Clinical risk score for tumor recurrence proposed by Fong et al. [31].
\r\n\tFurther development of geophysical methods in the direction of constructing more and more adequate models of media and phenomena necessarily leads to more and more complex problems of mathematical geophysics, for which not only inverse, but also direct problems become significantly incorrect. In this regard, it is necessary to develop a new concept of regularization for simultaneously solving a system of heterogeneous operator equations.
\r\n\r\n\tCurrently, the study of processes associated not only with geophysics and astrophysics but also with biology and medicine requires even more complication of interpretation models from non-linear and heterogeneous to hierarchical. This book will be devoted to the creation of new mathematical theories for solving ill-posed problems for complicated models.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"d93195bb64405dd9e917801649f991b3",bookSignature:"Prof. Olga Alexandrovna Hachay",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8253.jpg",keywords:"Ill-Posed, Inverse Problems, Geophysics, Seismic, Electromagnetic, Thermal, Magnetic, Medicine, \r\nMathematical, Algorithms, Hierarchical, Nonlinear, Historical Description, Regularization",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 7th 2019",dateEndSecondStepPublish:"March 27th 2020",dateEndThirdStepPublish:"May 26th 2020",dateEndFourthStepPublish:"August 14th 2020",dateEndFifthStepPublish:"October 13th 2020",remainingDaysToSecondStep:"10 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"150801",title:"Prof.",name:"Olga",middleName:"Alexandrovna",surname:"Hachay",slug:"olga-hachay",fullName:"Olga Hachay",profilePictureURL:"https://mts.intechopen.com/storage/users/150801/images/system/150801.jpg",biography:"Dr. Olga A. Hachay graduated with a degree in Astrophysics from Ural State University in 1969. She obtained her PhD from the Pushkov Institute of Terrestrial Magnetism, Ionosphere and Radiowave Propagation of the Russian Academy of Sciences (IZMIRAN) in 1979 with her thesis “The inverse problem for electromagnetic research of one-dimensional medium.”\nSince 1969, she has been a scientific member of the Institute of Geophysics Ural Branch of Russian Academy of Sciences (UB RAS), Ekaterinburg, Russia. From 1995 to 2004, she served as chief of the group of seismic and electromagnetic research. Her research interests include developing new methods for searching the structure and the state of the Earth’s upper crust, as well as elaborating a new theory of interpretation of electromagnetic and seismic fields. From 2002, she has been the main scientific researcher of the Institute of geophysics UB RAS. Since 2008, she has been a lead scientific researcher for UB RAS in the laboratory of borehole geophysics. Dr. Hachay is a member of various organizations and societies, including the American Mathematical Society, Mathematical Association of America, International Association of Geomechanics, and the European Geosciences Union, among others. \nDr. Hachay is fluent in Russian, English and German language",institutionString:"Ural Branch of the Russian Academy of Sciences",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Ural Branch of the Russian Academy of Sciences",institutionURL:null,country:{name:"Russia"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"15",title:"Mathematics",slug:"mathematics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247865",firstName:"Jasna",lastName:"Bozic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247865/images/7225_n.jpg",email:"jasna.b@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"64018",title:"Colorectal Liver Metastases",doi:"10.5772/intechopen.80558",slug:"colorectal-liver-metastases",body:'\nThe adenocarcinoma of the colon and rectum (CRC) affect more than 1.3 million patients each year, being the third most common malignancy in the world [1]. Approximately, 30–50% of these patients will present with liver metastasis at the time of diagnosis or will develop metastasis later [2, 3].
\nDue to the fact that venous drainage of the intestinal tract is via the portal system, the first site of hematogenous spreading is usually the liver. The most common site of metastatic CRC is the liver, occurring in 80% of cases, representing nearly half of all patients with CRC. It is also the single site of metastasis in 20–50% of the cases [2]. The majority of metastatic CRC liver disease will be potentially resectable at the time of diagnosis, approximately 75–80% of cases [3]. Recurrence after resection of the primary lesion depends on the stage. The overall recurrence rate ranges from 9% in stage 1–56% in stage 3 CRC tumors [3].
\nA majority of CRC metastases (mCRC) occurs within the first 3 years. The incidence of mCRC is approximately 4.3% at 1 year, 8.7% at 2 years, 12% at 3 years, and 16.5% at 5 years after resection [2]. The frequency of metachronous CRC metastases is highly variable in the literature, arising from database differences and diversity of definitions. Metachronous CRC metastases are restricted to the liver in 44% of patients with distant recurrence following potentially curative resection of the primary lesion. In prospective and retrospective studies of referral centers, this rate reaches 35% [4]. In prospective observational studies and population studies, this frequency is lower, ranging from 5.7 to 16.3% [5]. In population studies, the frequency of synchronous liver metastases from CRC varies from 14.5 to 24% [2]. Patients presenting with stage 4 disease at the time of the diagnosis will have liver-confined metastases (synchronous metastases) in 77% of the cases [6].
\nRecently, the clinical outcome for patients with mCRC has improved. Nowadays, the median overall survival (OS) for patients with mCRC is approximately 30 months, more than twice of that observed 20 years ago [7]. It is not clear which improvements and/or strategic changes in the treatment and management of patients with mCRC in recent years have been responsible for the improved treatment outcomes for these patients. Some changes that might have contributed for this gain in OS are (i) changes in the clinical presentation of patients, before the commencement of treatment, due to closer follow-up after resection of the primary tumor and earlier detection of metastatic disease; (ii) improvements in the efficacy of systemic therapies in terms of regimens used, sequence of administration, number of lines of therapy administered, and biomarker-based patient selection; (iii) an increase in the number of patients being treated with a view to facilitating resection of their metastases, offering an increased number of patients the chance of cure and/or durable relapse-free survival and, more recently, the utilization of other ablative therapy techniques with the aim of achieving the same outcome; and (iv) implementation of “continuum of care” treatment strategies coupled with the early integration of optimal supportive care measures [7].
\nThe best treatment strategies for patients with mCRC are evolving rapidly. Superior clinical outcomes are reached when the treatment approaches for individual patients are discussed within a multidisciplinary team (MDT) of experts, meeting regularly as a tumor board to review mCRC cases [8]. The responsibility of the MDT is to define the initial diagnostic workup and then the treatment focus, based on the best diagnostic and therapeutic decision-making available. Initially, the MDT member should critically define whether or not a patient has clearly resectable or initially unresectable metastatic disease. Contrariwise, for patients whose disease is believed “never to be resectable,” the discussion may be left to the treating medical oncologist (after discussion with the MDT) and patient as to the pros and cons of various approaches and sequences based on the perceived aims (e.g., duration of disease control versus quality of life and toxicity profiles, etc.) [7].
\nThe preferred method for the diagnosis of extrahepatic disease is computed tomography (CT) [9, 10, 11]. It is the method of choice for staging and follow-up of patients with colorectal cancer, as imaging methods are widespread in our environment, familiar to oncologists, radiologists, and surgeons, with good cost/benefit. Therefore, the use of CT is recommended as the initial method in the diagnosis of extrahepatic metastases.
\nMagnetic resonance imaging (MRI) is the most accurate imaging technique for the detection and characterization of focal liver lesions. However, costs are higher and it has restricted availability. Other limitations include magnetic field exposure and gadolinium use restrictions in patients with renal insufficiency. Retrospective and meta-analyses have shown that MRI has a superior sensitivity to TC both in analysis per patient (81.1–88.2% vs. 74.8–83.6%) and in analysis per lesion (80.3–86.3% vs. 74.4–82.6%); such superiority is related to higher detection of lesions smaller than 1 cm [12, 13]. MRI with hepatobiliary contrast has demonstrated to have greater accuracy than FDG-PET/CT in detection of small liver metastases (92 vs. 60%) [14]. In a multicenter randomized prospective study, the performance of MRI with hepatobiliary contrast was superior to CT with iodinated contrast and MRI with extracellular gadolinium as first-line method in the initial evaluation of liver mCRC [14].
\nPET/CT have shown to be of great value in the evaluation of extrahepatic sites of metastases undetected by other methods in patients eligible for surgical resection of liver mCRC, altering the therapeutic plan [15, 16].
\nSince cross-sectional imaging modalities have improved sensitivity of the diagnosis of mCRC, diagnostic laparoscopy is no longer standard for evaluating patients with mCRC. Instead, it is only used in patients with a suspicion of small-volume carcinomatosis on radiographic imaging studies or who are at particularly high risk for harboring unresectable diseases [17].
\nThe pathologic stage at presentation is the most important indicator of outcome after treatment in general, followed by the presence of extramural tumor deposits, lymphovascular and perineural invasion, histologic grade of differentiation, the preoperative level of serum carcinoembryonic antigen (CEA), microsatellite instability (MSI), and RAS and BRAF mutations [18, 19].
\nMicrosatellite instability (MSI) status or mismatch repair deficiency (MMR-D) has been the biomarker for adjuvant 5-FU monotherapy and immune checkpoint inhibitor. Hematogenous and lymphogenous metastasis-dominant CRC with high-frequency MSI (MSI-H) are reported to have poor prognosis. However, the validity as the prognostic factor of MMR is still to be confirmed, and it should thus be used cautiously [20, 21].
\nOn the other hand, it is also known that RAS and BRAF mutations are of prognostic and predictive value in mCRC [21]. The pathogenesis of CRC involves the accumulation of genetic and epigenetic modifications within pathways that regulate proliferation, apoptosis, and angiogenesis.
\nKRAS mutations involving either codon 12 or 13 can be identified in 12–75% of tumors, and they have been individually correlated with a worse prognosis in most studies [22]. BRAF V600E mutations are present in 8–10% of patients, are consistently associated with poor prognosis, and result in possible patient ineligibility for resection of mCRC [23]. Recently, a small single-center cohort study showed that 21 of 52 patients with BRAF V600E mutant who underwent metastasectomy had longer OS (29.1 vs. 22.7 months) and progression-free survival (13.6 vs. 6.2 months) than the non-metastasectomy cohort. The authors concluded that multimodality therapy incorporating metastasectomy for BRAF V600E metastatic CRC should be considered and might be associated with improved OS in selected patients [24]. Meanwhile, BRAF V600E can be a biomarker for selecting the appropriate chemotherapy regimen [21].
\nAnother feature that also appears to affect the prognosis of patients who develop liver metastases is the embryonic origin of the primary colon cancer. In an analysis of 727 patients who were submitted to chemotherapy followed by resection, mCRC from midgut origin (right colon tumors) was associated with worse pathologic response to chemotherapy and worse survival after resection than mCRC from hindgut origin (left/sigmoid colon tumors) [25]. This effect was independent of the RAS mutation status. Primary tumor from right-sided colon might be more prone to recur. Therefore, palliative resection might not be done since these patients showed no benefit from resection [26].
\nThe treatment approach for patients with colorectal liver metastases should be focused toward complete resection whenever possible, with both “oncological” (prognostic) and “technical” (surgical) criteria being considered when evaluating patients for surgery [27, 28].
\nThe “technical” definitions of resectable mCRC have evolved over time, with the current consensus proposing that disease should be considered technically resectable as long as complete macroscopic resection is feasible while maintaining at least a 30% future liver remnant (FLR) or a remnant liver to body weight ratio >0.5 (e.g., >350 g of the liver per 70 kg patient) [29]. Nevertheless, not all patients with technically resectable liver-limited metastases benefit from surgery; approximately half of the patients submitted to resection of mCRC will present widespread systemic disease within 3 years of the resection [30].
\nPrognostic information that predicts a longer disease-free survival (DFS) or a higher probability of cure is provided by the “oncological” criteria. Strong parameters for the oncological criteria are the number of lesions; the presence, or suspicion, of extrahepatic disease; and numerous other criteria used in retrospective studies. Fong et al. proposed a score based on the following parameters: nodal status of primary tumor, disease-free interval from the primary to discovery of the liver metastases of <12 months, number of tumors >1, preoperative CEA level >200 ng/ml, and size of the largest tumor >5 cm (Table 1) [31]. Thus, for some patients, neoadjuvant chemotherapy may be a better option than upfront surgery.
\nSurvival (%) | \n||||||
---|---|---|---|---|---|---|
Score | \n1 year | \n2 year | \n3 year | \n4 year | \n5 year | \nMedian (mo) | \n
0 | \n93 | \n79 | \n72 | \n60 | \n60 | \n74 | \n
1 | \n91 | \n76 | \n66 | \n54 | \n44 | \n51 | \n
2 | \n89 | \n73 | \n60 | \n51 | \n40 | \n47 | \n
3 | \n86 | \n67 | \n42 | \n25 | \n20 | \n33 | \n
4 | \n70 | \n45 | \n38 | \n29 | \n25 | \n20 | \n
5 | \n71 | \n45 | \n27 | \n14 | \n14 | \n22 | \n
Clinical risk score for tumor recurrence proposed by Fong et al. [31].
Each risk factor is one point: node-positive primary, disease-free interval <12 months, >1 tumor, size >5 cm, CEA >200 ng/ml.
In practice, the patients can be categorized, based upon the criteria above, whether or not they are eligible for resection, as proposed by Adam et al. (Table 2) [28]. The disease can be categorized as resectable, not optimally resectable, or unresectable. The not optimally resectable disease is defined as difficult to resect for technical reasons (proximity to hepatic vein and portal vein branches) or technically possible to resect, but oncologically problematic (number of liver metastases greater than 4, maximum diameter 5 cm or more, synchronous liver metastases, primary lymph node metastasis positive, and high levels of tumor markers) [32].
\nCategory | \nContraindication | \n
---|---|
Technical | \n|
1. Absolute | \nImpossibility of R0 resection and functional residual liver volume preserved (≥ 25–30% liver remnant) Presence of unresectable extrahepatic disease | \n
2. Relative | \nR0 resection possible only with complex procedure (portal vein embolization, two-stage hepatectomy, hepatectomy combined with ablationa) R1 resection | \n
Oncological | \n|
1. | \nConcomitant extrahepatic disease (unresectable) | \n
2. | \nNumber of lesion ≥5 | \n
3. | \nTumor progression | \n
Contraindications to hepatic resection in patients with CRC liver metastases (adapted from Adam et al. [28]).
aIncludes all methods, including radiofrequency ablation.
Any patient should be categorized as A1 or A2/B1, B2, or B3. This classification may help to clearly define the type of unresectable patients included in all clinical trials.
Considering the fact that nearly 80% of patients with mCRC are not candidates for resection at diagnosis [33], initial treatment options include chemotherapy and several locoregional therapies. In these cases, chemotherapy in combination with molecular targeted drugs is recommended, followed by curative resection if a response is achieved.
\nIn patients with “favorable oncological” criteria (i.e., >50% likelihood of cure based on various factors including long-term metachronous disease) and “favorable surgical” criteria (no massive disease infiltration), both upfront surgery and perioperative chemotherapy are options. The EPOC study with perioperative chemotherapy has shown no clear predilection for one option over the other, since the 5-year OS rate reported for the perioperative chemotherapy group was 51% (95% CI 45–58) versus 48% (95% CI 40–55) in the surgery-only group [34].
\nHowever, in cases with disease that is not technically challenging to resect but where the prognostic situation is unclear, perioperative chemotherapy should be the preferable treatment strategy. These patients should undergo perioperative chemotherapy, 3 months before surgery and 3 months after surgery. The preferred treatment in this situation should be FOLFOX (or alternatively capecitabine with oxaliplatin—CAPOX) as reported for the EPOC trial [34]. EGFR-targeting monoclonal antibodies (cetuximab and panitumumab) are not to be used in this setting, based on the data from the New EPOC trial [35]. No data with bevacizumab are available for this specific patient group; thus, bevacizumab is not indicated [7]. Hence, especially in the case of synchronous metastatic disease, neoadjuvant chemotherapy preceding liver resection is often undertaken as a way of assessing the natural history of metastatic disease prior to resection.
\nThe use of conversion chemotherapy in clinical practice is based on the fact that initially unresectable tumors that are judged resectable after responding to chemotherapy and that undergo surgery display better long-term result than those treated with chemotherapy only [7, 36]. It is reported that up to 33% of patients with “initially unresectable” hepatic metastases have a sufficient objective response to conversion therapy to permit a subsequent complete (R0) resection [17, 37]. However, it has also been reported that the probability of downstaging a truly unresectable disease to the point of resectability is only up to 15 [38].
\nAnother important aspect that has to be studied when considering conversion therapy is that longer durations of chemotherapy increase the possibility of liver toxicity and postoperative complications. Evaluation of the response through imaging tests should be made each 6–8-week gap, and the resection should be made as soon as the metastases are considered undoubtedly resectable [38].
\nIn this scenario the response of the disease to the systemic treatment is also very important. If a growth of the disease is perceived while on chemotherapy or even the development of extrahepatic disease appears in this period, it may indicate that the tumor is biologically aggressive and it would not benefit from resection [17].
\nAfter complete resection of mCRC, the best postoperative strategy is debatable as well. Due to the lack of published randomized trials to conduct clinical practice, some suggest completion of a 6-month course of systemic chemotherapy (including courses administered as neoadjuvant therapy), as also suggested by updated guidelines from the National Comprehensive Cancer Network (NCCN) [38].
\nThe strong tumor responses for mCRC with the new agents in chemotherapy can even reach a complete response status. The tumors with less than 2 cm in diameter and more than 1 cm deep in the hepatic parenchyma are the ones with greater risk of vanishing [39]. Nevertheless, the resection is still needed considering that true pathologic complete response or clinical long-term response is, after chemotherapy alone, present in only 17% of the patients [40]. Therefore, those at risk of disappearing with the neoadjuvant treatment should be marked with a fiducial marker such as a coil before chemotherapy [41].
\nThough resection is considered the gold standard care of mCRC, sometimes there are contraindications due to anatomical reasons. Additionally, there may be comorbidities or liver dysfunction associated which grades the patient as ineligible for major surgery. In these cases, radiofrequency ablation (RFA) represents a great alternative [21].
\nConsidered as a parenchymal-sparing approach, the ablation therapy has been used for managing tumors that can vary from small to unresectable. It can be used as part of a combined ablation/resection tactic in cases of borderline resectable tumors or cases with risk of insufficient future liver remnant [17]. In a multicenter study of 288 patients who underwent combined intraoperative ablation and resection of mCRC, the 5-year overall survival was 37%, and local recurrence-free survival from ablated lesions was 78%. Postoperative mortality was 1%, and the overall complication rate was 35% [42].
\nAssociating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has emerged as modification on classic two-staged hepatectomy (TSH) with portal vein embolization. This new concept of liver resection, ALPPS, was first described in 2011 [43]. The main advantage of ALPPS is its ability to generate extensive and accelerated hypertrophy of the future liver remnant (FLR), achieving adequate volume for completion of the second stage of the ALPPS in as short as 1 week. This method for hepatic resection has also been described to treat various hepatic tumors in children [44]. ALPPS brings solution to a major flaw of classic TSH, where a considerable percentage (≈30%) of patients are unable to complete the second stage due to insufficient future liver remnant (FLR) growth and short-interval progression of the disease [45].
\nIn the initial study, 68% of the patients experienced complications, and the surgical mortality rate was 12% [43]. Since the first description of ALPPS, there has been a great deal of interest in this treatment. However, criticism of the approach has been raised mainly regarding surgical morbidity and mortality [46].
\nRecently, Wanis et al. [47] reported a cohort of 58 patients who underwent ALPPS for colorectal liver metastases. They observed no perioperative mortalities and a rate of severe complications of 21%. The 3-year post-ALPPS overall survival was 50%, while the disease-free survival was 13%. The most common site of first recurrence was the liver alone (38%). Patient-reported quality of life after ALPPS was similar to reference values for general population
\nAdditionally, the Scandinavian Multicenter Randomized Controlled Trial (LIGRO Trial) comparing ALPPS with TSH [48], showed a much higher resection rate for ALPPS, 92% (44/48), than TSH, 57% (28/49) (P < 0.0001). Considering other parameters, such as complications [43% (19/44) vs. 43% (12/28)] and 90-day mortality [8.3% (4/48) vs. 6.1% (3/49)] or R0 RRs [77% (34/44) vs. 57% (16/28)], no differences were observed.
\nIn experienced hepatobiliary centers and in well-selected patients, ALPPS can be performed with low perioperative morbidity and minimal to no mortality, resulting in good intermediate-term survival and excellent quality of life [47].
\nAlthough many centers have been using ALPPS associated with right hepatectomy with good results to treat liver mCRC, indications for ALPPS should continue to be scrutinized critically by multidisciplinary tumor boards based on accepted criteria of remnant liver volume, number of prior cycles of chemotherapy, and histologic criteria of the presence or absence of underlying parenchymal hepatic damage based on at the least a fresh frozen section during stage 1, when considering ALPPS [49].
\nThe technique consists of a bilateral subcostal laparotomy using an adult subcostal retractor. A thorough inspection of the abdominal cavity is carried out in order to detect any previously missed metastases. A cholecystectomy and hepatic hilum dissection are then performed. The right and left hepatic arteries, as well as the arteries for segment 4, were dissected and identified. The common bile duct was dissected. The left or right portal vein is ligated. When the tumor is located on the right hemi-liver with involvement of segment 4, the portal branch for segment 4 is ligated and divided. Full mobilization of the liver is obtained by sectioning the falciform, coronary, and right and left triangular ligaments of the liver. The right or left hepatic vein of the liver to be resected is dissected and encircled with a vessel loop, as seen in Figure 1. An intraoperative ultrasound is performed to verify a tumor-free parenchymal transection line.
\nPostoperative CT image of a patient who underwent portal vein ligation and staged hepatectomy: (a) treated liver metastases of the FRL, (b) metastases on liver to be resected, and (c) line of liver bipartition.
The liver parenchyma is transected using combined ultrasonic energy (Ultracision®), monopolar and bipolar electrocautery, and ligation of the blood vessels and bile ducts. Biologic fibrin sealant can be used in both surfaces of the spitted liver. Closed drainage is placed in the liver hilum. We do not use any plastic film, mesh, or plastic bag to separate both surfaces of the liver. Metastases located in the future remnant liver (FRL) can be treated either by local resection or radiofrequency tumor ablation (RFA).
\nDuring the second operation, the hepatic artery and the bile duct of the diseased liver are ligated and transected. A clamp is applied at the right or left hepatic vein, and the vein is then transected. A 4–0 Prolene® running suture is applied to the stump of the hepatic vein. Liver segment 1 is usually preserved [46].
\nWhen facing a situation of synchronous disease, with both primary tumor and hepatic metastases, the timing for surgical approach of the hepatic lesions is still a topic of discussion.
\nThe lesions can be accessed simultaneously in one procedure, or they can be treated with a staged resection. In the staged manner, there is the classic approach, which means accessing the primary tumor first; and there is the reverse approach, also known as liver-first approach. No difference has been shown by various studies, regardless of which method is used [50].
\nTherefore, the decision should be established on a case-by-case basis, considering the symptoms presented by the patient, location, size, and possible complications of each one such as bowel perforation, risk of liver failure, whether the patient underwent chemotherapy or not, performance status, and the surgeon expertise [17, 51].
\nThe surgical approach of the mCRC in the liver can be performed through an anatomic resection or a nonanatomic/parenchymal-sparing resection (PSR). Since the type of resection has not been associated with significant differences in rates of positive margin, recurrence, or survival [50], and considering that the PSR preserves greater hepatic reserve, recent studies are leaning toward the nonanatomic method, particularly when chemotherapy-induced liver injury is a concern [17].
\nKeeping in mind that recurrences after initial resection of mCRC can occur in up to 57% of cases and the most common site of recurrences is the liver [52] and considering that repeat liver resection in a second recurrence, with satisfactory morbidity and perioperative mortality, has been associated with a 5-year survival up to 43% [38], the PSR becomes an even more attractive option.
\nConsidering the width of the resection margin, a 2017 meta-analysis reported that margins greater than 10 mm were related with superior 5-year OS [53]. Still, numerous retrospective studies revealed that less than 10 mm but negative margin is not related with poorer survival [54]. In a multicenter study of 551 patients, surgical margins were classified as positive or negative with 1–4, 5–9, and >10 mm of tumor-free parenchyma. The positive margins were associated with a greater risk of recurrence, and the width of negative margins did not affect survival, recurrence, or site of recurrences [54].
\nThere is one situation where anatomic resection and/or a wider surgical margin (>10 mm) may be indicated which is before a RAS-mutated mCRC as it constitutes a more aggressive tumor biology group and has been associated with more positive margins and worse survival after surgery [55]. Others reported that even a wider resection margin might not be sufficient to overcome the aggressive tumor biology associated with a RAS mutation. In a study of 411 patients who underwent resection for mCRC at Johns Hopkins University, a 1–4-mm margin was associated with improved survival compared with a positive margin (<1 mm or R1) for wild-type KRAS tumors, with which a wider resection margin did not further improve survival. In KRAS-mutated tumors, however, negative margin status, which included a 1-cm margin, did not improve survival [56].
\nAccording to the consensus-based guidelines from the National Comprehensive Cancer Network (NCCN), the recommendation is carcinoembryonic antigen (CEA) testing every 3–6 months for 2 years followed by every 6 months for 3 years; computed tomography (CT) of the chest/abdomen and pelvis every 3–6 months for 2 years and then every 6–12 months up to a total of 5 years; colonoscopy in 1 year; if negative, repeat in 3 years and then every 5 years; and if advanced adenoma is found, repeat in 1 year [38].
\nAn important point is that posttreatment follow-up should only be performed for those patients considered candidate for a second potentially curative surgical procedure [38].
\nRe-resection for recurrence of mCRC is a safe and viable option in properly selected patients. In order to prevent post-hepatectomy liver failure, sufficient future liver reserve is paramount, as well as no evidence of extrahepatic disease and good performance status [57, 58, 59].
\nAlthough randomized trials have not been conducted to prove benefit, several reported series have demonstrated perioperative mortality rates lower than 5%, and overall survival rates ranged from 20 to 43% at 2–5 years [57, 58, 59].
\nPatients with a relapse-free interval of longer than 1 year appear to have a more favorable outcome from re-resection. Factors associated with a poor outcome include synchronous resection for the first liver metastases and the presence of multiple lesions at second hepatectomy [60, 61].
\nInterestingly, recurrences at the margin are uncommon [62, 63]. Some studies have reported 5-year overall survival rates after re-resection of 33–73% with no perioperative mortality [64, 65].
\nIt is known that the majority of metastatic CRC liver disease will be potentially resectable at the time of diagnosis. Considering that hepatic resection is the only curative option for these patients, the parameters of resectability have expanded through the years due to a wider knowledge of the disease, improving diagnostic techniques, new drugs, and technical surgical advances. It is safe to say that the treatment strategies have advanced rapidly enough to change dramatically the natural history of the mCRC.
\nALPPS has been recently introduced as an option to the treatment of mCRC. It has been shown to increase drastically the resection rates, with complications rates not different from standard two-staged hepatectomy.
\nSeveral treatment options are available to treat patients with mCRC. It is important to have in mind that the treatment approach must be established for each case. Not only the patient and anatomic factors are important, but also the tumor factors must be considered. Best results are obtained when the treatment approaches for individual patients are discussed within a multidisciplinary team (MDT) of experts, meeting regularly as a tumor board to review mCRC cases.
\nMicrobial biofilms that are sticky exopolymeric substances (EPS) causing adherence of microorganism to biotic surfaces such as host cells or abiotic surfaces such as medical devices cause antimicrobial resistance, due to its molecular contents such as eDNA and exoenzymes (β-lactamase, toxins, etc.), limited diffusion of antimicrobials through the biofilm matrix, persister cell content, and limited nutrient and oxygen. Surface proteins and polysaccharide intercellular adhesions (PIA) play a role in the biofilm production and development. It is hard to treat biofilm-embedded bacteria than planktonic forms. Biofilm producer microorganism causes biofilm-related infections such as indwelling and medical device-related infections such as endocarditis, urinary tract infections, septic arthritis, chronic rhinosinusitis, ocular infections, wound infections, etc. The results of biofilm produced on indwelling medical devices are recurrent, untreatable infections and failure of medical device. To overcome chronic and recurrent infections, it is important to detect biofilms of microorganisms, maturation and dispersion, and determine antibiofilm and antibacterial activity of agents against biofilm and bacteria within biofilm, respectively [1]. Identification of genes involved in biofilm formation and measurement of gene expression as a result of antibiofilm and antibacterial activity of agents can be advantageous with carrying out high-throughput screens using microtiter plate assay system.
The standard antimicrobial susceptibility tests such as broth macrodilution and microdilution methods that are routinely used in laboratories and published by Clinical Laboratory Standards Institute (CLSI), National Committee for Clinical Laboratory Standards (NCCLS), and European Committee on Antimicrobial Susceptibility Testing (EUCAST) could never yield accurate results in biofilm producer microorganisms, due to being appropriate for the detection of antimicrobial activity of agents against planktonic microorganism [2].
There are several methods which have been used by clinical microbiologist for detection and measurement of microbial biofilms in response to agents (Tables 1–3). Several instruments as model system have been improved such as modified Robbins device, Calgary biofilm device, disk reactor, Centers for Disease Control (CDC) biofilm reactor, perfused biofilm fermenter, and model bladder. Model systems help to define susceptibility of antimicrobial agents against biofilm producer microorganisms by providing information about biofilm mechanisms. Substratums of modified Robbins device, Calgary biofilm device, disk reactor, CDC biofilm reactor, and perfused biofilm fermenter are silastic disks, plastic pegs, Teflon coupons, plastic needleless connectors, and cellulose acetate filters, respectively, whereas substratum of model bladder is urinary catheters (UCs). Medical devices of which dimensions are adjusted to appropriate sizes can also be used as a substratum (abiotic surfaces) for biofilm production by adapting and modifying to related methods by some biofilm researchers. The methods of modified Robbins device and Calgary biofilm device are based on viable counting. In Calgary biofilm device, pegs are sonicated before counting. The methods of disk reactor and CDC biofilm reactor based on direct and viable counting, after substratums, are sonicated, vortexed, and homogenized. In perfused biofilm fermenter, viable counting is done, after filters are shaken in sterile distilled water, whereas in model bladder, UCs are examined directly by scanning electron microscopy (SEM) or transmission electron microscopy (TEM) or by chemical analysis [2]. Rate of biofilm formed on model system can be adjusted by parameters such as composition of medium that can contain glucose, iron, antimicrobial agents, multivalent cations such as Ca2+ and Mg2+ supporting adhesion of bacteria by cross-linking anionic groups on bacteria and substratum, shear force, retention time, flow rate, roughness, and chemistry of substratum and species of organisms (Table 4) [2, 3].
Method | Action of application | Aim |
---|---|---|
Roll plate | Extraluminal biofilm detection | Growth of biofilm-embedded bacteria |
Sonication, vortex, and plate counting | Intraluminal and extraluminal biofilm detection | Growth of biofilm-embedded bacteria |
Acridine orange staining | Extraluminal biofilm detection | Direct investigation of biofilm produced on catheter by microscopy |
Streak plating of alginate swab | Investigation of biofilm produced on indwelling catheter | Growth of biofilm-embedded bacteria |
The methods used for detection and measurement of biofilms produced on medical devices.
Method | Aim |
---|---|
Tube method (TM) | Qualitative detection by observing biofilm lined on bottom and walls of tube |
Congo red agar (CRA) | Qualitative detection by observing colony color change |
Microtiter plate (MtP) | Quantitative detection of biofilm by microplate reader (microELISA) |
Real-time PCR | Detection of biofilm genes |
Conventional PCR | |
Multiplex PCR |
The methods used for detection of biofilm.
Method | Application | Target |
---|---|---|
Microtiter plate (MtP) | Measurement of biofilm produced on walls of wells in response to agent | Measures the effect of agents against biofilm production |
Microtiter plate (MtP) (MBEC) | Measurement of biofilm remained on walls of wells in response to agent and detecting MBEC of agents | Measures the effect of agents against mature biofilm formed on walls of wells |
Vortex and plate counting | Plate counting of biofilm-embedded bacteria and detecting bMBC of agents | Screens antimicrobial activity of agents against biofilm-embedded bacteria |
Checkerboard assay | Plate counting of biofilm-embedded bacteria and FIC indexes are calculated | Screens antimicrobial activity of combination of agents |
Sonication, vortex, and plate counting | Plate counting of biofilm-embedded bacteria and detecting bMBC of agents | Screens antimicrobial activity of agents against biofilm-embedded bacteria |
Quantitative PCR | Measurement of specific biofilm gene expression | Monitors expression of biofilm genes in response to agents |
Mass spectrometry (MS) | Measurement of exoenzymes located in biofilm matrix | Monitors expression of bacterial proteins in response to agents |
The screening methods for antibiofilm and antimicrobial activity of agents against biofilm producer bacteria.
Instruments | Culture dynamics | Substratum | Method |
---|---|---|---|
Modified Robbins device | Batch culture | Silastic disks | Viable counting |
Calgary biofilm device | Batch culture | Plastic polycarbonate pegs | Viable counting, after pegs are sonicated |
Disk reactor | Batch culture | Teflon coupons | Direct or viable counting, after coupons are sonicated, vortexed, and homogenized |
CDC biofilm reactor | Continuous culture | Plastic connectors | |
Perfused biofilm fermenter | Continuous culture | Cellulose-acetate filters | Viable counting, after filters are shaken in sterile distilled water |
Model bladder | Continuous culture | Urinary catheters | Examining directly by SEM or TEM or analyzing chemically |
Flow cell | Continuous culture | Chambers with transparent surfaces | Examining by confocal laser scanning microscopy |
Instruments used to produce biofilm and examine biofilm process.
CDC biofilm reactor, Centers for Disease Control biofilm reactor; SEM, scanning electron microscopy; TEM, transmission electron microscopy.
The aim of this chapter is to overview certain methods used by biofilm detection and antibacterial and antibiofilm researches such as tube method (TM), Congo red agar (CRA) method, microtiter plate (MtP) assay, plate counting of biofilm-embedded bacteria (sessile bacteria), PCR, mass spectrometry (MS), confocal laser scanning microscopy (CLSM), etc.
Complexity and dynamics of biofilms can be observed by biofilm imagining optical technology including light microscopy, SEM, TEM, and CLSM. These techniques are used to visualize 3D structure and check the existence of biofilm [4].
Light microscopy is the easiest, cheapest, most simple, convenient and fastest method to quantitatively observe the morphology of microorganisms adhered to surfaces and to semiquantitatively estimate the amount of microorganism attached on surface (exist, absent, abundant, rare, etc.). Microorganisms including Candida albicans, E. coli, Pseudomonas, and Staphylococcus epidermidis adhered on acrylic sheets of polymethacrylate films, glass cover slips, and polystyrene petri dishes have been observed by light microscope, respectively. Observation with light microscopy that requires clear, transparent, and planar surfaces on which microorganisms attach does not create 3D vision of biofilm. Dyes can be used such as epifluorescence and fluorescent to enhance image clarity of microorganisms. The observation with the light microscope enables researchers to compare morphologies of sessile form and planktonic form of microorganism required by making smear and centrifuging of sample, respectively [3].
Images of cells and cell structures such as protein and nucleic acid are obtained by electrons at high magnification and resolution. Monitoring of components of cell can be done directly in TEM by negative staining. Due to photons and electrons penetrating cells poorly, thin section of cell cut is stabilized and stained by certain chemicals with the treatment of osmic acid, permanganate, uranium, lanthanum, or lead salts. These stains contain high atomic weight. Due to stains having high atomic weight, contrast is accelerated by electron dispersion from sample. If observation of outer structure of cells will be done, it is not important whether the section of cell is thin or thick.
Due to inadequate stabilization of polysaccharides is done by the conventional fixatives such as aldehydes, glutaraldehyde, paraformaldehyde, and osmium tetroxide, water content of biofilm is eliminated by graded dehydration with alcohol after this postfixation step. After sample is infiltrated with resin, sample is embedded in gelatin capsule and headed for polymerization. Then, thin section taken is poststained with uranyl acetate and lead citrate.
Exopolysaccharide constituents are not observed with its own electron dense and staining poststains such as uranyl acetate and lead citrate with TEM, due to not only having high electron translucent, but also contrast is not developed by conventional poststains. According to the studies, glycocalyx of Staphylococcus hominis and Staphylococcus epidermidis can be stabilized by the usage of certain cationic reagent combinations including ruthenium red, alcian blue, lysine, lysine monohydrochloride, or lysine acetate and paraformaldehyde [5]. After all these steps are done, sample is observed in TEM (Figure 1).
The SEM image of S. aureus embedded in biofilm colonized on intravenous catheter [6].
To visualize 3D images of cell sample is coated with heavy metals such as gold. Electrons released from metal coating of sample are caught by SEM for image production. The procedure of SEM is similar to TEM except for some additional chemicals (gold), lacking infiltration, embedment in resin, polymerization, and thin section staining with lead citrate and uranyl acetate [5]. As in the steps of TEM method, postfixation and dehydration steps of SEM are similar to TEM. The step is applied after dehydration step is drying and coating sample with gold in the processing for SEM, rather than infiltration with resin, embedment in gelatin capsule, and staining with lead citrate and uranyl acetate in the processing for TEM. After dehydration process with graded alcohol, sample is dried and coated with gold palladium [5]. After all these steps are done, sample is observed in SEM (Figure 2).
The TEM image of Staphylococcus spp. surrounded by glycocalyx [6].
Biofilms formed on flow cells of which surface are transparent can be observed by confocal laser screening microscopy (CLSM). Three-dimensional (3D) morphology and physiology of biofilms can be screened by CLSM [2]. Thick samples such as biofilms and microorganisms localized in the depth such as biofilm-embedded microorganisms need to be observed by CLSM (Figure 3).
Bacterial community embedded in a biofilm matrix visualized by CLSM. Each bacterium observed with a distinct color located at different depths of biofilm [11].
For observation of biofilm with confocal microscopy and related methods, biofilm must be fluorescent as a result of fluorescent molecules such as green fluorescent protein (GFP) that is fluorescent protein expressed by biofilm producer microorganism within biofilm (gene of cell interested is tagged by gene cassette encoding GFP) or staining components of heterogeneous mass of biofilm with fluorescence or fluorescence-labeled dyes [2]. Stains such as lectins target extracellular matrix, whereas certain fluorophores target extracellular DNA (eDNA) to visualize eDNA content of biofilm matrix [2, 7].
By scanning laser light across the sample, deep penetration of excitated energy is provided. As a result of fluorescence of biomolecules such as GFP or chlorophyll that are intrinsic fluorophores or molecules signed by exogenous probes such as fluorescent-labeled antibodies detected by photomultiplier, 3D digital image is formed. Observation of biofilms that are multilayered and have complex 3D structures requires additional resolution [2]. Images of each layers of biofilm obtained are combined by computer for construction of digital 3D images of whole biofilm.
Biofilm producer microorganisms can be manipulated genetically by tagging of microbial gene of interest by gene cassette encoding GFP as a reporter gene (gfp genes) to monitor gene expression and metabolic physiology activity in biofilms and determine location of microorganism within biofilm [2, 8, 9].
Idea about gene activity in biofilms is given by confocal microscopy applied to 3D localization of nonenzyme reporter systems such as GFP. Growth phase and activity of bacteria embedded in biofilms can be defined by promoter-reporter systems that is designed and fluoresced just in living dividing cells. In situ cellular growth activity of bacteria embedded in biofilms is determined by measuring ribosome-hybridization-signal intensity, due to synthesis rate and content of ribosome correlated with the growth rate (especially in exponential phase). Expression cassette that is active only in growing cells, labeled by GFP and controlled by rRNA promoter, can be constructed to monitor growth phase and activity of bacteria within biofilm [2, 10].
Specific microorganisms present in a heterogeneous biofilm community can be identified by the probes of fluorescent in situ hybridization (FISH) method. GFP that is translated enables procedure not to require fixation or staining. Fluorescent-labeled microorganism within biofilm can also be examined by FISH. DNA probes designed to hybridize 16S rRNA of microorganism integrated to either fluorescent dye such as FITC or Rhodamine or enzyme such as horseradish peroxidase. The advantage of probes conjugated with horseradish peroxidase is not to destroy microorganism within biofilm. The growth rate of microorganism within biofilm can be determined by FISH method, due to the amounts of ribosomes existing in a microorganism that is directly proportional to growth activity of microorganism. Probe must be designed to label conserved region of only a single species (Figure 4) [2, 12].
Fluorescence image of 28 distinct E. coli strains labeled by fluorophore-conjugated oligonucleotides complementary to 16S rRNA of E. coli [11].
Roll plate method is applied for the detection of possible microbial colonization having a potential to develop indwelling device-associated infection on the outer surface of cylindrical materials such as catheters and vascular grafts. Microorganism colonize on external surface of catheter is detected by roll plate method, instead of microorganism colonize on intraluminal site of catheter. Material is touched and rolled on the surface of medium [3].
Congo red agar (CRA) method that is a qualitative assay for detection of biofilm producer microorganism, as a result of color change of colonies inoculated on CRA medium, is described by Freeman et al. The CRA medium is constructed by mixing 0.8 g of Congo red and 36 g of sucrose to 37 g/L of Brain heart infusion (BHI) agar. After incubation period that was 24 h at 37°C, morphology of colonies that undergone to different colors is differentiated as biofilm producers or not. Black colonies with a dry crystalline consistency indicate biofilm producers, whereas colonies retained pink are non-biofilm producers (Figure 5) [13].
CRA method applied on CRA medium. Black crystalline colonies of biofilm producer cell and pinkish-red colonies of biofilm nonproducer cell.
Tube method (TM) that is a qualitative assay for detection of biofilm producer microorganism, as a result of the occurrence of visible film, is described by Christensen et al. [14]. Isolates are inoculated in polystyrene test tube which contained TSB and incubated at 24 h at 37°C. The sessile isolates of which biofilms formed on the walls of polystyrene test tube are stained with safranine for 1 h, after planktonic cells are discharged by rinsing twice with phosphate-buffered saline (PBS). Then, safranine-stained polystyrene test tube is rinsed twice with PBS to discharge stain. After air drying of test tube process, the occurrence of visible film lined the walls, and the bottom of the tube indicates biofilm production (Figure 6) [14].
Tube method. The first two polystyrene test tubes from the left indicate biofilm production. Other test tubes rather than the first two polystyrene test tubes from the left indicate lacking of biofilm production.
Microtiter plate (MtP) assay is a quantitative method to determine biofilm production by microplate reader. Bacterial suspension is prepared in MHB supplemented with 1% glucose and adjusted to 0.5 McFarland (1.108 cfu/ml). This bacterial suspension is 20-fold (1/20) diluted to reach 5.106 cfu/ml. Then 180 μl of Mueller-Hinton Broth (MHB) supplemented with 1% glucose [15] and 20 μl of bacterial suspensions are inoculated into 96-well flat-bottomed sterile polystyrene microplate to obtain 5.105 cfu/ml as a final concentration (tenfold dilution (1/10)). Microplates are incubated at 24 h at 37°C. The sessile isolates of which biofilms formed on the walls of wells of microplate are stained with only 150 μl of safranine for 15 min, after planktonic cells in wells of microplate are discharged by washing twice with phosphate-buffered saline (PBS) (pH 7.2) and wells are dried at 60°C for 1 h [14]. Before staining with safranine, fixation of biofilms can be done by either subjecting to 150 μl of methanol for 20 min or drying at 60°C for 1 h. Then safranine-stained wells of microplates are washed twice with PBS to discharge safranine stain. After air drying process of wells of microplate, dye of biofilms that lined the walls of the microplate is resolubilized by 150 μl of 95% ethanol or 33% glacial acetic acid or methanol. Then microplate is measured spectrophotometrically at 570 nm by a microplate reader [15, 16]. The studies are repeated in triplicates. Uninoculated wells containing sterile MHB supplemented with 1% glucose that are considered to be the negative controls are used as blanks. The blank absorbance values are used to identify whether biofilm formation of isolates exists or not. The wells of isolates of which OD values are higher than blank well are considered to be biofilm producers. Cut off value (ODc) can provide categorization of isolates as biofilm producer or not.
Negative value obtained from this formula and represented as zero indicates lack of biofilm production, whereas positive value indicates biofilm production (Figure 7).
Microtiter plate assay indicating biofilm production.
To interpret results, categorization can be done as no biofilm production (0), weak (+ or 1), moderate (++ or 2), and strong biofilm production (+++ or 3) by the calculation of cutoff value (ODc) shown below [15]:
OD ≤ ODc no biofilm production
ODc< OD ≤ 2 × ODc weak biofilm production
2 × ODc< OD ≤ 4 × ODc moderate biofilm production
4 × ODc< OD strong biofilm production.
PCR techniques is used for not only identification of pathogens by amplifying species-specific nucleic acid sequences but also detection of virulence factors by amplifying target virulence genes such as biofilm genes with the usage of gene-specific primers, even in the uncultured pathogen present in the sample.
Forward and reverse primers of biofilm-associated gene are designed. Firstly, multiple alignments were done in the NCBI to find oligonucleotide sequences specific to the species. Then primer pair of biofilm-associated gene is designed by using Primer3Plus verified by FASTA analysis checking specificity of primers for microbial sequences in the database [17, 18].
Genomic DNA of microorganism is extracted by extraction kits of which protocols can vary according to species and Gram-positivity or Gram-negativity of microorganisms. DNA of microorganism is measured spectrophotometrically by microplate spectrophotometry reader to determine the amount of DNA extracted as microgram per microliter.
Biofilm-associated gene is amplified by PCR such as qualitative real-time PCR, multiplex and conventional PCR that is used to detect whether biofilm-associated gene is present or not in microorganism. If conventional and multiplex PCR protocols are applied to detect biofilm gene, rather than qualitative real-time PCR, PCR product isolated is visualized on an agarose gel containing a DNA-intercalating dye such as ethidium bromide to confirm the presence of amplified gene (Figure 8). Only in qualitative real-time PCR, the amplicon is detected by fluorescence using a pair of specific hybridization probes labeled with fluorescence dye [11].
Image of mecA gene on agarose gel. First sample is DNA size marker (ranging from 250 to 10,000 kb), second sample is ATCC 43300 methicillin-resistant Staphylococcus aureus (MRSA) positive control, third and fourth samples are mecA gene-positive isolates, and fifth sample is ATCC 29213 methicillin-sensitive Staphylococcus aureus (MSSA) as a negative control.
Microtiter plate (MtP) assay is a qualitative assay to detect efficacy of agent against biofilm production by microplate reader.
Bacterial suspension is prepared in MHB supplemented with 1% glucose and adjusted to 0.5 McFarland (1.108 cfu/ml). This bacterial suspension is 20-fold (1/20) diluted to reach 5.106 cfu/ml.
A 180 μl of agent doses and 20 μl of bacterial suspension are dispersed to each well of microplate to obtain 5.105 cfu/ml as a final concentration (tenfold dilution (1/10)). After incubation at 37°C for 24 h, ongoing processes are done according to MtP assay as mentioned previously for the determination of effect of agent against biofilm production [14, 16].
Biofilms remained after eradication by agent are measured by this technique. Biofilms of bacteria that line the walls of wells are formed according to MtP method.
After the content of microplate is discharged, 200 μl of each dose of agents is dispersed to each well of microplate of which the walls are lined with biofilm. A 200 μl of distilled water is added into a well of microplate of which the walls are lined with biofilm as a control. Then the effect of agent against mature biofilm is determined according to MtP assay as mentioned previously. Minimum concentration of agent eradicating mature biofilm that is named as minimum biofilm eradication concentration (MBEC) can be determined by this modified plate assay. MBEC50 and MBEC90 indicate the minimum concentrations of agents inhibiting 50 and 90% of mature biofilm formed.
In summary, biofilm formation process on abiotic surfaces by bacteria is done. Quantification of sessile biofilm-embedded bacteria lined on abiotic surface and sessile biofilm-embedded bacteria remained on abiotic surface after addition of agent on abiotic surface on which mature biofilms formed is determined by plate counting. Bacterial suspension is prepared and adjusted to 0.5 McFarland (1.108 cfu/mL) in Mueller-Hinton Broth (MHB) supplemented with 1% glucose [15]. This bacterial suspension is 200-fold (1/200) diluted to gain 5.105 cfu/mL. Kirschner wire orthopedic implants are placed into each test tube containing 5.105 cfu/mL isolate and incubated at 37°C for 24 h to lead bacteria to produce biofilm on Kirschner wire. After incubation, Kirschner wires on which biofilms are produced are discharged and rinsed with PBS (pH 7.2) and then transferred into each test tubes containing agent concentrations. After incubation at 37°C for 24 h, Kirschner wires are discharged and placed into test tubes containing 1 mL of sterile MHB and sonicated at 42 kHz for 2 min after vortexed for 5 min. Then 100 μl samples of each test tube sonicated and vortexed are inoculated on Mueller-Hinton agar (MHA) and incubated at 37°C for 24 h [19].
The lowest concentration of agent in which bacterial growth is below or equal to control is determined as biofilm minimum inhibitory concentration (bMIC) for biofilm. bMIC50 and bMIC90 indicate the minimum concentrations of agent inhibiting 50 and 90% of biofilm-embedded bacteria. After incubation, the lowest concentration of agent in which colonies of biofilm-embedded bacteria are not grown is determined as biofilm minimum bactericidal concentration (bMBC) of agent for biofilm [19].
Checkerboard assay is used for the determination of combination effects of two different agents. A 250 μl twofold dilutions of each agent from the stock solutions are dispersed to each row and column to obtain final varying concentrations by starting at fourfold of zero MIC for each isolate. So each well contains distinct combination of concentrations of two agents. First wells of rows and columns are left behind for sole treatments of each dose of agents. One well is used for bacterial control (Figure 9). Kirschner wires on which bacterial biofilm is produced are dispersed to each well. This microplate is incubated at 37°C for 24 h. After incubation, Kirschner wires are discharged and sonicated at 42 kHz for 2 min after vortexed for 5 min. The lowest concentration of agent in which bacterial growth that is not observed is determined as biofilm minimum inhibitory concentration (bMIC) of agent for biofilm. Then 100 μl samples of each test tube sonicated and vortexed are inoculated on MHA and incubated at 37°C for 24 h. After incubation, the lowest concentration of agent in which colonies of biofilm-embedded bacteria are not grown is determined as biofilm minimum bactericidal concentration (bMBC) of agent for biofilm. For the determination of whether the synergism is present between agents or not, fractional inhibitory concentrations (FICs) index that are calculated for each agent are summed up according to formula written below:
The schematization of checkerboard assay.
When ∑FIC is equal and lesser than 0.5, between 0.5 and 1, equal to 1, higher than 1 and equal and lesser than 4, and higher than 4, it is interpreted that the effect between agents in combination is synergistic, partial synergistic, additive, indifferent, and antagonistic, respectively [20].
The wells having the highest synergy rates of two agents that constitute the combinations are determined by taking the average and standard deviation of FIC indexes calculated of the wells with the lowest drug combination without bacterial growth in each row and column (Figure 9).
Measurements of biofilm genes repressed or induced by agent are done by quantitative real-time PCR (qPCR). So efficacy of agent against biofilm-associated genes can be detected by qPCR.
Complementary DNA (cDNA) is copied from RNA by enzyme reverse transcriptase. Gene expression in pathogen is monitored by qPCR copying cDNA from RNA of target gene. Amplified cDNA probed for identification. Fluorescent probes such as dye SYBR Green are used to indicate double-stranded DNA, consequently amplification. Accumulation of PCR amplicons labeled fluorescently is monitored through the qPCR processes (Figure 10). Visualization of amplicon on agarose gel is not needed to confirm amplification in qPCR [11].
Quantitative real-time polymerase chain reaction (qPCR) of atl (light blue), 16S RNA (red), mecA (purple), and nuc (light pink) genes of sample; icaA (gray), icaD (plato), atl (pink), mecA (blue), and nuc (green) genes of ATCC 43300 methicillin-resistant Staphylococcus aureus (MRSA); and icaA (orange), 16S RNA (yellow), and nuc (grayish blue) genes of ATCC 29213 methicillin-sensitive Staphylococcus aureus (MSSA). Expressions of all these genes are monitored by qPCR except nuc (light pink) gene sample. Lines below threshold monitored by qPCR indicate the negativity of genes such as icaA and icaD genes samples and icaD (turquoise), atl (plato), and mecA (light pink) genes of ATCC 29213 MSSA. RFI, relative fluorescence intensity.
Total RNA of microorganism is isolated according to protocols of RNA isolation kits. Kit protocols can vary according to the species of microorganism. Total RNA of microorganism is measured spectrophotometrically by microplate spectrophotometry reader to determine the amount of total RNA isolated as microgram per microliter. Then cDNA is synthesized from total RNA with qPCR using primer pair of the biofilm-associated gene, which is designed using Primer3 and verified by FASTA analysis, which controls the specificity of the primers for microbial sequences in the data system, after multiple alignments were done in the NCBI to find oligonucleotide sequences specific to the species [17, 18].
Extracellular polymeric substances (EPS) not only contain polysaccharides but also contain proteins such as extracellular enzymes. These expressed proteins located in the matrix of EPS can be detected and characterized by mass spectrometry (MS) [1]. Large biologic molecules can be also detected and characterized in complex biologic structures such as EPS by MS. Chemicals involved in biofilm process are examined in detail by MS. Electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI) are the types of MS [2]. In time-of-flight (TOF) mass spectrometer, mass is analyzed by ions desorbed in vacuum chamber. These two technics are combined and called MALDI-TOF.
Sample is ionized and vaporized by laser. Ions generated from sample by laser pass through the column of MALDI-TOF device toward TOF detector by an electric field. Depending on the mass/charge ratio of molecule, measurements are done by TOF. If this ratio is smaller, ions move faster (Figure 11).
MALDI-TOF mass spectrometry device [11].
Bacteria are identified, expression of bacterial proteins such as surface proteins and exoenzymes like β-lactamase in response to antimicrobials can be monitored, and growth of bacteria is measured by applications of MALDI. MS has high sensitivity and requires minimum amount of sample [2].
Biofilm-embedded bacteria can be estimated by biologic assays that is an indirect assay. Biological assays that measure production of microbial product give an opinion about estimation of the number of microorganism within biofilm. Amount of biologic product is correlated with biofilm-embedded microorganism producing the product by standardization of planktonic microorganism. Biologic products produced by planktonic microorganism are similar to biologic products produced by biofilm-embedded bacteria. Standardization curves of each microorganism tested need to be formed. Measurement of total protein at the absorbance is 550 or 950 nm; tryptophan fluorescence, endotoxin [2], ATP production via bioluminescence caused by luciferin and luciferase, urease production to estimate number of attached microorganism, and electron transport via the production of formazan are done by biological assays [3].
Biofilms cause resistance to many antimicrobial agents. The results of biofilm produced on indwelling medical devices are recurrent, untreatable infections and failure of medical device. To overcome chronic and recurrent infections, it is important to detect biofilms of microorganisms, determine antibiofilm activity of agents against biofilm, and determine antibacterial activity of agents against biofilm-embedded microorganism with the appropriate methods by clinical microbiologist and biofilm researcher microbiologist. Identification of genes involved in biofilm formation and measurement of gene expression as a result of antibiofilm and antibacterial activity of agents can be advantageous in biofilm studies.
At IntechOpen, we not only specialize in the publication of Book Chapters as part of our Edited Volumes, but also the publication and dissemination of longer manuscripts, known as Long Form Monographs. Monographs allow Authors to focus on presenting a single subject or a specific aspect of that subject and publish their research in detail.
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\n\nFor a complete overview of all publishing process steps and descriptions, go to How Open Access Publishing Works.
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