Benchmarks and Geographic Differences in Gallbladder Cancer Surgery: An International Multicenter Study.

BACKGROUND: High-quality surgery plays a central role in the delivery of excellent oncologic care. Benchmark values indicate the best achievable results. We aimed to define benchmark values for gallbladder cancer (GBC) surgery across an international population. PATIENTS AND METHODS: This study included consecutive patients with GBC who underwent curative-intent surgery during 2000-2021 at 13 centers, across seven countries and four continents. Patients operated on at high-volume centers without the need for vascular and/or bile duct reconstruction and without significant comorbidities were chosen as the benchmark group. RESULTS: Of 906 patients who underwent curative-intent GBC surgery during the study period, 245 (27%) were included in the benchmark group. These were predominantly women (n = 174, 71%) and had a median age of 64 years (interquartile range 57-70 years). In the benchmark group, 50 patients (20%) experienced complications within 90 days after surgery, with 20 patients (8%) developing major complications (Clavien-Dindo grade ≥ IIIa). Median length of postoperative hospital stay was 6 days (interquartile range 4-8 days). Benchmark values included ≥ 4 lymph nodes retrieved, estimated intraoperative blood loss ≤ 350 mL, perioperative blood transfusion rate ≤ 13%, operative time ≤ 332 min, length of hospital stay ≤ 8 days, R1 margin rate ≤ 7%, complication rate ≤ 22%, and rate of grade ≥ IIIa complications ≤ 11%. CONCLUSIONS: Surgery for GBC remains associated with significant morbidity. The availability of benchmark values may facilitate comparisons in future analyses among GBC patients, GBC surgical approaches, and centers performing GBC surgery.

Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic: Chilean Air Force Experience in the Air Transport of Critically Ill Patients-The First 100 Cases.

OBJECTIVE: Critical care air transport has played an important role during the coronavirus disease 2019 (COVID-19) pandemic. The goal of this article is to analyze results and lessons learned from the evacuation of the first 100 COVID-19 patients transported between medical facilities in Chile. METHODS: We reviewed prospective data of patients who were referred for air transport between March 27, 2020, and July 9, 2020. RESULTS: Of 115 referred patients, 100 were transported by air. All patients were intubated and mechanically ventilated. Hypertension, diabetes, and obesity were the most commonly observed comorbidities. Our service did not experience any major problems in patient care en route or among the crewmembers. We did not observe any severe acute respiratory syndrome coronavirus 2 infections among our flight team members during the study period. Twelve (12%) patients died at their destination intensive care unit, whereas the remaining 88 patients (88%) returned to their primary hospitals after recovery. CONCLUSIONS: Air transport of mechanically ventilated patients with COVID-19 infection has been shown to be a safe way of transport, with no in-flight deaths and an in-hospital mortality of 12%, which compares favorably with the in-hospital mortality of similar patients who did not undergo air transport.

Conditional Recurrence-Free Survival after Oncologic Extended Resection for Gallbladder Cancer: An International Multicenter Analysis.

BACKGROUND: Data to guide surveillance following oncologic extended resection (OER) for gallbladder cancer (GBC) are lacking. Conditional recurrence-free survival (C-RFS) can inform surveillance. We aimed to estimate C-RFS and identify factors affecting conditional RFS after OER for GBC. PATIENTS AND METHODS: Patients with ≥ T1b GBC who underwent curative-intent surgery in 2000-2018 at four countries were identified. Risk factors for recurrence and RFS were evaluated at initial resection in all patients and at 12 and 24 months after resection in patients remaining recurrence-free. RESULTS: Of the 1071 patients who underwent OER, 484 met the inclusion criteria; 290 (60%) were recurrence-free at 12 months, and 199 (41%) were recurrence-free at 24 months. Median follow-up was 24.5 months for all patients and 47.21 months in survivors at analysis. Five-year RFS rates were 47% for the overall population, 71% for patients recurrence-free at 12 months, and 87% for the patients without recurrence at 24 months. In the entire cohort, the risk of recurrence peaked at 8 months. T3-T4 disease was independently associated with recurrence in all groups: entire cohort [hazard ratio (HR) 2.16, 95% confidence interval (CI) 1.49-3.13, P < 0.001], 12-month recurrence-free (HR 3.42, 95% CI 1.88-6.23, P < 0.001), and 24-month recurrence-free (HR 2.71, 95% CI 1.11-6.62, P = 0.029). Of the 125 patients without these risk factors, only 2 had recurrence after 36 months. CONCLUSION: C-RFS improves over time, and only T3-T4 disease remains a risk factor for recurrence at 24 months after OER for GBC. For all recurrence-free survivors after 36 months, the probability of recurrence is similar regardless of T category or disease stage.

Gallbladder cancer who is really cured?

BACKGROUND: Although gallbladder cancer (GBCA) is characterized by a dismal prognosis, there is a proportion of patients who are cured. The aim of this study was to analyze the profile of these patients. METHODS: A database was queried for patients who underwent curative resection with a follow-up of at least 5 years. Patients were prospectively treated and registered by the same surgical team. A multivariate regression analysis was used to identify factors associated with long-term survival. RESULTS: From 1988 to 2013, 461 patients were evaluated and 112 who underwent resection were analyzed. Among the patients, five year survival was 57% while lymph node and liver compromise were the only independent factors associated with survival. On the other hand, the elapsed time between the cholecystectomy and the resection, the differentiation grade and the level of wall invasion did not have an independent effect on the prognosis. CONCLUSION: Despite its poor prognosis, a subset of patients can be cured of GBCA. R0 resection of patients without lymph and liver infiltration are key to GBCA survival.

Choices of Therapeutic Strategies for Colorectal Liver Metastases Among Expert Liver Surgeons: A Throw of the Dice?

OBJECTIVE: To test the degree of agreement in selecting therapeutic options for patients suffering from colorectal liver metastasis (CRLM) among surgical experts around the globe. SUMMARY/BACKGROUND: Only few areas in medicine have seen so many novel therapeutic options over the past decades as for liver tumors. Significant variations may therefore exist regarding the choices of treatment, even among experts, which may confuse both the medical community and patients. METHODS: Ten cases of CRLM with different levels of complexity were presented to 43 expert liver surgeons from 23 countries and 4 continents. Experts were defined as experienced surgeons with academic contributions to the field of liver tumors. Experts provided information on their medical education and current practice in liver surgery and transplantation. Using an online platform, they chose their strategy in treating each case from defined multiple choices with added comments. Inter-rater agreement among experts and cases was calculated using free-marginal multirater kappa methodology. A similar, but adjusted survey was presented to 60 general surgeons from Asia, Europe, and North America to test their attitude in treating or referring complex patients to expert centers. RESULTS: Thirty-eight (88%) experts completed the evaluation. Most of them are in leading positions (92%) with a median clinical experience of 25 years. Agreement on therapeutic strategies among them was none to minimal in more than half of the cases with kappa varying from 0.00 to 0.39. Many general surgeons may not refer the complex cases to expert centers, including in Europe, where they also engage in complex liver surgeries. CONCLUSIONS: Considerable inconsistencies of decision-making exist among expert surgeons when choosing a therapeutic strategy for CRLM. This might confuse both patients and referring physicians and indicate that an international high-level consensus statements and widely accepted guidelines are needed.

A systematic review of the effectiveness of adjuvant therapy for patients with gallbladder cancer.

BACKGROUND: Equipoise exists regarding the benefit of adjuvant therapy (AT) in patients with gallbladder cancer (GBC). The aim of this study was to critically review the available evidence for the effectiveness of AT in patients with GBC following surgery with curative intent. METHODS: A systematic review was performed. Relevant studies were identified from Trip Database, BIREME-BVS, SciELO, Cochrane Central Register, WoS, MEDLINE, EMBASE and SCOPUS. Adjuvant therapies considered included chemotherapy, chemoradiotherapy, and radiotherapy. The primary outcome was overall survival (OS). Subgorup analysis of patients with positive lymph node disease (PLND), positive surgical margin (PSM), or advanced stage (AS) were performed. RESULTS: 748 related articles were identified; 27 met the selection criteria (3 systematic reviews and 24 observational studies). Evidence provided was moderate, poor and very poor for chemotherapy, chemoradiotherapy, and radiotherapy. Existing evidence is not robust, but suggests certain benefits with AT in improving OS, especially in patients with PLND, PSM and AS. CONCLUSION: Results do not provide strong evidence that AT is effective in patients who undergo resection for GBC. Subgroups of PLND and PSM may have a survival advantage. Future studies with appropriate internal validity and adequate number of patients are required to better answer this question.

Incidental Gallbladder Cancer: How Residual Disease Affects Outcome in Two Referral HPB Centers from South America.

BACKGROUND: Residual disease (RD) has been described as one of the most relevant prognostic factors after radical surgical resection for incidental gallbladder cancer (IGC). The purpose of the present study was to analyze patterns of RD and determinant prognostic factors in patients undergoing re-resection for IGC. METHODS: Patients undergoing re-exploration due to IGC between 1990 and 2014 were identified in two referral centers from different South-American countries. Patients submitted to a radical definitive operation were included in the study. Demographics and tumor-treated related variables were analyzed in correlation with RD and survival. The site of RD, local (gallbladder bed) or regional (lymph nodes and bile duct) was correlated with disease-specific survival (DSS). RESULTS: Of 265 patients with IGC submitted to surgery, 168 underwent a radical re-resection and RD was found in 58 (34.5%). Demographic, clinical and surgical variables were compared between both centers showing differences in type of resection, laparoscopic approach, T stages and disease stage. Location of RD was regional in 34 (20.2%) and local in 24 (14.3%), and no residual disease was found in 110 (65.5%) patients. T stage (T1b = 20%, T2 = 23.8%, T3 = 71.7%, p < 0.001) and disease stage (p < 0.001) were independent predictors of RD. Finding RD at any location reduced the DSS in comparison with non-RD patients (19.6 months vs. 62.7 months p < 0.001). No differences in DSS according to the location of RD were found, and all anatomic sites were equally poor (p = 0.27). RD at any site predicted DSS (p < 0.001), independently of all other IGC variables. CONCLUSIONS: IGC presented similar clinical parameters in two different countries of South America. RD was demonstrated as the most critical prognostic variable in patients with IGC treated by a radical resection. The presence of RD was associated with poor outcome, independently of any anatomic location. Future studies incorporating neoadjuvant chemotherapy in the treatment of patients with prognostic factors for RD are required to improve survival in this entity.

Genetic landscape of gallbladder cancer: Global overview.

Gallbladder cancer (GBC) is a rare malignancy of biliary tract cancer (BTC), characterized by late presentation and poor prognosis. It exhibits wide geographical as well as ethnical variations. So, diverse epidemiology along with etiological factors have been discussed in the current article. Present review unravels the germ line polymorphisms contributing to GBC susceptibility through candidate gene approach and GWAS. GBC is enriched with multiple mutations consisting of both passenger and driver mutations. The identification of the hotspot driver mutations which are involved in the etiopathogenesis of this cancer is necessary, before targeted therapies could be implemented clinically. Thus, this review sheds lights on both traditional low throughput methods along with high throughput NGS used to determine somatic mutations in cancer. With the advent of GWAS and high throughput sequencing methods, it is possible to comprehend the mutational landscape of this enigmatic disease. This article is the first one to provide insights into the genetic heterogeneity of GBC along with somatic mutational data from Catalogue of Somatic Mutations in Cancer (COSMIC) database. In addition, management of tumor heterogeneity as a therapeutic challenge has been discussed. Future goals involve liquid biopsy based research for better clinical management of the disease. Therefore, research efforts involving discovery of non- invasive markers for early stage cancer detection along with novel therapies should be directed.

Laparoscopic management of incidental gallbladder cancer.

BACKGROUND: The laparoscopic cholecystectomy has allowed the detection of an increasing number of incidental gallbladder cancers (IGBC). Although laparoscopy is employed in the management of a variety of abdominal tumors, its use in gallbladder cancer is reduced and controversial. This study analyzes the role of laparoscopy in gallbladder cancer with the focus in IGBC. METHOD: We evaluated our prospective series of 51 patients with an IGBC who were treated by laparoscopy between 2006 and 2016 at the Clinica Alemana in Santiago, Chile. RESULTS: The series comprised 7 men and 44 women. Age ranged from 43 to 76 years (mean age 60). Regarding wall involvement, 29 patients had a T2 tumor, which was the most common. 8 and 14 patients had T1b and T3 tumors, respectively. Of the patients, 17 underwent only laparoscopic exploration. This was due to the presence tumor dissemination not being observed in the preoperative staging. 10 patients had to be converted to complete the resection, whereas 24 patients were laparoscopically resected. The quality of the resected material was not different between those who were converted and those who were treated by laparoscopy. In the laparoscopic group, the average number of harvested lymph nodes was 7.9, not statistically different from the converted group. The mean of hospital stay in the laparoscopic group (4.3 days) was significantly lower than the converted group. CONCLUSIONS: Laparoscopy has been shown to be a safe and feasible method for the management of IGBC. This method not only allows for a complete exploration, identifying a previously unseen residual tumor, but also makes it possible to accomplish the same oncology objectives as the open procedure. Therefore, laparoscopy should be considered a valid alternative in the management of IGBC.

Somatic Mutations of PI3K in Early and Advanced Gallbladder Cancer: Additional Options for an Orphan Cancer.

Gallbladder cancer (GBC) is the second-leading cause of death from malignant tumors in Chilean women. The phosphatidylinositol 3-kinase (PI3K) pathway is involved in proliferation, cell survival, and growth. We investigated mutations in exons 9 and 20 of the PI3K gene in GBC. Mutations in exons 9 (E542K, E545G, E545K) and 20 (H1047L and H1047R) of PI3K were determined by direct sequencing in 130 cases of GBC. The patient group consisted of 110 women and 20 men, and mutations were found in 22 cases (16.9%). Of these, 14 cases had mutations in exon 9 (63.6%) (E542K, 64%; E545K, 29%; and E545G, 7%) and 8 in exon 20 (37.4%; H1047L, 50%; H1047R, 50%). No differences were noted in the frequency and type of mutations analyzed by sex, age, or histologic features. We observed mutations in 22% of the early-stage GBC and 14.6% of the advanced cases. In this series of GBC, 17% of cases were noted as having mutations in either exons 9 or 20 of PI3K. These results suggest that therapeutic testing of inhibitors of the PI3K/AKT pathway may be of benefit in advanced GBC patients.

Inactivation of tumor suppressor gene pten in early and advanced gallbladder cancer.

BACKGROUND: PTEN is a tumor suppressor gene that regulates the PTEN/PI3k/AKT/mTOR pathway, which is frequently altered in human cancers including gallbladder cancer (GBC). To determine the frequency of PTEN expression in GBC and to establish its relation to clinical and morphological parameters and survival in GBC. METHODS: The immunohistochemical expression of PTEN was studied in 108 GBC. All the cases included areas of non-tumor mucosa adjacent to the tumor. RESULTS: The group was comprised of 108 patients, 91 women (84.3%) and 17 men (15.7%) with an average age of 65.2 years (SD ± 12.3 years). Thirty-five cases (33%) were early carcinomas (EC) and the remaining 73 (67%) were advanced cases (AC). All the internal controls were positive (moderate or intense in 96.3%). Only in three AC (4.1%) was there a complete absence of PTEN immunohistochemical expression. There were no significant differences in relation between PTEN expression and tumor infiltration or degree of differentiation. The three patients with PTEN inactivation died before 10 months; however, the other patients with AC had a survival of 53% at 10 months. DISCUSSION: Loss of PTEN expression was observed in 4.1% of the advanced GBC. All the patients with this alteration died before 10 months. PTEN inactivation could be a rare event, but with a poor prognosis in advanced GBC.

Gallbladder cancer in Chile: what have we learned?

PURPOSE OF REVIEW: Gallbladder cancer (GBC) should be considered an orphan disease in oncology and represent a unique carcinogenetic model. This review will analyse some of the current aspects of GBC. RECENT FINDINGS: Chile has the highest incidence and mortality of GBC in the world. Most patients are diagnosed in advanced stages with few treatment options. During the last two decades, little progress has been made in early diagnosis and treatment. At the molecular level, recent access to next-generation sequencing and other techniques for detecting the mutations of multiple genes have made advances in this area. SUMMARY: The use of therapies targeted according to the detection of specific molecular alterations is in the early stages of evaluation and could represent a significant advance in the treatment of a large number of patients from developing countries.

Tumor location is a strong predictor of tumor progression and survival in T2 gallbladder cancer: an international multicenter study.

OBJECTIVE: To determine the prognostic impact of tumor location in gallbladder cancer. BACKGROUND: Depth of tumor is a strong predictor of survival after curative resection of gallbladder cancer. However, the gallbladder has a unique anatomical relationship with the liver, and the clinical significance of tumor location remains unclear. METHODS: For 437 patients with gallbladder cancer who underwent resection at 4 international institutions, clinicopathologic characteristics and their association with survival were analyzed. Tumor location was defined as "hepatic side" or "peritoneal side," and the prognostic significance of tumor location was evaluated. RESULTS: Among the 252 patients with T2 disease, patients with tumors on the hepatic side (T2h, n = 99) had higher rates of vascular invasion, neural invasion, and nodal metastasis than patients with tumors on the peritoneal side (T2p, n = 153) (51% vs 19%, 33% vs 8%, and 40% vs 17%, respectively; P < 0.01 for all). After a median follow-up of 58.9 months, 3-year and 5-year survival rates were 52.1% and 42.6%, respectively, for T2h tumors and 73.7% and 64.7%, respectively, for T2p tumors (P = 0.0006). No such differences were observed in T1 or T3 tumors. Multivariate analysis confirmed the independent association of hepatic-side location with survival in T2 tumors (hazard ratio, 2.7; 95% confidence interval, 1.7-4.2; P < 0.001). This subclassification of T2 tumors predicted recurrence in the liver (23% vs 3%; P = 0.003) and distant lymph nodes (16% vs 3%; P = 0.019) even after radical resection. CONCLUSIONS: After curative resection of T2 gallbladder cancer, tumor location predicts the pattern of recurrence and survival.

A review of recent data in the treatment of gallbladder cancer: what we know, what we do, and what should be done.

Gallbladder cancer is now considered a distinct clinical entity, allowing for a separate analysis from that of other malignancies of the biliary tree. Symptoms related to a malignant tumor of the gallbladder include jaundice and abdominal pain, or a palpable abdominal mass that occurs in a late stage of the disease. The majority of patients with operable gallbladder cancer are diagnosed by cholecystectomy performed for presumed benign disease, mostly cholelithiasis, a clinical entity known as incidental gallbladder cancer. Given the poor prognosis if tumor invasion beyond the muscular layer and/or nodal metastasis is found, adjuvant treatments have been implemented, but few data are available to guide treatment decisions in this setting. For advanced disease, a multidisciplinary treatment approach including biliary drainage procedures and palliative support is needed in the management of this aggressive disease. Palliative chemotherapy with a combination of gemcitabine and cisplatin or oxaliplatin is the standard treatment based on the findings of two phase III trials that showed improved overall survival compared to single-agent chemotherapy and best supportive care. Several phase II studies have been reported investigating the role of targeted agents against EGFR, VEGF, HER2, and MEK. International collaboration to enhance our knowledge of gallbladder cancer should be encouraged.

Overexpression of the HER2/neu Gene: A New Therapeutic Possibility for Patients With Advanced Gallbladder Cancer.

BACKGROUND: The HER2/neu gene is a proto-oncogene that can predict the response to treatment with trastuzumab, pertuzumab, and lapatinib. This study was conducted to determine the frequency of HER2/neu overexpression and to identify a subgroup of patients with gallbladder cancer who would benefit from targeted therapy. METHODS: Patients with gallbladder cancer (n = 187; 165 women and 22 men) with a recorded follow-up of at least 5 years were included, along with control subjects (n = 75). An automated immunohistochemical technique was used with an anti-ErbB2 antibody. Scoring was conducted according to the CAP/ASCO (College of American Pathologists/American Society of Clinical Oncology) criteria for breast cancer. RESULTS: Overexpression of HER2/neu was observed in 12.8% of the cases. Of those, 0% were mucosal, 14.3% muscular, 12.8% subserosal, and 10.6% serosal. In 20% of the cases, equivocal staining was observed. Overexpression was more frequent in the advanced cancers and in the better differentiated tumors (13.8% and 17.4%, respectively), but the difference was nonsignificant. The patients with overexpression of HER2/neu had a worse overall survival, when compared with those who had no expression at 5 years (34% vs. 41%). CONCLUSION: This is the single largest study of HER2/neu expression in gallbladder cancer to use commonly accepted scoring criteria. The results indicate that HER2/neu overexpression occurred in 14% of the advanced gallbladder cancer cases. This subgroup may benefit from inhibitors of the HER2/neu pathway.

Gallbladder cancer in Chile: Pathologic characteristics of survival and prognostic factors: analysis of 1,366 cases.

OBJECTIVES: To explore gallbladder cancer (GBC), the second leading cause of cancer-related death in women in Chile. METHODS: Analysis of macroscopic and microscopic variables, morphometry, and survival in 1,366 patients with GBC. RESULTS: Patients comprised 1,138 women and 228 men; diagnoses included 213 (15.6%) cases of mucosal carcinoma, 132 (9.7%) cases of muscular carcinoma, 316 (23.1%) cases of subserosal carcinoma, 382 (28.0%) cases of serosal carcinoma, and 323 (23.6%) cases beyond the serosa. Women older than 55 years with a gallbladder length greater than 9.5 cm had a five-times-greater relative risk of cancer. Those with a gallbladder wall thickness less than 7 mm had a better 5-year survival rate than those with a gallbladder wall thickness greater than 10 mm (P = .0001). Patients who had cholesterolosis of the gallbladder had 9.2 times less probability of having cancer. The infiltration level of the gallbladder wall was the most important independent prognostic factor (P < .001), followed by differentiation and lymphatic involvement (P < .001 and P = .05, respectively). Vascular infiltration had a mortality rate of 100%. CONCLUSIONS: Morphologic features are strongly associated with the prognosis of GBC and must be taken into consideration when supplementary treatment is recommended.

¿Es posible utilizar las muestras de colecistectomías con cáncer en investigación?: Calidad del ADN de muestras obtenidas del sistema público y privado de salud / Quality of DNA from archival pathological samples of gallbladder cancer

Background: The quality of the archival samples stored at pathology services could be a limiting factor for molecular biology studies. Aim: To determine the quality of DNA extracted from gallbladder cancer samples at different institutions. Material and Methods: One hundred ninety four samples coming from fve medical centers in Chile, were analyzed. DNA extraction was quantifed determining genomic DNA concentration. The integrity of DNA was determined by polymerase chain reaction amplification of different length fragments of a constitutive gene (β-globin products of 110, 268 and 501 base pairs). Results: The mean DNA concentration obtained in 194 gallbladder cancer samples was 48 ± 43.1 ng/µl. In 22% of samples, no amplification was achieved despite obtaining a mean DNA concentration of 58.3 ng/ul. In 81, 67 and 22% of samples, a DNA amplification of at least 110, 268 or 501 base pairs was obtained, respectively. No differences in DNA concentration according to the source of the samples were demonstrated. However, there were marked differences in DNA integrity among participating centers. Samples from public hospitals were of lower quality than those from private clinics. Conclusions: Despite some limitations, in 80% of cases, the integrity of DNA in archival samples from pathology services in our country would allow the use of molecular biology techniques.

[HER2 gene amplification and overexpression in advanced gastric cancer]. / Expresión y amplificación del gen HER2 en el cáncer gástrico avanzado.

BACKGROUND: Overexpression/amplification of the HER2 gene in advanced gastric cancer is a predictor of response to adjuvant therapy with monoclonal antibodies. AIM: To determine the frequency of HER2 gene overexpression and amplification in advanced gastric cancer. MATERIAL AND METHODS: One hundred nine advanced gastric cancer biopsy specimens, from 76 men and 33 women aged 67 ± 14 and 62 ± 12 years respectively, were selected. Three histological patterns (diffuse, intestinal and mixed) were recognized. Automated immunohistochemistry was performed with monoclonal c-erbB-2 (NCL-356) Novocastra. Fluorescent in situ hybridization (FISH) for HER2 was performed in positive cases. RESULTS: In 39% of cases, immunohistochemical staining was negative. It was 1+, 2+ and 3+ positive in 15, 36 and 11% of cases, respectively. It was positive in 16% and 3% of intestinal type and mixed carcinomas, respectively. It was negative in all diffuse carcinomas. FISH was performed in 39 (2 +) cases and in 11 (3 +) cases. The gene amplification was positive in two (2 +) and 11 (3 +) cases (11.9%). The overall concordance between immunohistochemical staining and in situ hybridization was 85%. CONCLUSIONS: In advanced gastric cancer, HER2 gene overexpression or amplification was observed in 11% and 12% of cases, respectively.