independent of other known markers of survival and allowed for a greater survival differentiation than PSA suppression alone. Response-time evaluations may play a new role in determining drug efficacy earlier than usual. I would propose study of an alternate expression for tumor acceleration or deceleration in terms of SGR as: SGR (accel…decal) = SGR2-SGR1/(t2-t1). The value of this expression may be positive for acceleration or negative for deceleration.
De Crevoisier [82] found that a PSA decline 6 weeks after the start of EBRT when used as monotherapy and 3 months after the start of androgen deprivation therapy (ADT) in patients treated with combined ADT and external beam radiation is predictive of progression and specific survival.
Figure 13.
Treatment-associated tumor/marker deceleration in response to docetaxel. The magnitude of rate of change (acceleration-deceleration) of SGR resulting from therapy is an early predictor of prostate-specific survival.
Figure 14 illustrates a computer analysis of a prostate cancer patient treated with docetaxel. A pelvic node is noted to grow over 4.5 months from 1.3 to 1.6 cm in greatest dimension. This establishes the pre-therapy SGR of 0.46%/d and the tumor volume (assuming a sphere) before starting therapy is 2.1 cc. Fifty-one days of therapy induces a decrease of tumor diameter to 0.9 cc and a decrease of tumor volume to 0.38 cc. Had the tumor grown uninterrupted the projected tumor volume would have been 2.7 cc. In this case, the value for deceleration of SGR for the tumor: is given as (SGR2 after Rx −SGR1 before Rx) / (t2−t1) =−0.021%/d/d.
This is an objective measure of the rate of change of SGR. The treatment response is displayed as = + 2.0. This assigns a calculated continuous variable as a measure of the degree of response and is used to objectively compare docetaxel efficacy to any other administered drug. Positive TR values represent tumor reduction compared to the projected tumor size while a negative TR represents tumor growth relative to the projected size. Estimated age of tumor, here approximated ~ 12.3 years, is a calculated value based on the initial SGR of 0.46%/d in the absence of therapy. This assumes constant, continuous exponential growth over many years. Tumor age calculations are gross approximations and notoriously subject to large error.
Figure 14.
This calculation displays results for a patient treated with docetaxel (see text).
Figure 15 illustrates the evaluation for a 68 year-old man undergoing watchful waiting for a Gleason score 3+3 = 6, T1c prostate cancer. Three PSA values are displayed for three sequential dates. When the patient was asked if he had changed medication between 3/2/11 and 5/1/11 he noted he was ingesting a new Chinese herbal mixture sold to enhance energy and libido.
Subtle acceleration of the tumor marker value was uncovered by inspection of the projected PSA value for 5/1/11 as compared to the actual measured value for that date. Notice the confirmative quantitative measures given by the calculation Figure 14 of the marker specific growth rate MSGR2 = 0.13%/d compared to MSGR1 = 0.07 %/d; marker doubling time MDT2 = 17.3 months compared to the initial MDT1 = 30.9 months; by both the positive value for MSGR acceleration = +0.001%/d/d and by the negative value for marker response MR = - 0.05. Based on the marker-specific growth rate (MSGR) for the first interval TDx thru TPRx (the date at initiation of therapy) of 0.07%/d, the App calculated the expected PSA on 5/1/11 to be 5.98 ng/ml. However, the measured value was higher = 6.3 ng/ml. The negative value for MR of -0.05 indicates a negative marker response thus PSA expansion (marker acceleration confirmed this = +0.001%/d/d). We suspected that the Chinese herb might have caused subtle acceleration of PSA production and or tumor growth. Other explanations for acceleration of the PSA value include decreased clearance of PSA or the subtle appearance of a mutated, faster growing clone of PSA-producing tumor cells. Note that in the absence of knowledge of the inherent initial PSA-SGR between 2/1/11 and 3/2/11 and calculation of the expected projected value of PSA for 5/1/11, the subtle PSA acceleration would have been missed.
Figure 15.
Evaluation of a 68 year-old man undergoing watchful waiting for a Gleason score 3+3 = 6, T1c prostate cancer. The patient was ingesting a stimulatory Chinese herb.
16. Predicting approximate tumor size or marker value for any arbitrary date in the future
Assuming untreated clinical cancers and their markers expand at a relatively constant exponential rate, it is possible to predict values for tumor diameter, volume and marker for any arbitrary future date. Figure 16 displays a PSA projection made for a patient with newly diagnosed prostate cancer who asked if a preplanned three-month holiday before initiation of therapy could jeopardize his chance for a curative procedure. The prediction, assuming constant exponential expansion of serum PSA, is that the PSA value upon returning from sabbatical would increase from 9.4 to 16.28 ng/ml. This alarmed the patient and he cancelled the trip to initiate therapy.
Figure 16.
PSA projection made for a patient with newly diagnosed prostate cancer
17. Unique treatment paradigms may be suggested by analysis of tumor growth rate
Figure 17 illustrates results for a patient with pancreatic cancer post Whipple procedure who was found on 6/4/10 to have an enlarged peri-aortic mass = 1.8 cm (3.1 cc). Repeat CT on 8/27/10 noted increased size to 2.9 cm (12.8 cc). Therapy with gemcitabine was initiated on 8/27/10. Post therapy reevaluation of the mass on 12/24/10 revealed growth to 3.1 cm (15.6 cc). The patient was discouraged and frightened and thought he had wasted precious time and subjected himself to undo toxicity for no gain. However, evaluation revealed that had the tumor never been treated with gemcitabine it would have reached the projected volume of 96.9 cc by 12/24/10. Thus, based on the initial exponential growth rate from 6/4/10 thru 8/27/10, the tumor volume was actually 84% less than what it would have been had no drug been given (15.6 cc vs. 96.9 cc).
This patient experienced substantial tumor suppression by gemcitabine in spite of its growth. Under these circumstances, when there are poor second choices for effective therapy, instead of discarding gemcitabine, perhaps addition of another compound with differing toxicity might be a reasonable option.
Several principles of prostate cancer management rely on the absolute and dynamic values of various formulations of PSA i.e. PSA-V, PSA-DT and PSA-SGR. This review introduces SGR, a parameter that is underused and closely reflects the true growth rate of tumors undergoing exponential expansion. Several instances are presented where results of studies employing PSA-DT yield statistically divergent results after converting PSA-DT to PSA-SGR. It is recommended that for some studies results be reevaluated in terms of PSA specific growth rate, PSA-SGR.
Newly introduced targeted therapies require innovative techniques to evaluate drug efficacy. Tumor or tumor marker specific growth rate and the concept of projected tumor or marker value are tools capable of quantitatively evaluating subtle effects of targeted drugs. Calculation of the projected tumor size and tumor marker values is critical to properly evaluate subtle drug-tumor proliferative outcomes.
Continuous variables for Tumor Response (TR) and Marker Response (MR) allow for quantitation of drug/biological response modulator effects. Negative values of TR and MR indicate tumor acceleration, values close to or equal to zero indicate lack of response while positive values confirm beneficial tumor response. Responses are numerically quantitated and elusive disease stability may now numerically be defined by a continuous variable. Drugs previously thought to be of no value may be found to induce useful and profound disease stability
The software is helpful for those patients followed by watchful waiting/active surveillance for prostate or any other cancer. Prostate tumors changing biological behavior are immediately identified in a quantitative and objective manner by rapidly uncovering changes in PSA kinetics without the errors inherent in the PSA doubling time (PSA-DT) parameter. The software can help determine whether metastectomy is a reasonable treatment modality for some patients with pulmonary metastasis [83].
Tumor Specific Volume Growth Rates for two intervals (TSGR1 and TSGR2)
Tumor Marker Specific Growth Rates for two intervals (MSGR1 and MSGR2)
Tumor Specific Growth Rate acceleration and deceleration
Tumor Volume Doubling Times for two intervals (TVDT)
Tumor Marker Doubling Time for two intervals (MDT)
Projected TSGR and MSGR at any user designated time in the future
Treatment Response as both Tumor Response and Tumor Marker Response, both as continuous numerical values used to quantitate the effect of therapy. Negative numbers reveal growth acceleration; values of zero reveal no effect and positive values indicate varying degrees of therapeutic efficacy.
Tumor volumes in cc are calculated for TDx, TPreRx and TPostRx.
Extrapolates back to the time of tumor initiation thus calculating how long it took for the tumor to reach the initial tumor diameter.
Calculates approximate time to death in the absence of therapy, assuming constant tumor growth rate.
Acknowledgments
Peter Jahn, Whittier, CA for manuscript review and discussion, mathematical suggestions and statistical considerations.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/41807.pdf",chapterXML:"https://mts.intechopen.com/source/xml/41807.xml",downloadPdfUrl:"/chapter/pdf-download/41807",previewPdfUrl:"/chapter/pdf-preview/41807",totalDownloads:2737,totalViews:574,totalCrossrefCites:1,totalDimensionsCites:2,totalAltmetricsMentions:0,introChapter:null,impactScore:1,impactScorePercentile:71,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"April 13th 2012",dateReviewed:"September 7th 2012",datePrePublished:null,datePublished:"January 16th 2013",dateFinished:"January 3rd 2013",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/41807",risUrl:"/chapter/ris/41807",book:{id:"3274",slug:"advances-in-prostate-cancer"},signatures:"Glenn Tisman",authors:[{id:"62945",title:"Dr.",name:"Glenn",middleName:null,surname:"Tisman",fullName:"Glenn Tisman",slug:"glenn-tisman",email:"glennmd@gmail.com",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 perspective of tumor growth kinetics, exponential and Gompertzian kinetics",level:"1"},{id:"sec_3",title:"3. Exponential growth",level:"1"},{id:"sec_4",title:"4. The tumor marker as a surrogate for tumor growth exemplified by PSA and prostate cancer ",level:"1"},{id:"sec_4_2",title:"4.1. PSA Velocity (PSA-V)",level:"2"},{id:"sec_5_2",title:"4.2. Tumor marker Doubling Time (DT)",level:"2"},{id:"sec_6_2",title:"4.3. PSA-DT as a surrogate for drug activity",level:"2"},{id:"sec_8",title:"5. Defining PSA response",level:"1"},{id:"sec_9",title:"6. PSA-DT and Survival of prostate cancer patients",level:"1"},{id:"sec_10",title:"7. PSA in the era of biologic and targeted therapy",level:"1"},{id:"sec_11",title:"8. Assessment of molecularly targeted, cytostatic or anti-angiogenic agents",level:"1"},{id:"sec_12",title:"9. Considerations in evaluating tumor growth effects of targeted therapies",level:"1"},{id:"sec_13",title:"10. Projected tumor size and projected PSA uncover hidden drug activity",level:"1"},{id:"sec_13_2",title:"10.1. Mathematical relationships of exponentially growing tumors and projected tumor marker or tumor size/volume",level:"2"},{id:"sec_14_2",title:"10.2. Targeted therapies might require SGR calculations to evaluate the full spectrum of tumor response",level:"2"},{id:"sec_16",title:"11. SGR is a useful tool to identify subtle drug-associated tumor or marker kinetic changes of tumors",level:"1"},{id:"sec_17",title:"12. Measuring tumor growth",level:"1"},{id:"sec_18",title:"13. Why PSA-SGR is more useful than PSA-DT",level:"1"},{id:"sec_19",title:"14. Clinical application of DT and SGR: Discordant results",level:"1"},{id:"sec_20",title:"15. Evaluation of tumor and surrogate marker drug responses, rate of change of response:SGR acceleration = (SGR after Rx − SGR before Rx) / (t2−t1) ; A positive number",level:"1"},{id:"sec_21",title:"16. Predicting approximate tumor size or marker value for any arbitrary date in the future",level:"1"},{id:"sec_22",title:"17. Unique treatment paradigms may be suggested by analysis of tumor growth rate",level:"1"},{id:"sec_23",title:"18. Conclusion",level:"1"},{id:"sec_24",title:"Appendix",level:"1"},{id:"sec_25",title:"Acknowledgments",level:"1"},{id:"sec_25",title:"Acknowledgments",level:"2"}],chapterReferences:[{id:"B1",body:'Bassukas ID. Comparative gompertzian analysis of alterations of tumor growth patterns. Cancer Res 1994, Aug 15; 54(16): 4385-92. '},{id:"B2",body:'Demicheli R, Foroni R, Ingrosso A, Pratesi G, Soranzo C, Tortoreto M. An exponential-gompertzian description of lovo cell tumor growth from in vivo and in vitro data. Cancer Res 1989, Dec 1; 49(23): 6543-6.'},{id:"B3",body:'Norton L. A gompertzian model of human breast cancer growth. Cancer Res 1988, Dec 15;48(24 Pt 1):7067-71.'},{id:"B4",body:'Mottram JC. 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Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA 2005, Jul 27; 294(4): 433-9.'},{id:"B42",body:'Armstrong AJ, Eisenberger MA, Halabi S, Oudard S, Nanus DM, Petrylak DP, et al. Biomarkers in the management and treatment of men with metastatic castration-resistant prostate cancer. Eur Urol 2012, Mar; 61(3): 549-59.'},{id:"B43",body:'Gupta S, Carballido E, Fishman M. Sipuleucel-T for therapy of asymptomatic or minimally symptomatic, castrate-refractory prostate cancer: An update and perspective among other treatments. Onco Targets Ther 2011; 4:79-96.'},{id:"B44",body:'Garcia JA. Sipuleucel-T in patients with metastatic castration-resistant prostate cancer: An insight for oncologists. Ther Adv Med Oncol 2011, Mar; 3(2): 101-8.'},{id:"B45",body:'Bitting RL, Armstrong AJ, George DJ. Management options in advanced prostate cancer: What is the role for sipuleucel-t? 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Recent developments in treatments targeting castration-resistant prostate cancer bone metastases. Ann Oncol 2012, May; 23(5): 1085-94.'},{id:"B55",body:'Dahut WL, Scripture C, Posadas E, Jain L, Gulley JL, Arlen PM, et al. A phase II clinical trial of sorafenib in androgen-independent prostate cancer. Clin Cancer Res 2008, Jan 1; 14(1): 209-14.'},{id:"B56",body:'Thuret R, Massard C, Gross-Goupil M, Escudier B, Di Palma M, Bossi A, et al. The postchemotherapy PSA surge syndrome. Ann Oncol 2008, Jul; 19(7): 1308-11.'},{id:"B57",body:'Chi KN, Ellard SL, Hotte SJ, Czaykowski P, Moore M, Ruether JD, et al. A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer. Ann Oncol 2008, Apr; 19(4): 746-51.'},{id:"B58",body:'Bellmunt J, Rosenberg JE, Choueiri TK. Recent progress and pitfalls in testing novel agents in castration-resistant prostate cancer. Eur Urol 2009; 56(4): 606.'},{id:"B59",body:'Bellmunt J, Oh WK. Castration-resistant prostate cancer: New science and therapeutic prospects. Ther Adv Med Oncol 2010, May; 2(3): 189-207.'},{id:"B60",body:'Rixe O, Fojo T. Is cell death a critical end point for anticancer therapies or is cytostasis sufficient? Clin Cancer Res 2007, Dec 15; 13(24): 7280-7.'},{id:"B61",body:' Nabhan C, Tolzien K, Lestingi T, Kelby SK, Galvez AG, Bitran JD. Activity of sorafenib (SOR) in chemotherapy-failure castration-resistant prostate cancer (CRPC). ASCO/GU Proceedings 2010; 122.'},{id:"B62",body:'Carmichael C, Lau C, Josephson DY, Pal SK. Comprehensive overview of axitinib development in solid malignancies: Focus on metastatic renal cell carcinoma. Clin Adv Hematol Oncol 2012 May; 10(5): 307-14.'},{id:"B63",body:'Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012, Feb 9; 366(6): 520-9.'},{id:"B64",body:'Kung HJ. Targeting tyrosine kinases and autophagy in prostate cancer. Horm Cancer 2011, Feb; 2(1): 38-46.'},{id:"B65",body:'Adamo V, Noto L, Franchina T, Chiofalo G, Picciotto M, Toscano G, Caristi N. Emerging targeted therapies for castration-resistant prostate cancer. Front Endocrinol (Lausanne) 2012; 3:73.'},{id:"B66",body:'Agarwal N, Sonpavde G, Sternberg CN. Novel molecular targets for the therapy of castration-resistant prostate cancer. Eur Urol 2012, May; 61(5): 950-60.'},{id:"B67",body:'Brindle K. Watching tumours gasp and die with MRI: The promise of hyperpolarised 13C MR spectroscopic imaging. Br J Radiol 2012, Jun; 85(1014): 697-708.'},{id:"B68",body:'Rosen MA. Use of modified RECIST criteria to improve response assessment in targeted therapies: Challenges and opportunities. Cancer Biol Ther 2010, Jan; 9(1): 20-2.'},{id:"B69",body:'Mehrara E, Forssell-Aronsson E, Ahlman H, Bernhardt P. Specific growth rate versus doubling time for quantitative characterization of tumor growth rate. Cancer Res 2007, Apr 15; 67(8): 3970-5.'},{id:"B70",body:'Mehrara E, Forssell-Aronsson E, Ahlman H, Bernhardt P. Quantitative analysis of tumor growth rate and changes in tumor marker level: Specific growth rate versus doubling time. Acta Oncol 2009; 48(4): 591-7.'},{id:"B71",body:'Mehrara E, Forssell-Aronsson E, Bernhardt P. Objective assessment of tumour response to therapy based on tumour growth kinetics. Br J Cancer 2011, Aug 23; 105(5): 682-6.'},{id:"B72",body:'Elmore S. Apoptosis: A review of programmed cell death. Toxicol Pathol 2007, Jun; 35(4): 495-516.'},{id:"B73",body:'Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009, Jan; 45(2): 228-47.'},{id:"B74",body:'Weber WA. Assessing tumor response to therapy. J Nucl Med 2009, May; 50 Suppl 1:1S-10S.'},{id:"B75",body:'Le Tourneau C, Servois V, Diéras V, Ollivier L, Tresca P, Paoletti X. Tumour growth kinetics assessment: Added value to RECIST in cancer patients treated with molecularly targeted agents. Br J Cancer 2012, Feb 28; 106(5): 854-7.'},{id:"B76",body:'Ferte C, Albiges L, Soria JC, Loriot Y, Fizazi K, Escudier BJ. The use of tumor growth rate (TGR) in evaluating sorafenib and everolimus treatment in mrcc patients: An integrated analysis of the TARGET and RECORD phase III trials data. J Clin Oncol 30, 2012 (suppl; Abstr 4540).'},{id:"B77",body:'Motulsky H. Intuitive statistics a nonmathematical guide to statistical thinking. Second Ed. New York: Oxford University Press; 2010k.'},{id:"B78",body:'Nishida K, Kaneko T, Yoneda M, Nakagawa S, Ishikawa T, Yamane E, et al. Doubling time of serum CA 19-9 in the clinical course of patients with pancreatic cancer and its significant association with prognosis. J Surg Oncol 1999, Jul; 71(3): 140-6.'},{id:"B79",body:'Smith MR, Manola J, Kaufman DS, Oh WK, Bubley GJ, Kantoff PW. Celecoxib versus placebo for men with prostate cancer and a rising serum prostate-specific antigen after radical prostatectomy and/or radiation therapy. J Clin Oncol 2006, Jun 20; 24(18): 2723-8.'},{id:"B80",body:'Srinivas S, Feldman D. A phase II trial of calcitriol and naproxen in recurrent prostate cancer. Anticancer Res 2009, Sep; 29(9) : 3605-10.'},{id:"B81",body:'Hanninen M, Venner P, North S. A rapid PSA half-life following docetaxel chemotherapy is associated with improved survival in hormone refractory prostate cancer. Can Urol Assoc J 2009, Oct; 3(5): 369-74.'},{id:"B82",body:'De Crevoisier R, Slimane K, Messai T, Wibault P, Eschwege F, Bossi A, et al. Early PSA decrease is an independent predictive factor of clinical failure and specific survival in patients with localized prostate cancer treated by radiotherapy with or without androgen deprivation therapy. Ann Oncol 2010, Apr; 21(4): 808-14.'},{id:"B83",body:'Lee JH, Gulec SA, Kyshtoobayeva A, Sim MS, Morton DL. 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1. Introduction
In patients with non-valvular atrial fibrillation (NVAF), oral anticoagulation (OAC) is part of mainstream therapy to prevent ischemic stroke [1], and the left atrial appendage (LAA) remains a focus of thrombus formation [2]. However, there are several situations that oral anticoagulation may be unsuitable, due to any individual history of major bleeding, personal risks of bleeding (e.g., fall risk in elderly or cerebral anomalies), noncompliant patients to OAC, or patients with high-risk occupation. Left atrial appendage occlusion (LAAO) has emerged as an alternative management to prevent stroke in NVAF patients who are not eligible for continuous OAC [3].
2. Left atrial appendage anatomy
The embryonic origin of LAA is different to atria. It is originated from the embryonic remnant of left atrium (LA) during first trimester, with a multilobed structure positioned anteriorly in the atrioventricular sulcus close to the left circumflex artery, the left phrenic nerve, and the left pulmonary veins [4]. The appendage contains numerous trabeculae, with a complex and highly variable anatomy. The LAA typically consists of three major components:
Ostium or “os,” which defines its junction with body of the LA;
Lobar region, which is known to be the most variable anatomically. The difference of lobar region of LAA as seen by computed tomography angiography (CTA) is categorized into: (1) chicken wing; (2) cactus; (3) windsocks; and (4) cauliflower. It has been shown that the difference in the LAA morphology was independently associated with thromboembolic events [5, 6]. The first type of chicken-wing LAA can be a challenge for device implantation; [7] however, it has been associated with a lower stroke risk compared with the other three main morphologies described [8]. Multiple lobes with LAA greater than 40 mm will limit the use of certain devices. Deployment of LAAO device will be difficult for LAA with multiple lobes with branching close to ostium.
“Neck” is a narrow junction between the ostium, lobar region, and the landing zone for LAAO device. The size of the neck determines the applicability to use of certain occlude devices. The Watchman requires an equivalent implant depth and the device diameter. The Amplatzer device requires 10 mm space for deployment from the ostium [7].
3. Rationale for LAAO
Thromboembolic events in AF are correlated to loss of atrial contraction, stasis of blood flow, and thrombus formation, particularly in the LAA. The LAA is notoriously labeled as “human most lethal attachment,” as it has been demonstrated that thrombus in the LAA is the primary source for thromboemboli [2]. A review of studies in patients with nonrheumatic heart disease demonstrated that 90% of LA thrombi examined by transesophageal echocardiography (TEE), cardiac surgery, or autopsy, were located in the LAA [9]. Another study also showed that LA thrombus was evident in 15% of patients without OAC after 48 hours of AF, in which almost all thrombi were found in LAA. The LAA is particularly prone to thrombus formation in AF due to its inherent anatomy with extensive trabeculations, increased blood stasis and hypercoagulability, and endothelial damage [10].
The role of the LAA as a source for thromboemboli in AF patients provides the rationale for ligation, amputation, or occlusion of the LAA structure, especially if patients are indicated for stroke prevention strategy; on the other hand, they are either contraindicated or noncompliant to long-term OAC. In addition, some LAAO techniques may have an additional role in sinus rhythm maintenance through non-pulmonary vein triggers elimination, atrial mass decrease, and atrial electrical remodeling reversion [11, 12].
4. Techniques for LAAO
Currently, there are two major different strategies in LAA exclusion from systemic circulation:
4.1 Surgical approach
The first reported resection of LAA in a human was by John Madden in 1949 [13]. In his report, he performed surgical excision of LAA structure during open heart surgery specifically aimed for stroke prevention in AF patients. This approach was not routinely done after this report was published. Nevertheless, LAA surgical closure is now class IIa indication in the 2020 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for management of patients with valvular heart disease undergoing heart surgery [14] and has currently become widely performed. Similarly, in patients with AF undergoing cardiac surgery, surgical LAA closure is also a class IIb indication based on 2019 ACC/AHA/Heart Rhythm Society (HRS) guidelines [15].
The method of LAA exclusion is usually dictated by the concomitant cardiosurgical procedure.
4.2 Percutaneous LAAO device
To date, several LAAO devices have been approved to be used worldwide (Figure 1).
Figure 1.
LAAO devices (modified from [10, 16, 17, 18]).
4.2.1 Endocardial system
the Watchman (Boston Scientific, Natick, MA)
This device has been approved by the Federal Drug Administration (FDA) in the year of 2015 as an alternative to warfarin OAC based upon data from the PREVAIL and PROTECT-AF trials. The device system comprises of a 14 Fr (outer diameter), frame with fixation barbs, and fabric cover [16].
the Amplatzer Cardiac Plug/ACP (St. Jude Medical, St. Paul, MN)
The Amulet is a second-generation self-expanded LAAO. The device system includes 14.4–16.5 Fr delivery sheath, lobe and stabilization hook, and fixed-size cover disk [16].
LAmbreTM LAA Closure System (Lifetech Scientific Corporation)
LAmbre occluder is a Conformité Européenne (CE) recognized LAA closure device. It is a self-expanded device consisting of a 10.4–12.3 Fr sheath (delivery system), hook-embedded umbrella, and size adaptive cover [19]. In 2020, LAmbreTM LAA Closure System has obtained the approval by FDA for the commencement of an investigator-initiated clinical trial in the United States.
4.2.2 Epicardial system
the LARIAT suture delivery system (SentreHeart, Redwood City, CA)
The LARIAT device is a percutaneous epicardial ligation of the LAA. The device comprises of a snare with a pre-tied suture for LAA ligation, a 15-mm compliant occlusion balloon catheter, magnet-tipped guidewires, and a 12-F suture delivery device.
5. Indications and current recommendation
Indication for LAAO occlusion procedure is similar to standard indication of OAC in patients with AF. The need of OAC is justified by stroke risk factors that are summarized in the clinical risk-factor-based on established CHA2DS2-VASc score [Congestive heart failure, Hypertension, Age, Diabetes mellitus, Stroke, Vascular disease, and Sex category (female)]. However, when initiation of OAC strategy, individual potential risk of bleeding also needs to be assessed (Table 1).
There are few absolute contraindications that potentially prevent some patients to have OAC as stroke prevention therapies. These include active major bleeding with unidentified and untreated source, comorbidities [e.g., severe anemia (Hb<80 g/L) or thrombocytopenia (<50 platelets/microliter)], or a high-risk bleeding episode such as intracranial hemorrhage. In such cases, non-drug options such as LAAO should be considered. Based on current existing guidelines, the recommendations of LAAO as stroke prevention option are:
5.1 Percutaneous approaches
Currently available recommendation for percutaneous LAAO is described in Table 2.
Non-modifiable
Potentially modifiable
Modifiable
Biomarkers
Age > 65 years
Previous major bleeding
Severe renal impairment (on dialysis or renal transplant)
Severe hepatic dysfunction (cirrhosis)
Malignancy
Genetic factors (e.g. CYP 2C9 polymorphisms)
Previous stroke, small-vessel disease, etc.
Diabetes mellitus
Cognitive impairment/dementia
Extreme frailty ± excessive risk of falls
Anemia
Reduced platelet count or function
Renal impairment with CrCl <60 mL/min
VKA management strategy
Hypertension/elevated SBP
Concomitant antiplatelet/NSAID
Excessive alcohol intake
Non-adherence to OAC
Hazardous hobbies/occupations
Bridging therapy with heparin
INR control (target 2.0–3.0), target TTR >70%c
Appropriate choice of OAC and
correct dosing
GDF-15
Cystatin C/CKD-EPI
cTnT-hs
von Willebrand factor
other coagulation markers
Table 1.
Risk factors for bleeding with OAC and antiplatelet therapy (ESC guidelines 2020) [1].
Surgical occlusion of the LAA may be considered in patients with AF undergoing cardiac surgery, as a component of an overall heart team approach to the management of AF
For patients with AF or atrial flutter who are undergoing valve surgery, LA appendage ligation/excision is reasonable to reduce the risk of thromboembolic events In patients undergoing LA surgical ablation of atrial arrhythmias and/or LA appendage ligation/excision, anticoagulation therapy is reasonable for at least 3 months after the procedure
For patients without atrial arrhythmias who are undergoing valvular surgery, LA appendage occlusion/exclusion/amputation is potentially harmful
Table 4.
Current recommendation for surgical LAAO.
ACC = American College of Cardiology; AF = atrial fibrillation; AHA = American Heart association; ESC = European Society of Cardiology; HRS = Heart Rhythm Society; LA = Left atrium; LAA = Left atrial appendage; NR = Non-randomized; NVAF = Non-valvular atrial fibrillation; VAF = Valvular atrial fibrillation.
6. Post-procedural management and complications of percutaneous LAAO
6.1 Acute procedural-related complications
Access-related complications
The most common complication for percutaneous LAA closure is the risk of having vascular complications, including bleeding or hematoma in the groin, arteriovenous fistula, pseudoaneurysm, or retroperitoneal bleed. Some of these complications may require further intervention or blood transfusion. These risks are slightly higher than other interventional procedure, especially due to large delivery sheath used, and the procedure is commonly performed under oral anticoagulation [21]. Furthermore, frailty or tortuosity in the vascular anatomy is also very common in elderly patients [22].
Transeptal access-related complications
There are few complications that can be related to transeptal access. Large delivery sheath for this procedure increases the risk of air embolism and subsequently increases the risk of stroke or myocardial infarction. In addition, transeptal puncture is also correlated with increased risk of pericardial effusion or tamponade that may require pericardiocentesis, with incidence of 1.39% [22, 23]. The risk of incidental aortic puncture from transeptal was also reported, which was closed by percutaneous approach with Amplatzer Septal Occluder [24].
Device embolization
Due to anatomical variability of LAA, the risk of embolization of LAAO is higher. The incidence of LAA device embolization ranges between 0% and 2%. Recent reports suggest that The Amplatzer family of devices carries a higher risk of embolization as compared with the Watchman device, with incidence of 0.78% (3,585 patients) vs. 0.26% (7,236 patients)]; p < 0.001) [25]. Device embolization can be located either in the LA, left ventricle (LV), or aorta (Ao). Although the majority cases can be managed in semi-elective manner, some can be life-threatening and need emergency procedure. Limited data of secondary adverse events related to LAA device embolization such as mitral or aortic valve damage, LV outflow tract obstruction, cardiogenic shock, or death have been described [26]. Percutaneous retrieval is preferable as compared with surgical approach. Identification of the location of the embolized device is crucial to determine the retrieval strategy. Successful retrieval using percutaneous snare has been reported [27]. However, several complications such as iatrogenic aortic rupture requiring endovascular repair may occur [28].
Other complication
Complications related to traumatic damage to surrounding structures (i.e., the circumflex coronary artery, pulmonary arteries, or pulmonary veins) have been previously described [29]. The NCDR registry showed that major complications, including in-hospital adverse events (2.16%), major bleeding (1.25%), were quite prevalent, whereas stroke (0.17%) and death (0.19%) were rare [23].
6.2 Long-term issues related to percutaneous LAAO
Iatrogenic atrial septal defects
Following transseptal LA access, iatrogenic atrial septal defects can be notable from either transthoracic or transesophageal echocardiogram. This complication can either disappear within 6 months after the procedure or persist in a small proportion of patients. Nevertheless, no hemodynamic consequences have been reported from this [30].
Peri-device leakage
The target of LAAO procedure is to get a complete closure of the LAA in order to lower the risk of thromboembolism in AF patients. In the early experience of LAAO, peri-device leakage was quite prevalent. The PROTECT-AF study showed that approximately 32% of patients still have residual leak at 1 year after procedure. However, this did not seem to increase the risk of thromboembolism [31]. Furthermore, the incidence of this outcome has markedly reduced in the more recent registries, which ranging from 0.2 to1% [23, 32].
Device-related thrombosis (DRT)
The main reasons of DRT remain unknown. It is postulated that the incidence of DRT is combination of either procedural factors (i.e., technique of implant or type of devices used), patient factors (i.e. patient frailty, LV dysfunction, or AF duration), or post-implant management factors (i.e., duration and type of antithrombotic therapies used) [33]. Few large studies of DRT for Watchman device such as the PROTECT AF, PREVAIL trials, CAP, and CAP2 evaluated procedural outcomes with TOE at 45 days and 12 months and at 6 months in the RCTs. Over 4 years of mean follow-up, it was demonstrated that the rate of DRT was 3.74%. The main characteristics of patients with DRT observed in this study are higher CHA2DS2VASc scores, permanent AF, and larger LAAs. The presence of DRT was also shown to be associated with a 3.55-fold increase rate of thromboembolic events [34].
7. Current evidence of short- and long-term outcomes after LAAO
The difficulties in managing patients with AF and high bleeding risk pursued a new approach of stroke prevention in AF patients. The first randomized study of LAAC with Watchman device, PROTECT AF [21], which was published in 2009, showed non-inferiority results as compared with standard warfarin therapy. This study randomized AF patients with a CHADS2 score ≥ 1, to either Watchman implantation or OAC with warfarin. At 1.5 years of follow-up, it is shown that LAAC was equivalent for stroke prevention or all-cause mortality. The efficacy of LAA occlusion was also demonstrated in a longer-term follow-up of PROTECT AF trial. At a mean follow-up of 2.3 years, the primary efficacy endpoint is shown to be non-inferior for device [35].
Similar results were shown by the second randomized trial, PREVAIL (Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation Versus Long-Term Warfarin Therapy) [36]. The PREVAIL trial has given additional information to PROTECT AF trial by a Bayesian non-inferiority design approach. The study showed that LAAO with the Watchman device was not non-inferior to warfarin for the primary efficacy composite endpoint, including all-cause stroke, cardiovascular or unexplained death, and serious events (SE). In addition, LAAO was non-inferior to warfarin for the occurrence of late ischemic events after the first 7 days following randomization. Furthermore, the safety endpoint and successful rate of LAAO are high, even in the center with high numbers of limited experience operators of LAAO implantation within a higher-risk patient population.
In a long-term 5-year outcomes report from the PREVAIL trial and PROTECT AF trial [37], it was demonstrated that LAAC with the Watchman device provides a similar degree of stroke prevention in non-valvular AF patients to OAC with warfarin. Furthermore, with its ability to minimize major bleeding, particularly hemorrhagic stroke. LAAC results in less death than Warfarin [37].
The more recent randomized prospective, multicenter, randomized noninferiority study, PRAGUE-17, compared two treatment strategies in moderate to high-risk AF patients (i.e., patients with history of significant bleeding or history of cardiovascular event(s) or a with CHA2DS2VASc ≥3 and HAS-BLED score ≥ 2) [38]. This study randomized 402 patients with AF into percutaneous LAAC versus NOAC. After median follow-up of 3.5 year, LAAC was shown to be non-inferior to DOACs for the primary endpoint and the components of the composite endpoint, such as cardiovascular death, all-stroke/transient ischemic attack, clinically relevant bleeding, and for nonprocedural clinically relevant bleeding [39].
8. Conclusion
LAA is an important anatomic area that is involved in thrombus formation in the left atrium, which is also a determinant in the risk of thromboembolic events in patients with AF. LAAO procedure provides an important alternative to pharmacological strategy in AF patients, especially for patients with stroke prevention indication and contraindicated or noncompliant to oral anticoagulation. It is evident that LAAO is safe and effective with high implant success rate and improving complication rate. Long-term data regarding in the stroke outcomes as compared with standard strategy are necessary.
\n',keywords:"atrial fibrillation, left atrial appendage closure, left atrial appendage device, ischemic stroke, oral anticoagulation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/82910.pdf",chapterXML:"https://mts.intechopen.com/source/xml/82910.xml",downloadPdfUrl:"/chapter/pdf-download/82910",previewPdfUrl:"/chapter/pdf-preview/82910",totalDownloads:1,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 20th 2022",dateReviewed:"June 8th 2022",datePrePublished:"August 9th 2022",datePublished:null,dateFinished:"August 2nd 2022",readingETA:"0",abstract:"Patients with non-valvular atrial fibrillation (NVAF) are at an increased risk of ischemic stroke due to the risks of thrombus formation. The left atrial appendage (LAA) is shown to be “the culprit” of thromboembolic events in NVAF and is currently a therapeutic target to prevent stroke. The absolute benefit of oral anticoagulation in the management of NVAF to improve cardiovascular outcomes has been well established. However, some patients are not good long-term candidates for oral anticoagulation for many reasons, including risks of bleeding, noncompliant to oral anticoagulation (OAC). Left atrial appendage occlusion (LAAO) provides an attractive alternative to reduce the risk of stroke for those who are contraindicated to OAC therapy.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/82910",risUrl:"/chapter/ris/82910",signatures:"Dian Andina Munawar, Anggia Chairuddin Lubis and Muhammad Munawar",book:{id:"11655",type:"book",title:"Atrial Fibrillation - Diagnosis and Management in the 21st Century",subtitle:null,fullTitle:"Atrial Fibrillation - Diagnosis and Management in the 21st Century",slug:null,publishedDate:null,bookSignature:"Prof. Ozgur Karcioglu and Associate Prof. Funda Karbek Akarca",coverURL:"https://cdn.intechopen.com/books/images_new/11655.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80356-123-3",printIsbn:"978-1-80356-122-6",pdfIsbn:"978-1-80356-124-0",isAvailableForWebshopOrdering:!0,editors:[{id:"221195",title:"Prof.",name:"Ozgur",middleName:null,surname:"Karcioglu",slug:"ozgur-karcioglu",fullName:"Ozgur Karcioglu"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Left atrial appendage anatomy",level:"1"},{id:"sec_3",title:"3. Rationale for LAAO",level:"1"},{id:"sec_4",title:"4. Techniques for LAAO",level:"1"},{id:"sec_4_2",title:"4.1 Surgical approach",level:"2"},{id:"sec_5_2",title:"4.2 Percutaneous LAAO device",level:"2"},{id:"sec_5_3",title:"4.2.1 Endocardial system",level:"3"},{id:"sec_6_3",title:"4.2.2 Epicardial system",level:"3"},{id:"sec_9",title:"5. Indications and current recommendation",level:"1"},{id:"sec_9_2",title:"5.1 Percutaneous approaches",level:"2"},{id:"sec_10_2",title:"5.2 Surgical approaches",level:"2"},{id:"sec_12",title:"6. Post-procedural management and complications of percutaneous LAAO",level:"1"},{id:"sec_12_2",title:"6.1 Acute procedural-related complications",level:"2"},{id:"sec_13_2",title:"6.2 Long-term issues related to percutaneous LAAO",level:"2"},{id:"sec_15",title:"7. Current evidence of short- and long-term outcomes after LAAO",level:"1"},{id:"sec_16",title:"8. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al. ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. European Heart Journal. 2020;42(5):373-498. DOI: 10.1093/eurheartj/ehaa612'},{id:"B2",body:'Johnson WD, Ganjoo AK, Stone CD, Srivyas RC, Howard M. The left atrial appendage: Our most lethal human attachment! Surgical implications. European Journal of Cardiothoracic Surgery. 2000;17(6):718-722. 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Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: A randomised non-inferiority trial. Lancet. 2009;374(9689):534-542'},{id:"B22",body:'Perrotta L, Bordignon S, Dugo D, et al. Complications from left atrial appendage exclusion devices. Journal of Atrial Fibrillation. 2014;7(1):1034-1034. DOI: 10.4022/jafib.1034'},{id:"B23",body:'Freeman JV, Varosy P, Price MJ, et al. The NCDR left atrial appendage occlusion registry. Journal of American College of Cardiology. 2020;75(13):1503-1518. DOI: 10.1016/j.jacc.2019.12.040'},{id:"B24",body:'Hartono, B., et al. “Amplatzer septal occluder sealed the complicating aortic root perforation during transseptal procedure.” JACC Cardiovasc Interv 2012;5(4):450-451'},{id:"B25",body:'Asmarats L, Rodes-Cabau J. Percutaneous left atrial appendage closure: Current devices and clinical outcomes. Circulation of Cardiovascular Intervention. 2017 Nov;10(11):e005359.'},{id:"B26",body:'Jazayeri MA, Vuddanda V, Turagam MK, et al. Safety profiles of percutaneous left atrial appendage closure devices: An analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database from 2009 to 2016. Journal of Cardiovascular Electrophysiology. 2018;29(1):5-13. DOI: 10.1111/jce.13362'},{id:"B27",body:'Lubis AC, Iqbal M, Munawar DA, Hartono B, Munawar M. A simple percutaneous retrieval technique for an embolized watchman left atrial appendage closure device in the thoracic aorta using a homemade snare. International Heart Journal. 2021;62(5):1153-1155'},{id:"B28",body:'Mastrangelo A, Galli S, Montorsi P, Bartorelli AL. Aortic rupture and hemorrhagic shock after percutaneous retrieval of an embolized left atrial appendage occluder. JACC Case Reports. 2022;4(8):486-490. DOI: 10.1016/j.jaccas.2022.03.004'},{id:"B29",body:'Sepahpour A, Ng MK, Storey P, McGuire MA. Death from pulmonary artery erosion complicating implantation of percutaneous left atrial appendage occlusion device. Heart Rhythm. 2013;10(12):1810-1811. DOI: 10.1016/j.hrthm.2013.07.046'},{id:"B30",body:'Onalan O, Crystal E. Left atrial appendage exclusion for stroke prevention in patients with nonrheumatic atrial fibrillation. Stroke. 2007;38(2 Suppl):624-630. DOI: 10.1161/01.Str.0000250166.06949.95'},{id:"B31",body:'Viles-Gonzalez JF, Kar S, Douglas P, et al. The clinical impact of incomplete left atrial appendage closure with the Watchman Device in patients with atrial fibrillation: A PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) substudy. Journal of American College of Cardiology. 2012;59(10):923-929. DOI: 10.1016/j.jacc.2011.11.028'},{id:"B32",body:'Boersma LV, Ince H, Kische S, et al. Evaluating Real-World Clinical Outcomes in Atrial Fibrillation Patients Receiving the WATCHMAN Left Atrial Appendage Closure Technology: Final 2-Year Outcome Data of the EWOLUTION Trial Focusing on History of Stroke and Hemorrhage. Circulation. Arrhythmia and Electrophysiology. 2019;12(4):e006841. DOI: 10.1161/circep.118.006841'},{id:"B33",body:'Alfadhel M, Nestelberger T, Samuel R, McAlister C, Saw J. Left atrial appendage closure – Current status and future directions. Progress in Cardiovascular Diseases. 2021;69:101-109. DOI: 10.1016/j.pcad.2021.11.013'},{id:"B34",body:'Dukkipati SR, Kar S, Holmes DR, et al. Device-related thrombus after left atrial appendage closure: Incidence, predictors, and outcomes. Circulation. 2018;138(9):874-885. DOI: 10.1161/CIRCULATIONAHA.118.035090'},{id:"B35",body:'Reddy VY, Doshi SK, Sievert H, et al. Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial. Circulation. 2013;127(6):720-729'},{id:"B36",body:'Holmes DR Jr, Kar S, Price MJ, et al. Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: The PREVAIL trial. Journal of American Colege of Cardiology. 2014;64(1):1-12. DOI: 10.1016/j.jacc.2014.04.029'},{id:"B37",body:'Reddy VY, Doshi SK, Kar S, et al. 5-year outcomes after left atrial appendage closure: From the PREVAIL and PROTECT AF Trials. Journal of American Colege of Cardiology. 2017;70(24):2964-2975'},{id:"B38",body:'Osmancik P, Tousek P, Herman D, et al. Interventional left atrial appendage closure vs novel anticoagulation agents in patients with atrial fibrillation indicated for long-term anticoagulation (PRAGUE-17 study). American Heart Journal. 2017;183:108-114. DOI: 10.1016/j.ahj.2016.10.003'},{id:"B39",body:'Osmancik P, Herman D, Neuzil P, et al. 4-year outcomes after left atrial appendage closure versus Nonwarfarin oral anticoagulation for atrial fibrillation. Journal of American Colege of Cardiology. 2022;79(1):1-14. DOI: 10.1016/j.jacc.2021.10.023'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Dian Andina Munawar",address:null,affiliation:'
Faculty of Medicine, Department of Cardiology and Vascular Medicine, Universitas Indonesia, Indonesia
Faculty of Medicine, Department of Cardiology and Vascular Medicine, Universitas Indonesia, Indonesia
Binawaluya Cardiac Centre, Indonesia
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All published Book Chapters are licensed under a Creative Commons Attribution 3.0 Unported License. Monographs are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others. Our Copyright Policy aims to guarantee that original material is published while at the same time giving significant freedom to our Authors. IntechOpen upholds a flexible Copyright Policy meaning that there is no copyright transfer to the publisher and Authors hold exclusive copyright to their work.
With the purpose of protecting our Authors' copyright and the transparent reuse of Open Access content, IntechOpen has developed an Attribution Policy for works published under Creative Commons licenses.
IntechOpen is committed to disseminating high-quality scientific research in a manner that exemplifies the best practice in scholarly publishing. IntechOpen is an official member of the Committee on Publication Ethics (COPE), which advocates the maintenance of the highest ethical standards for all parties involved in the act of publishing, including Authors, Academic Editors of the book, Peer Reviewers, the publisher and Societies, where applicable.
\\n\\n
Conflicts of Interest Policy
\\n\\n
In line with publication ethics practices recommended by COPE, ICMJE, and other similar organizations, IntechOpen's contributing Authors, Academic Editors, and Peer Reviewers are required to declare fully all possible conflicts of interest.
IntechOpen's Authorship Policy is based on ICMJE criteria for authorship. In order to be identified as an Author, the following requirements must be met:
\\n\\n
\\n\\t
A substantial contribution to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work
\\n\\t
Participation in drafting or revising the work
\\n\\t
Approval of the manuscript version to be published
All scientific works are subject to Peer Review prior to publishing. IntechOpen is a member of the Committee on Publication Ethics (COPE) and all participating referees and Academic Editors are expected to review submitted scientific works in line with the COPE Ethical Guidelines for Peer Reviewers where applicable.
The Internet has changed the dynamics of scholarly communication and publishing which is why we find it necessary to clearly indicate our stance on what we consider to be a published scientific work. A significant number of working papers, early drafts, and similar works in progress are shared openly online between members of the scientific community. It has become common practice for researchers to announce their work on a personal website or a blog in order to gather comments and suggestions from other researchers. Such works and online postings are ‘published’ in the sense that they are made publicly available, but this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
To identify instances of fraud and misconduct during the publishing process, IntechOpen implements a robust policy governing such occurrences. In line with our general commitment to openness, and in order to maintain the highest scientific standards, we are committed to transparency about our editorial policy regarding retractions and corrections.
When faced with potential misconduct, IntechOpen accepts its responsibility to maintain the integrity of the academic record. For particularly complex cases, IntechOpen might ask for the assistance of formal industry bodies or seek advice from an appropriate team of advisors.
\\n\\n
IntechOpen's advisors are professionals and scholars with broad knowledge and understanding of different aspects of the scientific publishing process: editorial, authorship, and reviewing roles; publication ethics, copyright, and general legal issues; as well as bibliographic and technical standards.
\\n\\n
In order to provide us with unbiased insights, without compromising the privacy of third parties, IntechOpen presents problematic cases to its advisors in an anonymized format.
\\n\\n
Translation Policy
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IntechOpen publishes books in the English language. If you are interested in the translation of Book Chapters, please check IntechOpen's Translation Policy.
In line with the Principles of Transparency and Best Practice in Scholarly Publishing, you can access a more detailed description of IntechOpen's Advertising Policy.
At IntechOpen we realize that exceptional circumstances can occur, resulting in a request for a refund. We will honor all justified requests in the specific instances outlined in our Refund Policy.
All chapters will be published via IntechOpen's 'Online First' service meaning chapters will be published individually, immediately after review and before the entire book is ready for publication, allowing content to be shared, searched and cited straightaway, thereby generating early stage interest and momentum for your research
\\n\\n
Online First Chapters are considered published on the day they are posted and are citable from that date.
\\n\\n
Chapters will remain listed as Online First until the final versions of the books are published online. Following publication of the full monograph, Chapters will be redirected from the Online First version and will be available only through the final link of the official published page.
\\n\\n
You are invited to download, use, reproduce, make derivative works of, display, distribute and cite the Online First works. You can find "How to Cite and Reference" by following the link at the end of each online book chapter. Please be aware that it is possible that further editing and changes might be made before the final release of the book.
\\n\\n
If there are supplemental materials to the chapter, these will be published at the time the final book is published online.
\\n\\n
Readers and Authors can notify us if they find any errors in the works published under Online First. All major errors will be accompanied by a separate correction notice, erratum or corrigendum (Retraction and Correction Policy.)
\\n\\n
Access policy
\\n\\n
IntechOpen books are available online by accessing all published content on a chapter level.
All published Book Chapters are licensed under a Creative Commons Attribution 3.0 Unported License. Monographs are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others. Our Copyright Policy aims to guarantee that original material is published while at the same time giving significant freedom to our Authors. IntechOpen upholds a flexible Copyright Policy meaning that there is no copyright transfer to the publisher and Authors hold exclusive copyright to their work.
With the purpose of protecting our Authors' copyright and the transparent reuse of Open Access content, IntechOpen has developed an Attribution Policy for works published under Creative Commons licenses.
IntechOpen is committed to disseminating high-quality scientific research in a manner that exemplifies the best practice in scholarly publishing. IntechOpen is an official member of the Committee on Publication Ethics (COPE), which advocates the maintenance of the highest ethical standards for all parties involved in the act of publishing, including Authors, Academic Editors of the book, Peer Reviewers, the publisher and Societies, where applicable.
\n\n
Conflicts of Interest Policy
\n\n
In line with publication ethics practices recommended by COPE, ICMJE, and other similar organizations, IntechOpen's contributing Authors, Academic Editors, and Peer Reviewers are required to declare fully all possible conflicts of interest.
IntechOpen's Authorship Policy is based on ICMJE criteria for authorship. In order to be identified as an Author, the following requirements must be met:
\n\n
\n\t
A substantial contribution to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work
\n\t
Participation in drafting or revising the work
\n\t
Approval of the manuscript version to be published
All scientific works are subject to Peer Review prior to publishing. IntechOpen is a member of the Committee on Publication Ethics (COPE) and all participating referees and Academic Editors are expected to review submitted scientific works in line with the COPE Ethical Guidelines for Peer Reviewers where applicable.
The Internet has changed the dynamics of scholarly communication and publishing which is why we find it necessary to clearly indicate our stance on what we consider to be a published scientific work. A significant number of working papers, early drafts, and similar works in progress are shared openly online between members of the scientific community. It has become common practice for researchers to announce their work on a personal website or a blog in order to gather comments and suggestions from other researchers. Such works and online postings are ‘published’ in the sense that they are made publicly available, but this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
To identify instances of fraud and misconduct during the publishing process, IntechOpen implements a robust policy governing such occurrences. In line with our general commitment to openness, and in order to maintain the highest scientific standards, we are committed to transparency about our editorial policy regarding retractions and corrections.
When faced with potential misconduct, IntechOpen accepts its responsibility to maintain the integrity of the academic record. For particularly complex cases, IntechOpen might ask for the assistance of formal industry bodies or seek advice from an appropriate team of advisors.
\n\n
IntechOpen's advisors are professionals and scholars with broad knowledge and understanding of different aspects of the scientific publishing process: editorial, authorship, and reviewing roles; publication ethics, copyright, and general legal issues; as well as bibliographic and technical standards.
\n\n
In order to provide us with unbiased insights, without compromising the privacy of third parties, IntechOpen presents problematic cases to its advisors in an anonymized format.
\n\n
Translation Policy
\n\n
IntechOpen publishes books in the English language. If you are interested in the translation of Book Chapters, please check IntechOpen's Translation Policy.
In line with the Principles of Transparency and Best Practice in Scholarly Publishing, you can access a more detailed description of IntechOpen's Advertising Policy.
At IntechOpen we realize that exceptional circumstances can occur, resulting in a request for a refund. We will honor all justified requests in the specific instances outlined in our Refund Policy.
All chapters will be published via IntechOpen's 'Online First' service meaning chapters will be published individually, immediately after review and before the entire book is ready for publication, allowing content to be shared, searched and cited straightaway, thereby generating early stage interest and momentum for your research
\n\n
Online First Chapters are considered published on the day they are posted and are citable from that date.
\n\n
Chapters will remain listed as Online First until the final versions of the books are published online. Following publication of the full monograph, Chapters will be redirected from the Online First version and will be available only through the final link of the official published page.
\n\n
You are invited to download, use, reproduce, make derivative works of, display, distribute and cite the Online First works. You can find "How to Cite and Reference" by following the link at the end of each online book chapter. Please be aware that it is possible that further editing and changes might be made before the final release of the book.
\n\n
If there are supplemental materials to the chapter, these will be published at the time the final book is published online.
\n\n
Readers and Authors can notify us if they find any errors in the works published under Online First. All major errors will be accompanied by a separate correction notice, erratum or corrigendum (Retraction and Correction Policy.)
\n\n
Access policy
\n\n
IntechOpen books are available online by accessing all published content on a chapter level.
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The literature source was Web of Science and SSCI, SCI-EXPANDED, A&HCI, CPCI-S, CPCI-SSH, and ESCI indexes. Fifty-two articles were reviewed; however, 14 of them were not been included in the study. As a result, 38 articles were examined. Level of education, field of education, and material types of AR used in education and reported educational advantages of AR have been investigated. All articles are categorized according to target groups, which are early childhood education, primary education, secondary education, high school education, graduate education, and others. AR technology has been mostly carried out in primary and graduate education. “Science education” is the most explored field of education. Mobile applications and marker-based materials on paper have been mostly preferred. The major advantages indicated in the articles are “Learning/Academic Achievement,” “Motivation,” and “Attitude”.",book:{id:"6543",slug:"state-of-the-art-virtual-reality-and-augmented-reality-knowhow",title:"State of the Art Virtual Reality and Augmented Reality Knowhow",fullTitle:"State of the Art Virtual Reality and Augmented Reality Knowhow"},signatures:"Rabia M. Yilmaz",authors:[{id:"225838",title:"Dr.",name:"Rabia",middleName:null,surname:"Yilmaz",slug:"rabia-yilmaz",fullName:"Rabia Yilmaz"}]},{id:"63639",doi:"10.5772/intechopen.81086",title:"Cooperative Learning: The Foundation for Active Learning",slug:"cooperative-learning-the-foundation-for-active-learning",totalDownloads:3475,totalCrossrefCites:18,totalDimensionsCites:24,abstract:"The role of instructors is evolving from the presenter of information to the designer of active learning processes, environments, and experiences that maximize student engagement. The more active a lesson, the more students tend to engage intellectually and emotionally in the learning activities. Cooperative learning is the foundation on which many of the active learning procedures are based. Cooperative learning is the instructional use of small groups so that students work together to maximize their own and each other’s learning. Most of the active learning procedures, such as problem-based learning, team-learning, collaborative learning, and PALS, require that students work cooperatively in small groups to achieve joint learning goals. Cooperative learning is based on two theories: Structure-Process-Outcome theory and Social Interdependence theory. Four types of cooperative learning have been derived: formal cooperative learning, informal cooperative learning, cooperative base groups, and constructive controversy. There is considerable research confirming the effectiveness of cooperative learning. To be cooperative, however, five basic elements must be structured into the situation: positive interdependence, individual accountability, promotive interaction, social skills, and group processing.",book:{id:"6929",slug:"active-learning-beyond-the-future",title:"Active Learning",fullTitle:"Active Learning - Beyond the Future"},signatures:"David W. Johnson and Roger T. Johnson",authors:[{id:"259976",title:"Dr.",name:"David",middleName:null,surname:"Johnson",slug:"david-johnson",fullName:"David Johnson"},{id:"263004",title:"Dr.",name:"Roger",middleName:null,surname:"Johnson",slug:"roger-johnson",fullName:"Roger Johnson"}]},{id:"58060",doi:"10.5772/intechopen.72341",title:"Pedagogy of the Twenty-First Century: Innovative Teaching Methods",slug:"pedagogy-of-the-twenty-first-century-innovative-teaching-methods",totalDownloads:8826,totalCrossrefCites:17,totalDimensionsCites:22,abstract:"In the twenty-first century, significant changes are occurring related to new scientific discoveries, informatization, globalization, the development of astronautics, robotics, and artificial intelligence. This century is called the age of digital technologies and knowledge. How is the school changing in the new century? How does learning theory change? Currently, you can hear a lot of criticism that the classroom has not changed significantly compared to the last century or even like two centuries ago. Do the teachers succeed in modern changes? The purpose of the chapter is to summarize the current changes in didactics for the use of innovative teaching methods and study the understanding of changes by teachers. In this chapter, we consider four areas: the expansion of the subject of pedagogy, environmental approach to teaching, the digital generation and the changes taking place, and innovation in teaching. The theory of education, figuratively speaking, has two levels. At the macro-level, in the “education-society” relationship, decentralization and diversification, internationalization of education, and the introduction of digital technologies occur. At the micro-level in the “teacher-learner” relationship, there is an active mix of traditional and innovative methods, combination of an activity approach with an energy-informational environment approach, cognition with constructivism and connectivism.",book:{id:"5980",slug:"new-pedagogical-challenges-in-the-21st-century-contributions-of-research-in-education",title:"New Pedagogical Challenges in the 21st Century",fullTitle:"New Pedagogical Challenges in the 21st Century - Contributions of Research in Education"},signatures:"Aigerim Mynbayeva, Zukhra Sadvakassova and Bakhytkul\nAkshalova",authors:[{id:"201997",title:"Dr.",name:"Aigerim",middleName:null,surname:"Mynbayeva",slug:"aigerim-mynbayeva",fullName:"Aigerim Mynbayeva"},{id:"209208",title:"Dr.",name:"Zukhra",middleName:null,surname:"Sadvakassova",slug:"zukhra-sadvakassova",fullName:"Zukhra Sadvakassova"},{id:"209210",title:"Dr.",name:"Bakhytkul",middleName:null,surname:"Akshalova",slug:"bakhytkul-akshalova",fullName:"Bakhytkul Akshalova"}]},{id:"59468",doi:"10.5772/intechopen.74344",title:"Virtual and Augmented Reality: New Frontiers for Clinical Psychology",slug:"virtual-and-augmented-reality-new-frontiers-for-clinical-psychology",totalDownloads:2359,totalCrossrefCites:13,totalDimensionsCites:21,abstract:"In the last decades, the applied approach for the use of virtual reality (VR) and augmented reality (AR) on clinical and health psychology has grown exponentially. These technologies have been used to treat several mental disorders, for example, phobias, stress-related disorders, depression, eating disorders, and chronic pain. The importance of VR/AR for the mental health field comes from three main concepts: (1) VR/AR as an imaginal technology, people can feel “as if they are” in a reality that does not exist in external world; (2) VR/AR as an embodied technology, the experience to feel user’s body inside the virtual environment; and (3) VR/AR as connectivity technology, the “end of geography’. In this chapter, we explore the opportunities provided by VR/AR as technologies to improve people’s quality of life and to discuss new frontiers for their application in mental health and psychological well-being promotion.",book:{id:"6543",slug:"state-of-the-art-virtual-reality-and-augmented-reality-knowhow",title:"State of the Art Virtual Reality and Augmented Reality Knowhow",fullTitle:"State of the Art Virtual Reality and Augmented Reality Knowhow"},signatures:"Sara Ventura, Rosa M. Baños and Cristina Botella",authors:[{id:"106036",title:"Dr.",name:"Rosa Maria",middleName:null,surname:"Baños",slug:"rosa-maria-banos",fullName:"Rosa Maria Baños"},{id:"227763",title:"Ph.D.",name:"Sara",middleName:null,surname:"Ventura",slug:"sara-ventura",fullName:"Sara Ventura"},{id:"229056",title:"Dr.",name:"Cristina",middleName:null,surname:"Botella",slug:"cristina-botella",fullName:"Cristina Botella"}]},{id:"64583",doi:"10.5772/intechopen.81714",title:"Evaluating a Course for Teaching Advanced Programming Concepts with Scratch to Preservice Kindergarten Teachers: A Case Study in Greece",slug:"evaluating-a-course-for-teaching-advanced-programming-concepts-with-scratch-to-preservice-kindergart",totalDownloads:1419,totalCrossrefCites:13,totalDimensionsCites:18,abstract:"Coding is a new literacy for the twenty-first century, and as a literacy, coding enables new ways of thinking and new ways of communicating and expressing ideas, as well as new ways of civic participation. A growing number of countries, in Europe and beyond, have established clear policies and frameworks for introducing computational thinking (CT) and computer programming to young children. In this chapter, we discuss a game-based approach to coding education for preservice kindergarten teachers using Scratch. The aim of using Scratch was to excite students’ interest and familiarize them with the basics of programming in an open-ended, project-based, and personally meaningful environment for a semester course in the Department of Preschool Education in the University of Crete. For 13 weeks, students were introduced to the main Scratch concepts and, afterward, were asked to prepare their projects. For the projects, they were required to design their own interactive stories to teach certain concepts about mathematics or physical science to preschool-age students. The results we obtained were more satisfactory than expected and, in some regards, encouraging if one considers the fact that the research participants had no prior experiences with computational thinking.",book:{id:"6936",slug:"early-childhood-education",title:"Early Childhood Education",fullTitle:"Early Childhood Education"},signatures:"Stamatios Papadakis and Michail Kalogiannakis",authors:null}],mostDownloadedChaptersLast30Days:[{id:"58060",title:"Pedagogy of the Twenty-First Century: Innovative Teaching Methods",slug:"pedagogy-of-the-twenty-first-century-innovative-teaching-methods",totalDownloads:8832,totalCrossrefCites:17,totalDimensionsCites:23,abstract:"In the twenty-first century, significant changes are occurring related to new scientific discoveries, informatization, globalization, the development of astronautics, robotics, and artificial intelligence. This century is called the age of digital technologies and knowledge. How is the school changing in the new century? How does learning theory change? Currently, you can hear a lot of criticism that the classroom has not changed significantly compared to the last century or even like two centuries ago. Do the teachers succeed in modern changes? The purpose of the chapter is to summarize the current changes in didactics for the use of innovative teaching methods and study the understanding of changes by teachers. In this chapter, we consider four areas: the expansion of the subject of pedagogy, environmental approach to teaching, the digital generation and the changes taking place, and innovation in teaching. The theory of education, figuratively speaking, has two levels. At the macro-level, in the “education-society” relationship, decentralization and diversification, internationalization of education, and the introduction of digital technologies occur. At the micro-level in the “teacher-learner” relationship, there is an active mix of traditional and innovative methods, combination of an activity approach with an energy-informational environment approach, cognition with constructivism and connectivism.",book:{id:"5980",slug:"new-pedagogical-challenges-in-the-21st-century-contributions-of-research-in-education",title:"New Pedagogical Challenges in the 21st Century",fullTitle:"New Pedagogical Challenges in the 21st Century - Contributions of Research in Education"},signatures:"Aigerim Mynbayeva, Zukhra Sadvakassova and Bakhytkul\nAkshalova",authors:[{id:"201997",title:"Dr.",name:"Aigerim",middleName:null,surname:"Mynbayeva",slug:"aigerim-mynbayeva",fullName:"Aigerim Mynbayeva"},{id:"209208",title:"Dr.",name:"Zukhra",middleName:null,surname:"Sadvakassova",slug:"zukhra-sadvakassova",fullName:"Zukhra Sadvakassova"},{id:"209210",title:"Dr.",name:"Bakhytkul",middleName:null,surname:"Akshalova",slug:"bakhytkul-akshalova",fullName:"Bakhytkul Akshalova"}]},{id:"61746",title:"Facilitation of Teachers’ Professional Development through Principals’ Instructional Supervision and Teachers’ Knowledge- Management Behaviors",slug:"facilitation-of-teachers-professional-development-through-principals-instructional-supervision-and-t",totalDownloads:3384,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"With the rise of global competition and the focus on teacher quality, teacher professional development is becoming increasingly crucial, and the stress and challenges for principals are more severe than ever. Teachers can improve their professional abilities through principals’ instructional supervision and their own knowledge-management (KM) behaviors to benefit students. Thus, this chapter analyzes the relationship among principals’ instructional supervision, teachers’ KM, and teachers’ professional development. The author believes that principals’ instructional supervision and effective KM can facilitate the professional development of teachers. The author also believes the readers can know the relationships among them, and teachers’ professional development can be improved through principal’s instructional supervision and teachers’ KM behaviors.",book:{id:"6674",slug:"contemporary-pedagogies-in-teacher-education-and-development",title:"Contemporary Pedagogies in Teacher Education and Development",fullTitle:"Contemporary Pedagogies in Teacher Education and Development"},signatures:"Chien-Chin Chen",authors:[{id:"232569",title:"Ph.D.",name:"Chien Chih",middleName:null,surname:"Chen",slug:"chien-chih-chen",fullName:"Chien Chih Chen"}]},{id:"75908",title:"From the Classroom into Virtual Learning Environments: Essential Knowledge, Competences, Skills and Pedagogical Strategies for the 21st Century Teacher Education in Kenya",slug:"from-the-classroom-into-virtual-learning-environments-essential-knowledge-competences-skills-and-ped",totalDownloads:519,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"As teachers in Kenya begin to migrate from the classroom to virtual learning spaces following COVID 19 pandemic, there is pressing need to realign Teacher Education to requisite Knowledge, competences, skills, and attitudes that will support online teaching. This chapter explores these needs using a combination of lived experiences and literature review that captured a meta-analysis of research trends on e-learning. While trends in Teacher Education indicate progression towards adoption of technology, there are disparities between the theory and practice. Evidence from recent research and reports; and the recollected experiences confirmed knowledge, competence, skills and pedagogical gaps in the implementation of online learning, that have been exacerbated by COVID-19. The researcher recommends that teacher education should sensitize and train teacher trainees on how to access, analyze and use new knowledge emerging with technology; they also should be coached on how learners learn with technology and on fundamentals of the communication process. Particularly the course on educational technology, should focus on how to create and manage online courses. The 5-stage E-Moderator Model and Universal Design for Learning (UDL) are recommended as effective pedagogical scaffold for online teaching.",book:{id:"10229",slug:"teacher-education-in-the-21st-century-emerging-skills-for-a-changing-world",title:"Teacher Education in the 21st Century",fullTitle:"Teacher Education in the 21st Century - Emerging Skills for a Changing World"},signatures:"Catherine Adhiambo Amimo",authors:[{id:"333482",title:"Dr.",name:"Catherine Adhiambo",middleName:null,surname:"Amimo",slug:"catherine-adhiambo-amimo",fullName:"Catherine Adhiambo Amimo"}]},{id:"75224",title:"Decoding the Digital Gap in Teacher Education: Three Perspectives across the Globe",slug:"decoding-the-digital-gap-in-teacher-education-three-perspectives-across-the-globe",totalDownloads:589,totalCrossrefCites:0,totalDimensionsCites:4,abstract:"Educational use of technology is regularly assessed, and results often show a gap between educational policies and what is actually practiced. This chapter will help clarify how teacher educators experience the changing educational contexts due to the digital revolution, how their meaning-making shifts, and how outside forces influence those processes. The results are based on comparative international studies. Central for this study is practitioners’ professional digital competence, their attitudes towards digital technology and the use of digital technology in education. We found that the influence and contribution of digital practice is carried out quite differently across the globe. Our research questions were: How do practitioners experience teaching in a rapidly changing context? How do attitudes change due to top-down governing of education? and What motivates teacher educators to implement digital technology?",book:{id:"10229",slug:"teacher-education-in-the-21st-century-emerging-skills-for-a-changing-world",title:"Teacher Education in the 21st Century",fullTitle:"Teacher Education in the 21st Century - Emerging Skills for a Changing World"},signatures:"Steinar Thorvaldsen and Siri Sollied Madsen",authors:[{id:"332624",title:"Associate Prof.",name:"Siri Sollied",middleName:null,surname:"Madsen",slug:"siri-sollied-madsen",fullName:"Siri Sollied Madsen"},{id:"332626",title:"Prof.",name:"Steinar",middleName:null,surname:"Thorvaldsen",slug:"steinar-thorvaldsen",fullName:"Steinar Thorvaldsen"}]},{id:"75416",title:"Self-Study Research: Challenges and Opportunities in Teacher Education",slug:"self-study-research-challenges-and-opportunities-in-teacher-education",totalDownloads:777,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This article aims to describe what self-study research is, why self-study can be a good approach to teacher educators’ professional development and improvements in practice and highlight some challenges and opportunities in this research approach. In addition, the article will shed light on some methodological aspects related to self-study. Self-study refers to teacher educators who in an intentionally and systematically way examine their practice to improve it, based on a deeper understanding of practice, as well as the context practice takes place. 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She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\r\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\r\nHer topics of interest are biomaterials science and cell culture studies. 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Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Orthodontist, Assoc Prof in the Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"344229",title:"Dr.",name:"Sankeshan",middleName:null,surname:"Padayachee",slug:"sankeshan-padayachee",fullName:"Sankeshan Padayachee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"315727",title:"Ms.",name:"Kelebogile A.",middleName:null,surname:"Mothupi",slug:"kelebogile-a.-mothupi",fullName:"Kelebogile A. 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