Mutant KRAS as a prognostic biomarker after hepatectomy for rectal cancer metastases: Does the primary disease site matter?

BACKGROUND: The prognostic implication of mutant KRAS (mKRAS) among patients with primary disease in the rectum remains unknown. METHODS: From 2000 to 2018, patients undergoing hepatectomy for colorectal liver metastases at 10 collaborating international institutions with documented KRAS status were surveyed. RESULTS: A total of 834 (65.8%) patients with primary colon cancer and 434 (34.2%) patients with primary rectal cancer were included. In patients with primary colon cancer, mKRAS served as a reliable prognostic biomarker of poor overall survival (OS) (hazard ratio [HR]: 1.58, 95% CI 1.28-1.95) in the multivariable analysis. Although a trend towards significance was noted, mKRAS was not found to be an independent predictor of OS in patients with primary rectal tumors (HR 1.34, 95% CI 0.98-1.80). For colon cancer, the specific codon impacted in mKRAS appears to reflect underlying disease biology and oncologic outcomes, with codon 13 being associated with particularly poor OS in patients with left-sided tumors (codon 12, HR 1.56, 95% CI 1.22-1.99; codon 13, HR 2.10 95% CI 1.43-3.08;). Stratifying the rectal patient population by codon mutation did not confer prognostic significance following hepatectomy. CONCLUSIONS: While the left-sided colonic disease is frequently grouped with rectal disease, our analysis suggests that there exist fundamental biologic differences that drive disparate outcomes. Although there was a trend toward significance of KRAS mutations for patients with primary rectal cancers, it failed to achieve statistical significance.

Animal Models for the Calculation of Circulating Tumor Cells for Experimental Demonstration.

Metastasis is a process which is characterized by the existence of tumor cells in the bloodstream. This is a necessary situation in order for the malignant cells to be transported to other organs. Thus, the importance of circulating tumor cells (CTCs) in the study of carcinogenesis is widely accepted. These tumor cells are nowadays a topic of intensive research all over the world. CTCs are expressed from tumor cells and the clinical analysis of this expression may help the recognition of a tumor in an earlier stage and also there is an effort to monitor the tumor burden according to these cells. Although a plethora of clinical studies has been conducted, it is still unclear whether the use in clinical aspect will prove to be beneficial in the near future. Few animal models with neoplasia have been studied concerning the circulating tumor cells and it is likely that CTCs may have a predictive, diagnostic or therapeutic value. Herein, the authors review all studies in which human CTCs were transplanted into animals. Therefore, more clinical studies using standardized methods for measuring CTCs are required to elucidate these issues.

The Interplay Between Innate Immunity (TLR-4) and sCD40L in the Context of an Animal Model of Colitis-associated Cancer.

BACKGROUND/AIM: Several studies have found elevated soluble CD40 Ligand (sCD40L) in the serum of patients with malignancies as well as those with inflammatory bowel disease (IBD). Our goal was to determine the possible causal role of sCD40L in colitis-associated colorectal cancer (CAC) by using the well-established azoxymethane/dextran sulfate sodium (AOM/DSS) protocol. MATERIALS AND METHODS: Twelve wild type (WT) and twelve TLR4 knock out (KO) female C57BL6 mice were divided into 4 experimental groups. Six WT and six TLR4 KO mice were treated with a single intraperitoneal dose (10 mg/kg of body weight) of AOM followed by three 7-day cycles of oral 2.5% DSS. The other two groups included 6 WT and 6 TLR4 KO mice that received only water and served as the control groups. The mice were sacrificed after 84 days. RESULTS: All mice in the AOM/DSS WT group developed CAC while all mice from the AOM/DSS TLR4 KO group were protected from CAC. We measured the serum and pathologic tissue levels of sCD40L with quantitative sandwich enzyme-linked immunoassay (ELISA) and found that serum sCD40L was significantly higher in wild-type mice that developed CAC compared to their healthy counterparts (wild-type and TLR-4 KO controls). In comparison, serum sCD40L levels were comparable between TLR-4 KO mice, which are protected from developing CAC, and their healthy counterparts (wild-type and TLR-4 KO controls). Of note, tissue levels of sCD40L were not affected by the development of CAC. CONCLUSION: Our findings point to the presence of an axis between TLR-4 and sCD40L, which may lead to decreased immunosurveillance and the subsequent development of colitis-associated cancer.

Platelet Depletion/Transfusion as a Lethal Factor in a Colitis-associated Cancer Mouse Model.

BACKGROUND/AIM: TLR-4 Knock-out (KO) mice are protected from colitis-associated cancer in the established AOM/DSS mouse model. The aim of this study was to assess whether the TLR4 KO mice would still be protected from carcinogenesis after platelet depletion and transfusion with TLR4 wild-type platelets. MATERIALS AND METHODS: Thirty-two female C57BL6 mice were divided into 6 groups. Among the three groups that received Azoxymethane/Dextran Sulfate Sodium (AOM/DSS), one group included TLR4KO mice, which were depleted of their platelets and were then transfused with platelets from TLR4 wild-type mice. The other two groups included wild-type and TLR-4KO mice that only received AOM/DSS. RESULTS: All 6 animals in the KO group that underwent platelet depletion/transfusion succumbed. Three of them died before the administration of DSS and three in the week following DSS administration. In contrast, mice in the other two groups experienced less weight loss and only 1 mouse died in each of them. CONCLUSION: Platelet depletion/transfusion was detrimental in TLR-4 transgenic mice that received AOM/DSS.

KRAS mutational status impacts pathologic response to pre-hepatectomy chemotherapy: a study from the International Genetic Consortium for Liver Metastases.

BACKGROUND: A major response to pre-hepatectomy chemotherapy has been associated with improved survival in patients who undergo resection of colorectal liver metastases (CRLM). However, the role of tumor biology, as exemplified by overall and codon-specific KRAS mutational status, in predicting response to chemotherapy is not well defined. METHODS: Pathologic response was characterized as minor or major depending on the percentage of remnant viable cells (>50% vs <50%, respectively). Multivariable logistic regression was used to identify factors associated with major response. RESULTS: 319 patients met inclusion criteria. 229 patients had a KRAS wild-type (wtKRAS) tumor and 90 harbored KRAS mutations (mutKRAS). A major pathologic response was more commonly noted in patients with wtKRAS compared to mutKRAS (48.5% vs 33.3%, P = 0.01) and wtKRAS status remained independently associated with a major response (P = 0.04). On a codon-specific level, major pathologic response occurred less frequently in those with codon 13 mutations (17.7%) compared to those with codon 12 (35.4%), and other KRAS mutations (33.3%). Importantly, codon 13 mutations were independently associated with minor pathologic response (P = 0.023). CONCLUSIONS: Patients with wtKRAS tumors appear to have the highest likelihood of experiencing a major response after preoperative chemotherapy. Future studies in "all-comer" cohorts are needed to confirm these findings and further investigate the response of codon 13 mutations.

Enhanced Recovery After Surgery: Is It Time to Change Our Strategy Regarding Laparoscopic Colectomy?

Enhanced recovery after surgery or 'fast-track' methods are evidence-based protocols designed to standardize post-operative medical care, improve patient outcomes, promote early recovery, and reduce healthcare expenditure. Fast-track surgery is a multifunctional concept involving pre-, peri- and post-operative measures aiming to reduce the length of hospital stay and morbidity and complication rates, following elective abdominal surgery. Through the optimization of peri-operative care and the recovery process in adherence to these fast-track protocols, improved outcomes are reached, surgical trauma and post-operative stress are reduced, with less surgical pain, reduced complications, and shorter length of hospital stay. Fast-track care requires a multidisciplinary collaboration of all healthcare professionals, as well as a high rate of protocol compliance and a good organizational structure. Despite the existing evidence of the benefits of fast-track protocols in a variety of surgical procedures and the similar outcomes of laparoscopic colonic surgery compared to open surgery, clear evidence of the benefits of fast-track care after laparoscopic colonic surgery is yet to be clearly demonstrated.

Combined Hepatic Resection and Radio-frequency Ablation for Patients with Colorectal Cancer Liver Metastasis: A Viable Option for Patients with a Large Number of Tumors.

BACKGROUND/AIM: Radiofrequency ablation (RFA) is thought to result in inferior prognosis than hepatic resection among patients with colorectal liver metastasis (CRLM). However, resection plus RFA may be an option for patients with a large number of tumors (≥4 liver lesions) and borderline resectability. MATERIALS AND METHODS: A total of 717 patients with CRLM who underwent hepatic resection +/- RFA at two tertiary institutions between 09/01/2000-12/01/2015 were eligible for inclusion in this study. RESULTS: Among patients with <4 lesions (n=568), OS in the resection + RFA group (n=48) was significantly worse than in the resection alone group (n=520) (5-year OS: 34.4 % versus 58.9%, p=0.007). Conversely, in patients with ≥4 lesions, OS in the resection + RFA (n=68) and resection alone(n=81) groups were not significantly different (5-year OS: 31.9% versus 34.1%, p=0.48). In patients with <4 lesions, carcinoembryonic antigen (CEA) ≥30 ng/ml, extrahepatic metastasis, preoperative chemotherapy and resection + RFA were independently associated with poor prognosis. Interestingly, in patients with ≥4 lesions, positive primary lymph nodes, KRAS mutation, CEA ≥30 ng/ml and extrahepatic metastasis were independent predictors of poor prognosis; however, the combination of hepatic resection with RFA was not associated with worse survival (p=0.93). CONCLUSION: Although surgeons should always strive for R0 resection when feasible, combined resection and RFA may be a viable alternative for CRLM patients with a large number of tumors.

Detecting Novel Urine Biomarkers for the Early Diagnosis of Prostate Cancer: Platelet Derived Growth Factor-BB as a Possible New Target.

INTRODUCTION: Although the prostate specific antigen revolutionized the diagnosis of prostate cancer (PCa), it has its limitations. We prospectively examined the potential use of the platelet-derived growth factor-BB (PDGF-BB) as a urine biomarker for the early diagnosis of PCa. MATERIALS AND METHODS: The urine samples of 118 patients were collected after a prostatic massage and all the patients subsequently underwent ultrasound-guided transrectal biopsy. PDGF-BB was detected in the urine by enzyme-linked immunosorbent assay. RESULTS: Patients with PCa had greater levels of prostate specific antigen and PDGF-BB. Receiver operating characteristic curve analysis showed that the optimal cut-of of PDGF-BB for the prediction of PCa was 1,504.9 with a sensitivity of 60% and a specificity of 51.3%. For a 100 unit increase in PDGF-BB, the likelihood for PCa increased about 4%. CONCLUSION: PDGF-BB showed a significant predictive ability for PCa. Detection of PDGF-BB in urine with Elisa was easy and improved our diagnostic accuracy in the diagnosis of PCa.

A Novel Modification of the AOM/DSS Model for Inducing Intestinal Adenomas in Mice.

BACKGROUND/AIM: Our aim was to develop an animal model of the precancerous stages of colitis-associated carcinogenesis by modifying the established azoxymethane/dextran sulfate sodium (AOM/DSS) protocol. MATERIALS AND METHODS: Six mice were treated with varying cycles of DSS following AOM administration as above (group 1: three mice received three 5-day cycles of 3.0% DSS and group 2: three mice received three 7-day cycles of 2.5% DSS; every cycle was followed by a 2-week rest period) and were sacrificed on day 84 of the experiment. By contrast, three female C57BL6 mice (group 3) were treated with a single intraperitoneal dose (10 mg/kg of body weight) of AOM followed by three 5-day cycles of oral 2.5% DSS, with each cycle interrupted by a 2-week rest period. The mice of this group were sacrificed at 60 days. RESULTS: In groups 1 and 2, cancer was noted in five out of the six mice. In group 3, adenomas with dysplastic lesions were noted in all of the mice, but none had developed adenocarcinoma. CONCLUSION: Our results suggest that the administration of three 5-day cycles of 2.5% DSS following an initial dose of AOM may successfully induce adenoma formation without the concurrent presence of carcinoma in female C57BL6 mice that are sacrificed on experimental day 60. In turn, this modification of the widely used AOM/DSS protocol may constitute a novel approach for investigating colitis-related colonic adenomas.

The Role of Soluble CD40L Ligand in Human Carcinogenesis.

BACKGROUND: The role of CD40/CD40L in carcinogenesis is widely examined. The mechanisms linking the CD40/CD40L system and the soluble form of CD40 ligand (sCD40L) with neoplasia are nowadays a topic of intensive research. CD40L and sCD40L belong to the TNF superfamily and are molecules with a proinflammatory role. A variety of cells express CD40L such as the immune system cells, the endothelial cells and activated platelets. Although many medications such as statins have been shown to reduce sCD40L, it is still debated whether specific treatments targeting the CD40/CD40L system will prove to be effective against carcinogenesis in the near future. MATERIALS AND METHODS: A comprehensive search of the Pubmed Database was conducted for English-language studies using a list of key words. RESULTS: At diagnosis, serum samples of patients with neoplasia contained higher levels of sCD40L than healthy controls, suggesting that sCD40L may play a predictive role in human carcinogenesis. CONCLUSION: Patients with neoplasia had higher circulating sCD40L levels and it is likely that sCD40L may have a predictive role. It is still unclear whether sCD40L can be used as a therapeutic target.

Incidence and Risk Factors for Organ/Space Infection after Radiofrequency-Assisted Hepatectomy or Ablation of Liver Tumors in a Single Center: More than Meets the Eye.

INTRODUCTION: Surgical site infections (SSIs) and especially organ/space infection (O/SI) after resection or ablation of liver tumors are associated with increased morbidity and mortality. A secondary blood stream infection (BSI) is considered an O/SI but the exact prevalence is unknown. We aimed to investigate the incidence of O/SI and BSIs in a cohort of consecutive patients after liver resection or ablation, to seek for a possible connection between them and to search for potential risk factors. MATERIALS AND METHODS: We reviewed all patients who underwent hepatic resection or intraoperative liver ablation between January 2012 and December 2016 in our department. We focused on age, gender, Child-Pugh score, preoperative biliary drainage, indication for surgery, type of resection, resection or ablation of tumor, need for bilioenteric reconstruction, additional procedure to hepatectomy, blood transfusion, operative time, postoperative admission to ICU, and antibiotic chemoprophylaxis. All positive cultures from intra-abdominal fluids and blood were recorded. O/SI and BSIs were diagnosed by the criteria set by Centers for Disease Control. All variables were compared between the group with O/SI and the group without infection. BSIs were associated with these infections also. RESULTS: Eighty-one consecutive patients with a mean age of 64 years were enrolled. Fifteen patients presented a positive culture postoperatively: intra-abdominal fluid in eight, blood cultures in six, and both blood and intra-abdominal fluid in one patient. The directly estimated incidence of O/SI amounted to 11.1%. Four blood cultures were secondary to O/SI, and the remaining two secondary to central line catheter. O/SI was diagnosed indirectly, through the BSI in an additional 4.9% of the patients, raising the incidence of SSI to 16%. Among the factors studied, only admission to the ICU was found to be statistically significant as a risk factor for the development of O/SI (p = 0.026). CONCLUSION: O/SI should be actively seeked for after liver surgery including blood cultures. Patients with affected physical status, comorbidities are in greater risk of developing O/SI.

Laparoscopic Approach in Colonic Diverticulitis: Dispelling Myths and Misperceptions.

BACKGROUND/AIM: Diverticular disease is a first-class health care problem and one of the most common gastrointestinal disorders in western industrialized countries, causing significant morbidity and mortality. In this review of the literature, we aim to assess the feasibility and effectiveness of the laparoscopic approach in both elective and emergency setting of diverticular disease. MATERIALS AND METHODS: A bibliographic search of articles was performed using the electronic database Medline from PubMed. Of 341 articles identified, 279 were excluded, resulting in 62 full-text articles for review. Our final review included 16 articles. RESULTS: The 16 articles included in the final review consisted of 6 retrospective studies, 5 prospective studies, 2 randomized controlled trials, 1 systematic review and meta-analysis, and 2 systematic reviews. Seven articles considered elective laparoscopic sigmoid resection, 7 articles evaluated laparoscopic peritoneal lavage, and 2 articles considered emergency laparoscopic sigmoid resection for perforated diverticulitis. The elective laparoscopic approach is feasible and safe. Laparoscopic peritoneal lavage has emerged as a safe and effective minimally invasive procedure for the treatment of perforated diverticulitis. Furthermore, in selected patients, emergency laparoscopic sigmoidectomy could also be feasible for perforated diverticulitis with generalized peritonitis. CONCLUSIONS: Laparoscopic approach can be a safe and effective option in both elective and emergency setting of diverticular disease. Large, prospective, randomized studies should be conducted to confirm these findings.

Single-Incision Laparoscopic Sleeve Gastrectomy: Review and a Critical Appraisal.

BACKGROUND: Single-incision laparoscopic surgery has attracted a great deal of interest in the surgical community in recent years, including bariatric surgery. Single-incision laparoscopic sleeve gastrectomy (SILSG) has been proposed as an alternative to the multiport laparoscopic procedure; however, it has yet to meet wide acceptance and application. OBJECTIVE: We aim to summarize existing data on SILSG and check the procedure's feasibility, technical details, safety, and, if possible, outcomes. MATERIALS AND METHODS: We checked the most important databases for studies concerning SILSG and included all these that summarized the criteria placed and contained the data needed for this review. We excluded case reports. RESULTS: Nineteen studies complied with the criteria of our review, containing a total of 1679 patients. Their mean age has been 38.91 years and the mean preoperative body mass index has been 41.8 kg/m2. In majority of cases (60.5%), a left upper quadrant incision has been preferred and in 97.6%, a commercially available multiport system has been picked. A wide variety of instruments have been used and mean operating time has been 94.6 minutes. One conversion to open surgery has been reported and 7.4% required the placement of additional ports. There was a complication rate of 7.38% (most common being bleeding with a rate of 2.5%) and a reoperation rate of 2.8%. Mean excess weight loss for a follow-up of 1 year was achieved in 53.7% of patients and was 70.06%. A tendency for less analgesia and better wound satisfaction has been reported. CONCLUSIONS: SILSG is safe and feasible. However, there is insufficient evidence to recommend it as the new gold standard for sleeve gastrectomy in the place of conventional laparoscopic sleeve gastrectomy. Randomized controlled trials are needed to analyze the results and the possible benefits of this technique.

Damage Control for Vascular Trauma from the Prehospital to the Operating Room Setting.

Early management of vascular injury, starting at the field, is imperative for survival no less than any operative maneuver. Contemporary prehospital management of vascular trauma, including appropriate fluid and volume infusion, tourniquets, and hemostatic agents, has reversed the historically known limb hemorrhage as a leading cause of death. In this context, damage control (DC) surgery has evolved to DC resuscitation (DCR) as an overarching concept that draws together preoperative and operative interventions aiming at rapidly reducing bleeding from vascular disruption, optimizing oxygenation, and clinical outcomes. This review addresses contemporary DCR techniques from the prehospital to the surgical setting, focusing on civilian vascular injuries.

Robotic single port cholecystectomy: current data and future perspectives.

INTRODUCTION: Minimally invasive techniques are used more and more frequently. Since conventional laparoscopic approach has been the gold standard, surgeons in their effort to further reduce the invasiveness of conventional laparoscopic cholecystectomy have adopted Single Incision approach. The widespread adoption of robotics has led to the inevitable hybridization of robotic technology with laparoendoscopic single-site surgery (LESS). As a result, employment of the da Vinci surgical system may allow greater surgical maneuverability, improving ergonomics. EVIDENCE ACQUISITION: A review of the English literature was conducted to evaluate all robotic single port cholecystectomy performed till today. Demographic data, operative parameters, postoperative outcomes and materials used for the operation were collected and assessed. EVIDENCE SYNTHESIS: A total of 12 studies, including 501 patients were analyzed. Demographics and clinical characteristics of the patients was heterogeneous, but in most studies a mean BMI <30 was recorded. Intraoperative metrics like operative time, estimated blood loss and conversion rate were comparable with those in multiport conventional laparoscopy. CONCLUSIONS: Robotic single port cholecystectomy is a safe and feasible alternative to conventional multiport laparoscopic or manual robotic approach. However, current data do not suggest a superiority of robotic SILC over other established methods.

Sorafenib as an adjuvant therapy for resectable hepatocellular carcinoma: A single center experience.

PURPOSE: Resectable hepatocellular carcinoma (HCC) is currently treated with surgical resection without any adjuvant therapy. We sought to assess the value of sorafenib as an adjuvant treatment in that clinical setting. METHODS: Of a total of 30 patients, 16 underwent curative- intent liver resection for HCC and subsequently received adjuvant sorafenib, while 14 underwent surgery alone. Clinicopathological characteristics were analyzed and the impact of adjuvant sorafenib on overall survival (OS) was assessed. RESULTS: The median follow up time was 38.2 months. The median patient age was 63.5 and 76.7% of them were male. The majority of patients had a solitary tumor (74.1%) with a median size of 7.75 cm. Five-year OS for the whole cohort was 60.2%. OS for patients who underwent only resection was 52.9 vs 68.1% for patients who underwent resection and received adjuvant sorafenib (p=0.19). CONCLUSION: Sorafenib seems to be associated with an acceptable safety profile but does not confer any substantial clinical benefit in terms of survival in HCC patients who have undergone curative-intent liver resection.

Prognostic Role of BRAF Mutations in Colorectal Cancer Liver Metastases.

BACKGROUND/AIMS: The impact of tumor biology on prognosis in patients with colorectal liver metastasis (CRLM) has been the topic of intense research. Specifically, the presence of BRAF mutations has been recently associated with adverse long-term outcomes. We examined the existing literature on the prognostic implications of BRAF mutations in patients with CRLM. MATERIALS AND METHODS: A structured review of the literature was performed between 5/1/2016 and 6/1/2016 using the PubMed database. Original research articles published between 1/1/2010 and 4/01/2016 were considered eligible. The primary end-points were overall survival (OS)/disease-specific survival (DSS) and recurrence-free survival (RFS) among patients with BRAF mutated CRLM who underwent resection. RESULTS: Eight studies were included. All studies reported on OS/DSS, while 6 reported on RFS. BRAF mutant status was a strong independent predictor of both worse OS/DSS and RFS in 7 and 4 studies, respectively. CONCLUSION: BRAF-mutant lesions are consistently associated with poor prognosis. Consequently, the indications of CRLM resection in this patient group should be reconsidered.

The TNBS-induced colitis animal model: An overview.

BACKGROUND: Despite recent advances the pathogenesis of Crohn's disease remains incompletely understood. A variety of animal models have been utilized in an effort to provide further insights and develop more therapeutic options. In order to simulate, to an extent, the pathogenesis and the clinical course of the disease, TNBS induced colitis is often used. Various approaches for inducing TNBS -colitis have been described in the literature. METHODS/RESULTS: In this review, we sought to present the animal model of TNBS induced colitis and outline the pathogenesis, pathophysiology, clinical course and pathological characteristics of the model. Furthermore, we describe the differences among those protocols regarding types of animals and colitis induction. DATA SOURCES: The MEDLINE database was thoroughly searched using the keywords: TNBS, colitis, Crohn's disease, animal model. Two investigators independently reviewed the abstracts and appropriate articles were included in this review. Additional articles were gathered and evaluated. CONCLUSION: The aim of this study was to thoroughly present an updated review of the TNBS-induced colitis protocols that are implemented by researchers.

The value of calprotectin S100A8/A9 complex as a biomarker in colorectal cancer: A systematic review.

PURPOSE: Associations between inflammation and carcinogenesis have been reported for many years, as originally postulated by Virchow in his studies, but the results from prospective cohort studies remain controversial. We evaluated the role of calprotectin as a biomarker for colorectal cancer (CRC). METHODS: The MEDLINE/PubMed database was thoroughly searched using the keywords: "inflammation", "colorectal cancer, "calprotectin", "carcinogenesis" and/or "biomarkers". We focused on human and animal (rodent) studies of CRC and the role of calprotectin as a new biomarker and its potential value to the diagnosis, follow-up and CRC prognosis. RESULTS: According to the literature, calprotectin seems to be a reliable sensitive marker in the diagnosis and postoperative evaluation of CRC patients at the cost of low specificity and no correlation with the progress and stage of disease. CONCLUSIONS: Calprotectin stands for a novel but well-evaluated biomarker in CRC. The experimental studies focus on the CRC microenvironment and suggest that malignant cells and tissues overexpress S100A8 and S100A9 and the heterodimer S100A8/A9.