Clinicopathological and prognostic significance of VEGF, PDGF-B, and HER2/neu expression in gallbladder cancer.

AIM: Gallbladder cancer (GBC) is usually diagnosed in advanced stages with poor survival. The molecular mechanisms of GBC still remain unexplored. Several angiogenesis factors play a pivotal role in tumor progression. We aimed to study the expression of VEGF, PDGF-B, and human epidermal growth factor receptor 2 (HER2/neu) and its association with clinicopathological features and survival in GBC. MATERIALS AND METHODS: VEGF, PDGF-B, and HER2/neu expression was studied by immunohistochemistry (IHC) after histological evaluation in 91 GBC cases. The relationship between these markers and clinicopathological features and survival was explained through the Cox regression model and Kaplan-Meier method. RESULTS: VEGF, PDGF-B, and HER2/neu overexpressed in 45, 79, and 68% GBC cases, respectively. VEGF was significantly overexpressed in GBC without gall stones (GS) (p = 0.007) and with moderately and poorly differentiated tumors (p = 0.012). HER2/neu was significantly overexpressed in GBC with GS (p = 0.022). Median overall survival (OS) was 39 months (95% CI: 23-55). In univariate analysis, histological type (adenocarcinoma and papillary) vs. others (signet ring/mucinous/adenosquamous) (p = 0.004), depth of tumor infiltration (p = 0.017), distant metastasis (p = 0.012), and adjuvant therapies (chemotherapy/radiotherapy) (p = 0.083) were associated with poor prognosis. Multivariate survival analysis showed histological type (p = 0.004) and distant metastasis (p = 0.032) to be independent prognostic factors for OS. Histological type (p = 0.002), distant metastasis (p = 0.003), and depth of tumor infiltration (T3-T4) (p = 0.012) showed poor median survival. Poor survival was seen in VEGF and HER2/neu positive cases. CONCLUSION: Overexpression of VEGF, PDGF-B, and HER2/neu might be possible prognostic biomarkers in GBC. Poor survival of VEGF and HER2/neu positive cases indicates the possibilities of using their blockers as therapeutic agents.

Pregnancy-associated mucinous cystic neoplasms of the pancreas - A systematic review.

INTRODUCTION: Mucinous cystic neoplasms (MCN) are mucin-producing epithelial cell tumors of pancreas. They consist of an ovarian-type stroma expressing estrogen and progesterone receptors. Pregnancy-associated MCNs are presumed to be larger in size and more aggressive without any concrete evidence. OBJECTIVE: and Data Sources: Systematic review of published literature using PubMed and Google Scholar databases. Original articles including case reports and series published between 1970&2021 were included wherein MCN was diagnosed during pregnancy/within one-year post-partum. Thirty-three publications having 36 cases, adding one of our own patient were analyzed in this review. RESULT: Median age at presentation was 32 years. Only three (9%) patients were asymptomatic. Mean size of MCN was 135 mm. Ten patients (27%) reported an increase in size during pregnancy. Most tumors involved body and tail of pancreas (60%). Distal pancreatectomy with splenectomy was the most common resection performed (57%). No foetal mortality was reported to date. CONCLUSION: Pregnancy may cause a rapid increase in size of MCN. Decision-making is more complex and needs a fine balance between optimal oncological and obstetric outcomes.

Gallbladder cancer.

Gallbladder cancer (GBC) is the most common cancer of the biliary tract, characterized by a very poor prognosis when diagnosed at advanced stages owing to its aggressive behaviour and limited therapeutic options. Early detection at a curable stage remains challenging because patients rarely exhibit symptoms; indeed, most GBCs are discovered incidentally following cholecystectomy for symptomatic gallbladder stones. Long-standing chronic inflammation is an important driver of GBC, regardless of the lithiasic or non-lithiasic origin. Advances in omics technologies have provided a deeper understanding of GBC pathogenesis, uncovering mechanisms associated with inflammation-driven tumour initiation and progression. Surgical resection is the only treatment with curative intent for GBC but very few cases are suitable for resection and most adjuvant therapy has a very low response rate. Several unmet clinical needs require to be addressed to improve GBC management, including discovery and validation of reliable biomarkers for screening, therapy selection and prognosis. Standardization of preneoplastic and neoplastic lesion nomenclature, as well as surgical specimen processing and sampling, now provides reproducible and comparable research data that provide a basis for identifying and implementing early detection strategies and improving drug discovery. Advances in the understanding of next-generation sequencing, multidisciplinary care for GBC, neoadjuvant and adjuvant strategies, and novel systemic therapies including chemotherapy and immunotherapies are gradually changing the treatment paradigm and prognosis of this recalcitrant cancer.

Unconventional Shunts in Extrahepatic Portal Venous Obstruction-A Retrospective Review.

Background: Proximal splenorenal shunt (PSRS) is one of the most commonly performed portosystemic shunt (PSS) in extrahepatic portal venous obstruction (EHPVO) for portal decompression. Sometimes various anatomical and surgical factors related to the splenic vein and/or left renal vein may make the construction of a PSRS difficult or impossible. Unconventional shunts are required to tide over such conditions. Methods: From January 2008 to December 2018, 189 patients with EHPVO underwent PSS, of which, the 10 patients who underwent unconventional shunts form the study group of this paper. Results: The ten unconventional shunts included 8 proximal splenoadrenal shunts, one collateral-renal shunt, and one inferior mesenteric vein to inferior vena cava (IMV-Caval) shunt. The mean percentage drop in omental pressure was 34.2% post-shunt with a mean anastomotic diameter of 13.7 ± 3.1 mm. Three patients experienced some form of postoperative complication. With a mean follow-up period of 32.3 months (maximum of 111 months) all patients had patent shunts on follow-up Doppler. None of the patients had variceal bleed, or features of biliopathy and hepatic encephalopathy in follow-up. Conclusion: Unconventional shunts can be used safely and effectively with good postoperative outcomes in EHPVO.

Gallbladder reporting and data system (GB-RADS) for risk stratification of gallbladder wall thickening on ultrasonography: an international expert consensus.

The Gallbladder Reporting and Data System (GB-RADS) ultrasound (US) risk stratification is proposed to improve consistency in US interpretations, reporting, and assessment of risk of malignancy in gallbladder wall thickening in non-acute setting. It was developed based on a systematic review of the literature and the consensus of an international multidisciplinary committee comprising expert radiologists, gastroenterologists, gastrointestinal surgeons, surgical oncologists, medical oncologists, and pathologists using modified Delphi method. For risk stratification, the GB-RADS system recommends six categories (GB-RADS 0-5) of gallbladder wall thickening with gradually increasing risk of malignancy. GB-RADS is based on gallbladder wall features on US including symmetry and extent (focal vs. circumferential) of involvement, layered appearance, intramural features (including intramural cysts and echogenic foci), and interface with the liver. GB-RADS represents the first collaborative effort at risk stratifying the gallbladder wall thickening. This concept is in line with the other US-based risk stratification systems which have been shown to increase the accuracy of detection of malignant lesions and improve management.

Roles of Salmonella typhi and Salmonella paratyphi in Gallbladder Cancer Development.

BACKGROUND: Typhoid (Salmonella typhi and paratyphi) carriers and gall bladder cancer (GBC) are endemic in northern India. Results of previous studies about association of typhoid carriers with GBC are inconsistent. We studied antibodies against Salmonella typhi and paratyphi in serum samples of patients with GBC. METHODS: We performed modified Widal test for antibodies against Salmonella typhi (Vi and O) and Salmonella paratyphi (AO and BO) antigens in patients with GBC (n=100), xanthogranulomatous cholecystitis (XGC, n=24), chronic cholecystitis (CC, n=200) and healthy controls (HC, n=200). RESULTS: Serum antibodies against Salmonella were more frequently positive in GBC (22%) and XGC (29%), particularly in males in age ≥50 years (GBC: 47% and XGC: 50%) vs. HC (0) (p <0.01). Vi antibody was more common in GBC (13%, OR:9.8) and XGC (8%, OR:5.9) than HC (2%). O antibody was more common in GBC (8%, OR: 8.6) and XGC (8%, OR: 9.0) than HC (1%). O antibody was also more common in males with GBC (12%) than CC (1%) and HC (1%) (P=0.02 and p <0.001, respectively). AO (6%) and BO (4%) antibodies were detected in GBC, particularly in males, than HC (0), (p <0.01). Salmonella antibodies were more frequent in GBC with GS than those without GS (50% vs. 20%, OR=3.94, P=0.01). CONCLUSIONS: Salmonella carrier state was more common in GBC and XGC, particularly in elderly males than HC. The Vi antibody was more common in GBC and XGC than HC. Salmonella infection was more common in GBC with GS than those without GS.

Knowledge of the Culture of Safety in Cholecystectomy (COSIC) Among Surgical Residents: Do We Train Them Well For Future Practice?

BACKGROUND: Biliary injury is the most feared complication of laparoscopic cholecystectomy (LC). This study aimed to assess the awareness of culture of safety in cholecystectomy (COSIC) concept among the surgical residents in India. METHODS: A manual survey was conducted among general surgery residents attending a postgraduate course. Survey consisted of questions pertaining to knowledge of various aspects of COSIC, e.g., the critical view of safety (CVS). RESULTS: With a response rate of 51%, 259 residents were included in this study. They had more exposure to LC (63.3% assisted / performed > 15 LC) than to open cholecystectomy (60.6% assisted / performed ≤ 10 open cholecystectomy). The majority (80.2%) clearly differentiated Calot triangle from the hepatocystic triangle (HCT). However, 25.8% could not correctly define HCT. The majority (88.5%) had seen the Rouviere's sulcus during LC. While almost all (98.4%) respondents claimed to know about the segment 4, only 41.9% could correctly describe it. Awareness of the correct direction of the gallbladder retraction was lower for the infundibulum (53.5%) than for fundus (89.2%). The majority (88.3%) claimed to know CVS but only 11.5% knew it correctly, and 15.1% described > 3 components. The majority (78.7%) practiced to identify the cystic duct-common bile duct junction. Awareness was low for time-out (28.1%), intraoperative cholangiography (20.6%), bailout techniques (18.9%), and for overall COSIC concept (15.7%). CONCLUSIONS: Knowledge of COSIC among surgical residents seems to be suboptimal, especially for the CVS, time-out, bailout techniques, and overall concept of COSIC. Strategies to educate them more effectively about COSIC are highly imperative to train them well for future practice.

Bile duct injury during laparoscopic cholecystectomy: An Indian e-survey.

BACKGROUNDS/AIMS: In the absence of national registry of laparoscopic cholecystectomy (LC) or its complications, it is impossible to determine incidence of bile duct injury (BDI) in India. We conducted an e-survey among practicing surgeons to determine prevalence and management patterns of BDI in India. Our hypothesis was that majority of surgeons would have experienced a BDI during LC despite large experience and that most surgeons who have a BDI tend to manage it themselves. METHODS: An 18-question e-survey of practicing laparoscopic surgeons in India was done. RESULTS: 278/727 (38%) surgeons responded. 240/278 (86%) respondents admitted to a BDI during LC and 179/230 (78%) affirmed to more than one BDI. A total of 728 BDIs were reported. 36/230 (15%) respondents experienced their first BDI even after ＞10 years of practice and 40% had their first BDI even after having performed ＞100 LCs. 161/201 (80%) of the respondents decided to manage the BDI themselves, including 56/99 (57%) non-biliary surgeons and 44/82 (54%) surgeons working in non-biliary center. 37/201 (18%) respondents admitted to having a mortality arising out of a BDI; the mortality rate of BDI was 37/728 (5%) in this survey. Only 13/201 (6%) respondents have experienced a medico-legal case related to a BDI during LC. CONCLUSIONS: Prevalence of BDI is high in India and occurs despite adequate experience and volume. Even inexperienced non-biliary surgeons working in non-biliary centers attempt to repair the BDI themselves. BDI is associated with significant mortality but litigation rates are fortunately low in India.

Carcinogen Metabolism Pathway and Tumor Suppressor Gene Polymorphisms and Gallbladder Cancer Risk in North Indians: A Hospital-Based Case-Control Study.

BACKGROUND: Carcinogen metabolism pathway and tumor suppressor gene polymorphisms have been reported to be associated with increased gallbladder cancer risk. However, the association of genetic variants and gallbladder cancer risk in Indians are not well studied. We examined whether genetic polymorphisms of metabolic enzymes cytochrome P450 1A1 and glutathione S-transferase and tumor suppressor gene p53 (TP53) are associated with an increased risk of gallbladder cancer in North Indians. METHODS: This hospital-based case-control study was conducted in 96 gallbladder cancer patients with gallstones (cases) and 93 cholelithiasis patients (controls) at the Sanjay Gandhi Postgraduate Institute of Medical Sciences in Lucknow, India from July 2014 through May 2017. Genomic DNA was extracted from white blood cells of each patient using a simple salting-out procedure. The genotypic frequencies of CYP1A1 rs4646903, CYP1A1 rs1048943, and TP53 rs1042522 polymorphisms were investigated using TaqMan SNP Genotyping Assay and GSTM1 and GSTT1 polymorphisms were analyzed using the multiplex PCR assay. RESULTS: The frequency of CC genotype of TP53 rs1042522 polymorphism was 27.1% (26/96) in cases and 12.9% (12/93) in controls. The CC genotype was associated with an increased risk of gallbladder cancer in North Indians (age- and sex-adjusted odds ratio, 2.81; 95% confidence interval, 1.19-6.61; P = 0.02). No significant differences in genotypic and allelic frequencies of the metabolic pathway gene polymorphisms were found between cases and controls. CONCLUSIONS: Our data provide preliminary evidence that the CC genotype of the TP53 rs1042522 polymorphism may be associated with an increased risk of gallbladder cancer in North Indians.

Epidemiology of gallbladder cancer in India.

India is a high incidence area for gallbladder cancer (GBC) and contributes to about 10% of the global GBC burden. Within India, the incidence is high in North, North-East, Central and Eastern India, and less common in South and West India. The incidence has been on a steady rise in both genders. The presentation is often with advanced disease and carries dismal prognosis. GBC in India usually affects younger patients in the 5th and 6th decade in contrast to the west. Gallstones are present in 80% of the Indian patients with GBC and its presence increases the vulnerability of the GB to mucosal injury. The incidence of GBC is out of proportion to the prevalence of gallstones in the country. Additional co-factors such as older age, lower socio-economic status, chronic Salmonella typhi (S. typhi) infection, Helicobacter pylori (H. pylori) infection, exposure to pollutants, heavy metals, chemicals, adulterated mustard oil and smoking in patients with gallstones have been identified which promote carcinogenesis. These risk factors act in tandem in an additive manner resulting in higher incidence of GBC as well as hasten the development of GBC. Environmental risk factors such as soil and water contamination by industrial wastes, agricultural effluents and human sewage have been identified as putative risk factors. Combination of a toxic environment, vulnerable GB and a susceptible host play a key role in the pathogenesis of GBC in the country. Large multicentric comprehensive studies are required in India to assess the attributable risk of each of the identified putative risk factors. This will help in formulating cost effective national strategies in preventing GBC related mortality in the country. Meanwhile a high index of suspicion to pick up incidental GBC, and improved access to healthcare facilities to manage GS appropriately will help in reducing GBC related mortality.

Jab1-siRNA Induces Cell Growth Inhibition and Cell Cycle Arrest in Gall Bladder Cancer Cells via Targeting Jab1 Signalosome.

BACKGROUND: The aberrant alteration in Jab1 signalosome (COP9 Signalosome Complex Subunit 5) has been proven to be associated with the progression of several carcinomas. However the specific role and mechanism of action of Jab1 signalosome in carcinogenesis of gall bladder cancer (GBC) are poorly understood. OBJECTIVE: The main objective of our study was to elucidate the role and mechanism of Jab1 signalosome in gall bladder cancer by employing siRNA. METHODS: Jab1 overexpression was identified in gall bladder cancer tissue sample. The role of Jab1-siRNA approach in cell growth inhibition and apoptotic induction was then examined by RT-PCR, Western Blotting, MTT, ROS, Hoechst and FITC/Annexin-V staining. RESULTS: In the current study, we have shown that overexpression of Jab1 stimulated the proliferation of GBC cells; whereas downregulation of Jab1 by using Jab1-siRNA approach resulted incell growth inhibition and apoptotic induction. Furthermore, we found that downregulation of Jab1 induces cell cycle arrest at G1 phase and upregulated the expression of p27, p53 and Bax gene. Moreover, Jab1-siRNA induces apoptosis by enhancing ROS generation and caspase-3 activation. In addition, combined treatment with Jab1-siRNA and gemicitabine demonstrated an enhanced decline in cell proliferation which further suggested increased efficacy of gemcitabine at a very lower dose (5µM) in combination with Jab1-siRNA. CONCLUSION: In conclusion, our study strongly suggests that targeting Jab1 signalosome could be a promising therapeutic target for the treatment of gall bladder cancer.

'Colleaguography' in place of cholangiography, to prevent bile duct injury during laparoscopic cholecystectomy.

Bile duct injury (BDI) is not uncommon during laparoscopic cholecystectomy (LC). Intra-operative cholangiography (IOC) has been recommended to reduce the risk of BDI during LC. Facilities for IOC are, however, scarcely available in India. The author suggests 'in vicinity colleaguography' (IVC) - opinion of a surgical colleague in vicinity - as an easy alternative to IOC.

Plasma Helicobacter pylori Antibody Titers and Helicobacter pylori Infection Positivity Rates in Patients with Gallbladder Cancer or Cholelithiasis: a Hospital-Based Case-Control Study

Objective: Gallbladder cancer is the commonest gastrointestinal cancer in northern Indian women. Some studies have examined the association between Helicobacter pylori infection and gallbladder cancer risk, but findings have been inconsistent. We aimed to examine the association between H. pylori infection and gallbladder cancer in Indian people. Materials and Methods: We conducted a hospital-based case-control study including 100 gallbladder cancer patients with gallstones who were 32 to 79 years old (cases; 72 women and 28 men), and 100 cholelithiasis patients aged 14 to 75 years (controls; 65 women and 35 men). All patients had a diagnosis of gallbladder cancer or cholelithiasis at the Sanjay Gandhi Post Graduate Institute of Medical Sciences in Lucknow having a high gallbladder cancer incidence in northern India, from May 2014 through July 2017. Plasma samples were collected from all patients before surgical treatment. Plasma H. pylori antibody titer was measured by the latex agglutination method and an autoanalyzer. H. pylori infection was defined as antibody titer ≥10 U/mL. Plasma antibody titers and H. pylori infection positivity rates were compared between cases and controls. Results: Mean plasma antibody titers (standard deviation, range) were 11.1 U/mL (11.6, 0­78) in cases and 13.6 U/mL (23.0, 1­164) in controls. H. pylori infection positivity rates were 41% and 42% in cases and controls, respectively. No significant differences in antibody titers or H. pylori infection positivity rates were found between cases and controls. Conclusions: We found no evidence of H. pylori infection as an important risk factor for gallbladder cancer in Indian people.

Culinary Medicine-Jalebi Adhesions.

Culinary terms have been used to describe anatomy (bean-shaped kidneys), pathology (strawberry gall bladder), clinical signs (café-au-lait spots), radiological images (sausage-shaped pancreas), etc. While Indian cuisine is popular all over the world, no Indian dish finds mention in medical terminology. In intra-abdominal adhesions, sometimes, the intestinal loops are so densely adherent that it is difficult to make out proximal from distal and it is impossible to separate them without injuring the bowel resulting in spill of contents-resection is the only option (Fig. 1). Jalebi, an Indian dessert, has a single long tubular strip of fried batter filled with sugary syrup so intertwined that it is impossible to discern its ends; if broken, the syrup spills out-the best way to relish it is to chew the whole piece (Fig. 2). Because of these similarities between them, I propose to name dense intra-abdominal adhesions as 'jalebi adhesions.'

Anticipatory extended cholecystectomy: the 'Lucknow' approach for thick walled gall bladder with low suspicion of cancer.

BACKGROUND: Gall stones (GS) cause inflammation of the gall bladder (GB) i.e., chronic cholecystitis (CC) and xantho-granulomatous cholecystitis (XGC) which can result in a thick walled GB (TWGB). Gall bladder cancer (GBC) may also present as TWGB. While CC and XGC can be treated with simple cholecystectomy (SC), GBC merits extended cholecystectomy (EC). We propose a new surgical approach, anticipatory extended cholecystectomy (AEC), for doubtful TWGB in the belief that AEC would not violate the sacrosanct cholecysto-hepatic plane in doubtful cases and thereby not ruin the chances of cure for a patient whose GB demonstrates malignancy on frozen section histopathology. The addition of lymphadenectomy in cases which turn out to be malignant completes the procedure for GB cancer, but spares all problems related to lymphadenectomy in an undeserving patient. METHODS: AEC involves removal of GB with a 2-cm wedge of liver, which is then subjected to frozen section histological examination. Lymphadenectomy is performed if GBC is confirmed. AEC was performed in 13 patients between January 2011 and June 2014. During the same period, 1,673 SC for CC/XGC and 116 EC for GBC were performed. RESULTS: All patients were symptomatic for GS (3 with acute cholecystitis). Ultrasonography (US) raised suspicion of GBC in 11 patients. CT raised suspicion of GBC in 9 patients. Preoperative FNAC was done in 2 patients; in 1 it was negative and in 1 it was suspicious for malignancy. Preoperative diagnosis was GBC in 8, TWGB in 2, XGC, porcelain GB and GB perforation in 1 each. AEC and frozen section was done in all 13 patients. It was reported as GBC in 2 patients and as suspicious of GBC in 1 patient; lymphadenectomy was performed in these 3 patients. Final histopathology revealed XGC in 9, CC in 2 and GBC in 2 patients. CONCLUSIONS: In patients with TWGB on US/ CT with low suspicion of cancer, AEC serves as a triage-if frozen section biopsy turns out to be positive for GBC, AEC can be completed to EC by performing lymphadenectomy. We wish to name this approach as the 'Lucknow' approach for TWGB.

Bile duct injury repair ­­ earlier is not better.

Bile duct injury is a common complication of cholecystectomy. The timing of bile duct injury repair remains controversial. A recent review conducted in France reported 39% complications and 64% failure after immediate repair in 194 patients compared with 14% complications and 8%failure after late repair in 133 patients. A national review of 139 consecutive early repairs conducted at five hepatopancreaticobiliary centers in Denmark reported 4% mortality, 36% morbidity, and 42 restrictures (30%) at a median follow-up of 102 months, and only 64 patients (46%) demonstrated uneventful short-term and long-term outcomes. Most patients with bile duct injury present with bile leak and sepsis; thus, early repair is not recommended. Percutaneous drainage of bile and endoscopic stenting are the mainstays of treatment of bile leak because they convert acute bile duct injury into a controlled external biliary fistula. The ensuing benign biliary stricture should be repaired by a biliary surgeon after a delay of 4­6 weeks once the external biliary fistula has closed.