Surgical Management of Gallbladder Cancer Patients

Gallbladder cancer (GBC) is the most common biliary tract malignancy and remains highly lethal. The best survival is obtained if GBC is diagnosed at an early stage and complete (R0) resection is achieved. This chapter provides an overview of the current state of surgical management of GBC patients and is structured according to the patient’s presentation. First, epidemiology, risk factors, and staging are discussed, followed by an overview of the current indications for surgical treatment. Next, surgical approach is described in detail according to the mode of presentation: incidental GBC (i.e., intra- or postoperatively during routine cholecystectomy) or in symptomatic patients with findings suspicious for malignancy on imaging. Furthermore, surgical controversies such as the extent of resection are discussed. Finally, postoperative care and complications as well as adjuvant and palliative treatment are depicted.</p

Gallbladder Cancer:Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

SIMPLE SUMMARY: Knowledge of genetic alterations in gallbladder cancer (GBC) continues to increase. This systematic review provides an overview of frequently occurring genetic alterations in GBC and describes their possible therapeutic implications. We detected three frequently (>5%) altered genes (ATM, ERBB2 and PIK3CA) for which targeted therapies are available in other cancer types. For solid cancers with microsatellite instability or a high tumor mutational burden pembrolizumab is FDA-approved. Altogether, these five biomarkers might be used in future molecular panels to enable precision medicine for patients with GBC. We found only nine clinical trials evaluating targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials. ABSTRACT: Due to the fast progression in molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) increases. This systematic review provides an overview of frequently occurring genetic alterations occurring in GBC and their possible therapeutic implications. A literature search was performed utilizing PubMed, EMBASE, Cochrane Library, and Web of Science. Only studies reporting genetic alterations in human GBC were included. In total, data were extracted from 62 articles, describing a total of 3893 GBC samples. Frequently detected genetic alterations (>5% in >5 samples across all studies) in GBC for which targeted therapies are available in other cancer types included mutations in ATM, ERBB2, and PIK3CA, and ERBB2 amplifications. High tumor mutational burden (TMB-H) and microsatellite instability (MSI-H) were infrequently observed in GBC (1.7% and 3.5%, respectively). For solid cancers with TMB-H or MSI-H pembrolizumab is FDA-approved and shows an objective response rates of 50% for TMB-H GBC and 41% for MSI-H biliary tract cancer. Only nine clinical trials evaluated targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM, and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials

Treatment patterns and survival in older adults with unresected nonmetastatic biliary tract cancers

INTRODUCTION: The optimal treatment for unresected nonmetastatic biliary tract cancer (uBTC) is not well-established. The objective of this study was to analyze the treatment patterns and compare the differences in overall survival (OS) between different treatment strategies amongst older adults with uBTC.MATERIALS AND METHODS: We identified patients aged ≥65 years with uBTC using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2004-2015). Treatments were classified into chemotherapy, chemoradiotherapy, and radiotherapy. The primary outcome was OS. The differences in OS were analyzed using Kaplan-Meier curves and multivariable Cox proportional hazard regression.RESULTS: A total of 4352 patients with uBTC were included. The median age was 80 years and median OS was 4.1 months. Most patients (67.3%, n = 2931) received no treatment, 19.1% chemotherapy (n = 833), 8.1% chemoradiotherapy (n = 354), and 5.4% radiotherapy alone (n = 234). Patients receiving no treatment were older and had more comorbidities. Chemotherapy was associated with significantly longer OS than no treatment in uBTC (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.79-0.95), but no difference was found in the subgroups of intrahepatic cholangiocarcinoma (iCCA; HR 0.87, 95% CI 0.75-1.00) and gallbladder carcinoma (GBC; HR 1.09, 95% CI 0.86-1.39). In the sensitivity analyses, capecitabine-based chemoradiotherapy showed significantly longer OS in uBTC compared to chemotherapy (adjusted HR 0.71, 95% CI 0.53-0.95).DISCUSSION: A minority of older patients with uBTC receive systemic treatments. Chemotherapy was associated with longer OS compared to no treatment in uBTC, but not in the subgroups of iCCA and GBC. The efficacy of chemoradiotherapy, especially in perihilar cholangiocarcinoma using capecitabine-based chemoradiotherapy, may be further evaluated in prospective clinical trials.</p

Assessment of available evidence in the management of gallbladder and bile duct stones:a systematic review of international guidelines

BACKGROUND: Gallstone disease is a frequent disorder in the Western world with a prevalence of 10-20%. Recommendations for the assessment and management of gallstones vary internationally. The aim of this systematic review was to assess quality of guideline recommendations for treatment of gallstones. METHODS: PubMed, EMBASE and websites of relevant associations were systematically searched. Guidelines without a critical appraisal of literature were excluded. Quality of guidelines was determined using the AGREE II instrument. Recommendations without consensus or with low level of evidence were considered to define problem areas and clinical research gaps. RESULTS: Fourteen guidelines were included. Overall quality of guidelines was low, with a mean score of 57/100 (standard deviation 19). Five of 14 guidelines were considered suitable for use in clinical practice without modifications. Ten recommendations from all included guidelines were based on low level of evidence and subject to controversy. These included major topics, such as definition of symptomatic gallstones, indications for cholecystectomy and intraoperative cholangiography. CONCLUSION: Only five guidelines on gallstones are evidence-based and of a high quality, but even in these controversy exists on important topics. High quality evidence is needed in specific areas before an international guideline can be developed and endorsed worldwide

The role of sagittal pelvic morphology in the development of adult degenerative scoliosis

Purpose: Pelvic morphology dictates the alignment and biomechanics of the spine. Recent observations in different types of adolescent idiopathic scoliosis indicate that individual pelvic morphology is related to the spinal levels in which scoliosis develops: primary lumbar adolescent scoliosis is associated with a higher pelvic incidence (PI) than thoracic scoliosis and non-scoliotic controls. We hypothesize that adult degenerative scoliosis (ADS) of the lumbar spine follows the same mechanical principles and is associated with a high PI. Methods: This study used an existing CT-scan database, 101 ADS patients were sex and age matched to 101 controls. The PI was measured by two observers with multi-planar reconstruction, perpendicular to the hip-axis according to a previously validated technique. Results: The PI was 54.1° ± 10.8° in ADS patients and 47.7° ± 10.8° in non-scoliotic controls (p < 0.001). The median ADS curve apex was the disc L2-3 and median curve length was 4 vertebral levels. The mean supine Cobb angle was 21° ± 8° (ranged 10°–47°). There was no significant correlation between PI and the apex level (p = 0.883), the curve length (p = 0.418) or the Cobb angle (p = 0.518). Conclusions: ADS normally develops de novo in the lumbar spine of patients with a higher PI than controls, similar to primary lumbar adolescent idiopathic scoliosis. This suggests a shared mechanical basis of both deformities. Pelvic morphology dictates spinal sagittal alignment, which determines the segments of the spine that are prone to develop scoliosis

Perioperative SARS-CoV-2 infections increase mortality, pulmonary complications, and thromboembolic events : a Dutch, multicenter, matched-cohort clinical study

Background: A direct comparison of severe acute respiratory syndrome coronavirus 2 positive patients with a severe acute respiratory syndrome coronavirus 2 negative control group undergoing an operative intervention during the current pandemic is lacking, and a reliable estimate of the assumed difference in morbidity and mortality between both patient categories remains unknown. Methods: We included all consecutive patients with a confirmed pre- or postoperative severe acute respiratory syndrome coronavirus 2 positive status (operated in 27 hospitals) and negative control patients (operated in 4 hospitals) undergoing emergency or elective operations. A propensity score-matched comparison of clinical outcomes was performed between severe acute respiratory syndrome coronavirus 2 positive and negative tested patients (control group). Primary outcome was overall 30-day mortality rate between both groups. Main secondary outcomes were overall, pulmonary, and thromboembolic complications. Results: In total, 161 severe acute respiratory syndrome coronavirus 2 positive and 342 control severe acute respiratory syndrome coronavirus 2 negative patients were included in this study. The 30-day overall postoperative mortality rate was greater in the severe acute respiratory syndrome coronavirus 2 positive cohort compared with the negative control group (16% vs 4% respectively; P = .007). After propensity score matching, the severe acute respiratory syndrome coronavirus 2 positive group consisted of 123 patients (median 70 years of age [interquartile range 59-77] and 55% male) were compared with 196 patients in the matched control group (median 69 years (interquartile range 58-75] and 53% male). The 30-day mortality rate and risk were greater in the severe acute respiratory syndrome coronavirus 2 positive group compared with the matched control group (12% vs 4%; P = .009 and odds ratio 3.4 [95% confidence interval 1.5-8.5]; P = .005, respectively). Overall, pulmonary and thromboembolic complications occurred more often in severe acute respiratory syndrome coronavirus 2 positive patients (P < .01). Conclusion: Patients diagnosed with perioperative severe acute respiratory syndrome coronavirus 2 have an increased risk of 30-day mortality, pulmonary complications, and thromboembolic events. These findings serve as an evidence-based argument to postpone elective surgery and selected emergency cases. (C) 2020 The Author(s). Published by Elsevier Inc

Development of a prediction model for recurrence in patients with colorectal peritoneal metastases undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy

INTRODUCTION: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes for selected patients with colorectal peritoneal metastases (PM), but recurrence rates are high. The aim of this study was to develop a tool to predict recurrence in patients with colorectal PM that undergo CRS-HIPEC.MATERIALS AND METHODS: For this retrospective cohort study, data of patients that underwent CRS-HIPEC for colorectal PM from four Dutch HIPEC centers were used. Exclusion criteria were perioperative systemic therapy and peritoneal cancer index (PCI) ≥20. Nine previously identified factors were considered as predictors: gender, age, primary tumor characteristics (location, nodal stage, differentiation, and mutation status), synchronous liver metastases, preoperative Carcino-Embryonal Antigen (CEA), and peritoneal cancer index (PCI). The prediction model was developed using multivariable Cox regression and validated internally using bootstrapping. The performance of the model was evaluated by discrimination and calibration.RESULTS: In total, 408 patients were included. During the follow-up, recurrence of disease occurred in 318 patients (78%). Significant predictors of recurrence were PCI (HR 1.075, 95% CI 1.044-1.108) and primary tumor location (left sided HR 0.719, 95% CI 0.550-0.939). The prediction model for recurrence showed fair discrimination with a C-index of 0.64 (95% CI 0.62, 0.66) after internal validation. The model was well-calibrated with good agreement between the predicted and observed probabilities.CONCLUSION: We developed a prediction tool that could aid in the prediction of recurrence in patients with colorectal PM who undergo CRS-HIPEC.</p

Development of a prediction model for recurrence in patients with colorectal peritoneal metastases undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy

INTRODUCTION: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes for selected patients with colorectal peritoneal metastases (PM), but recurrence rates are high. The aim of this study was to develop a tool to predict recurrence in patients with colorectal PM that undergo CRS-HIPEC.MATERIALS AND METHODS: For this retrospective cohort study, data of patients that underwent CRS-HIPEC for colorectal PM from four Dutch HIPEC centers were used. Exclusion criteria were perioperative systemic therapy and peritoneal cancer index (PCI) ≥20. Nine previously identified factors were considered as predictors: gender, age, primary tumor characteristics (location, nodal stage, differentiation, and mutation status), synchronous liver metastases, preoperative Carcino-Embryonal Antigen (CEA), and peritoneal cancer index (PCI). The prediction model was developed using multivariable Cox regression and validated internally using bootstrapping. The performance of the model was evaluated by discrimination and calibration.RESULTS: In total, 408 patients were included. During the follow-up, recurrence of disease occurred in 318 patients (78%). Significant predictors of recurrence were PCI (HR 1.075, 95% CI 1.044-1.108) and primary tumor location (left sided HR 0.719, 95% CI 0.550-0.939). The prediction model for recurrence showed fair discrimination with a C-index of 0.64 (95% CI 0.62, 0.66) after internal validation. The model was well-calibrated with good agreement between the predicted and observed probabilities.CONCLUSION: We developed a prediction tool that could aid in the prediction of recurrence in patients with colorectal PM who undergo CRS-HIPEC.</p

Towards Equal Access to Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy and Survival in Patients with Isolated Colorectal Peritoneal Metastases:A Nationwide Population-Based Study

Background: Before 2016, patients with isolated synchronous colorectal peritoneal metastases (PMCRC) diagnosed in expert centers had a higher odds of undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) and better overall survival (OS) than those diagnosed in referring centers. Nationwide efforts were initiated to increase awareness and improve referral networks. Methods: This nationwide study aimed to evaluate whether the between-center differences in odds of undergoing CRS-HIPEC and OS have reduced since these national efforts were initiated. All patients with isolated synchronous PMCRC diagnosed between 2009 and 2021 were identified from the Netherlands Cancer Registry. Associations between hospital of diagnosis and the odds of undergoing CRS-HIPEC, as well as OS, were assessed using multilevel multivariable regression analyses for two periods (2009–2015 and 2016–2021). Results: In total, 3948 patients were included. The percentage of patients undergoing CRS-HIPEC increased from 17.2% in 2009–2015 (25.4% in expert centers, 16.5% in referring centers), to 23.4% in 2016–2021 (30.2% in expert centers, 22.6% in referring centers). In 2009–2015, compared with diagnosis in a referring center, diagnosis in a HIPEC center showed a higher odds of undergoing CRS-HIPEC (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.02–2.67) and better survival (hazard ratio [HR] 0.80, 95% CI 0.66–0.96). In 2016–2021, there were no differences in the odds of undergoing CRS-HIPEC between patients diagnosed in HIPEC centers versus referring centers (OR 1.27, 95% CI 0.76–2.13) and survival (HR 1.00, 95% CI 0.76–1.32). Conclusion: Previously observed differences in odds of undergoing CRS-HIPEC were no longer present. Increased awareness and the harmonization of treatment for PMCRC may have contributed to equal access to care and a similar chance of survival at a national level.</p