The Utility of Biliary Manometry in Assessing Early Catheter Removal After Percutaneous Balloon Dilatation of Hepaticojejunostomy Strictures.

Background and objective Percutaneous balloon dilatation followed by long-term internal-external biliary catheter (IEBC) placement is the standard radiological management for postoperative hepaticojejunostomy (HJ) strictures. The treatment is considered successful when cholangiography shows a free flow of contrast across the anastomosis and the patient passes a "clinical test". However, these tests may not be suitable predictors of long-term successful treatment outcomes. The purpose of this study was to assess the utility of biliary manometry in the evaluation of successful treatment outcomes after HJ stricture dilatation and IEBC placement and its efficacy as a tool for early catheter removal. Patients and methods A total of 14 patients underwent percutaneous balloon dilatation of HJ strictures with IEBC placement. A two-to-three-month interval was maintained between sessions of exchanging or upsizing IEBCs. Biliary manometry was performed after a mean duration of 6.3 months. Intra-biliary pressure of <15 mmHg was considered as the success threshold. Results Among the 14 patients, 11 patients passed initial manometry and had their IEBCs removed and were followed up for a mean duration of 47.8 months. Of these, one patient developed biliary obstruction after six months and underwent repeat HJ stricture dilatation and long-term IEBC placement. Three patients failed manometry and underwent re-dilatation of HJ strictures with IEBC placement. Using Kaplan-Meier survival analysis, the probability of patients remaining stricture-free after HJ stricture dilatation was found to be 100% at three months and 91% at six, 12, 18, 24, 36, and 47.8 months. Conclusion Biliary manometry prevents subjective variations in determining treatment endpoints and helps to assess early catheter removal after percutaneous balloon dilatation of HJ strictures.

Retroperitoneal Lymph Node Metastasis in Gallbladder Cancer: As Bad as Distant Metastasis.

Ashish SinghBackground Regarding gallbladder cancer (GBC) there is conflicting evidence in the literature whether retroperitoneal lymph nodal metastases (RLNM) should be considered as regional nodal metastasis or as distant metastasis (DM) and the jury is out on radical curative surgery in presence of RLNM. This is an analysis of GBC patients, to see the effect of RLNM on survival and to compare with that of patients with DMs. Methods A retrospective analysis of a prospective database of patients of GBC with RLNM (interaortocaval and paraaortic) or DM on frozen section biopsy at surgery, between January 2013 and December 2018. Data was analyzed using the Statistical Package for the Social Sciences software (version 22.0). Survival in these two groups (RLNM and DM) was compared with log-rank test. A p -value of < 0.05 was considered significant. Results A total of 235 patients with ostensibly resectable GBC underwent surgical exploration. The planned curative resection was abandoned in 91 (39%) patients because of RLNM ( n = 20, 9%) or DM ( n = 71, 30%) on frozen section biopsy. Demographic profile and blood parameters were similar. The median survival for RLNM and DM groups were 5 (range 2-26) and 6 (range 2-24) months, respectively, with no significant difference on log-rank test ( p = 0.64). There was no 3-year or longer survivor in either group. Conclusion Due to similar poor survival in presence of RLNM or DM, RLNM should be considered as the equivalent of DM. This study strengthens evidence to avoid curative surgery in patients with RLNM. These lymph nodes should be sampled preoperatively, if suspicious on imaging, for fine-needle aspiration cytology and at surgery, as a routine for frozen section histological examination before initiating curative resection to avert a futile exercise.

Risk factors for gallbladder cancer development in northern India: A gallstones-matched, case-control study.

Background & objectives: A high incidence of gallbladder cancer (GBC) is observed in northern India. This study was aimed to identify the factors involved in developing GBC in this region. Methods: A gallstones-matched, case-control study was conducted in northern India. Ninety nine patients with GBC and gallstones (33 men and 66 women, mean age of 51.4 yr) comprised the case group, while 99 patients with cholelithiasis (40 men and 59 women, mean age of 45.7 yr) comprised the control group. All participants were interviewed to complete 183 questionnaire items that included 105 food items. Potential risk factors were identified using a multivariate analysis adjusted for age and sex. Significant risk factors were identified using a stepwise logistic-regression analysis. Results: Age (≥50 yr), education (illiterate), socioeconomic status (≤below poverty line), bowel habits (≤once a day), hypertension history, hypotensive drug use, non-vegetarian diet, use of firewood for cooking, tap water drinking, hand pump water drinking and high consumption of coffee and sweets were identified as the potential risk factors. In women, factors included menarche (<13 yr), number of pregnancies (≥3 pregnancies) and parity (≥3 babies). Of these factors, age, education, bowel habits, tap water drinking and multiple pregnancy and/or multiparity were identified as significant risk factors, whereas a high consumption of coffee and sweets or hypotensive drug use and/or hypertension history were protective factors. Interpretation & conclusions: Poor bowel habits and drinking unsafe water appear to be the main risk factors for developing GBC. These are, however, modifiable factors which are capable of decreasing the risk of GBC in the north Indian population.

Management of residual gall bladder: A 15-year experience from a north Indian tertiary care centre.

BACKGROUNDS/AIMS: A residual gallbladder (RGB) following a partial/subtotal cholecystectomy may cause symptoms that require its removal. We present our large study regarding the problem of a RGB over a 15 year period. METHODS: This study involved a retrospective analysis of patients managed for symptomatic RGB from January 2000 to December 2015. RESULTS: A RGB was observed in 93 patients, who had a median age of 45 (25-70) years, and were comprised of 69 (74.2%) females. The most common presentation was recurrence pain (n=64, 68.8%). Associated choledocholithiasis was present in 23 patients (24.7%). An ultrasonography (USG) failed to diagnose RGB calculi in 10 (11%) patients; whereas, magnetic resonance cholangio-pancreatography (MRCP) accurately diagnosed RGB calculi in all the cases except for 2 (4%) and, additionally, detected common bile duct (CBD) stones in 12 patients. Completion cholecystectomy was performed in all patients (open 45 [48.4%]; laparoscopic 48 [51.6%] and 19 [20.4%] patients required a conversion to open). The RGB pathology included stones in 90 (96.8%), Mirizzi's syndrome in 10 (10.8%) and an internal fistula in 9 (9.7%) patients. Additional procedures included CBD exploration (n=6); Choledocho-duodenostomy (n=4) and Roux-en-Y hepatico-jejunostomy (n=3). The mortality and morbidity were nil and 11% (all wound infection), respectively. Two patients developed incisional hernia during follow up. The mean follow up duration was 23.1 months (3-108) in 65 patients and the outcome was excellent and good in 97% of the patients. CONCLUSIONS: Post-cholecystectomy recurrent biliary colic should raise suspicion of RGB. MRCP is a useful investigation for the diagnosis and assessment of any associated problems and provides a roadmap for surgery. Laparoscopic completion cholecystectomy is feasible, but is technically difficult and has a high conversion rate.

1H nuclear magnetic resonance (NMR)-based serum metabolomics of human gallbladder inflammation.

OBJECTIVE AND DESIGN: We present in this article 1H nuclear magnetic resonance (NMR)-based metabolic approach to screen the serum metabolic alterations in human gallbladder inflammation with chronic cholecystitis (CC). MATERIAL/METHODS: Total of 71 human serum samples was divided into two groups, (n = 41, CC) and (n = 30 control). 1H NMR metabolic profiling was carried out for investigation of metabolic alterations. Multivariate statistical analysis was applied for pattern recognition and identification of metabolites playing crucial role in gallbladder inflammation. Receiver operating curve (ROC) and pathway analysis on NMR data were also carried out to validate the findings. RESULTS: Serum metabolites such as glutamine, low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), alanine, branch chained amino acids (BCAA), histidine and tyrosine were found to be depleted whereas formate, lactate, 1,2-propanediol were found to be elevated in CC. Metabolic pathways associated with metabolite alteration have also been reported. CONCLUSIONS: NMR has been established for disease diagnosis along with identification of metabolic pattern recognition in biofluids. Gallstones cause inflammation of the gallbladder in the form of CC. Inflammation plays a major role in causation of gall bladder cancer and leads the way to malignancy. Metabolic analysis of CC may lead to early diagnosis of disease and its progression to gallbladder cancer.

Gallstones: A Worldwide Multifaceted Disease and Its Correlations with Gallbladder Carcinoma.

BACKGROUND: Gallstones (GS) associated diseases are among the most recurrent and frequent diseases delineated in India and United Arab Emirates. Several reports suggest that the association of GS with gallbladder cancer (GBC) is very high in Northern part of India; however, its occurrence in UAE and Southern part of India is notably low. Therefore, in the present study, we aimed to perform compositional analysis of GS in three different geographical areas by Solid State Nuclear Magnetic Resonance and Fourier Transformed Infrared spectroscopy. METHODS: Natural abundance 13C cross polarization magic angle spinning Nuclear Magnetic Resonance and Fourier Transform Infrared spectroscopy is employed for the analysis of human gallstone. RESULTS: Cholesterol, bilirubin and calcium carbonate were present in variant concentrations in GS obtained from three different geographical regions. Cholesterol was present predominantly in gallstones from North India. Bilirubin was found to be a main constituent in gallstones pertaining to South India. Whereas GS from UAE showed both cholesterol and bilirubin as their major constituents. Calcium carbonate was found in varying concentrations in gallstones acquired from different regions. CONCLUSION: Variation in environmental condition and dietary habits may contribute and affect the GS formation. Alterations in bile composition influence the GB and augment the crystallization of cholesterol. Analysis of different geographical regions GS could be an important stride to understand the etiology of GS diseases.

Lack of an Apparent Association between Mycotoxin Concentrations in Red Chili Peppers and Incidence of Gallbladder Cancer in India : an Ecological Study.

Our recent studies conducted in South America have shown that mycotoxin contamination of red chili peppers (RCPs) may be associated with an increased risk of gallbladder cancer (GBC). Whether this relationship exists in India, a country with a high incidence of GBC and high consumption of RCPs, is unclear. We therefore measured concentrations of aflatoxins (AFs) and ochratoxin A (OTA) in RCPs from areas of low, medium, and high incidence of GBC in India, and compared these concentrations with GBC incidence in each area. Twentyone RCP samples were collected from nine cities (eight from a lowincidence area, five from a mediumincidence area, and eight from a highincidence area). Concentrations of AFs and OTA were measured using highperformance liquid chromatography. No significant differences in mean concentrations of AFs and OTA were found in the three areas. AFB1 levels in the lowincidence area (10.81 ?g/kg) and highincidence area (12.00 ?g/kg) were more than 2.2 and 2.4 times higher compared with the maximum permitted level of AFB1 in spices (5.0 ?g/kg) set by the Commission of the European Communities, or that (4.4 ?g/kg) obtained in our previous study in Chile. Our results show that the mean concentrations of mycotoxins in RCPs are similar among the three areas in India with different incidences of GBC. Further studies with human subjects are needed to evaluate any association between AFB1 and GBC.

RNA sequencing-based analysis of gallbladder cancer reveals the importance of the liver X receptor and lipid metabolism in gallbladder cancer.

Gallbladder cancer (GBC) is an aggressive malignancy. Although surgical resection may be curable, most patients are diagnosed at an advanced unresectable disease stage. Cholelithiasis is the major risk factor; however the pathogenesis of the disease, from gallstone cholecystitis to cancer, is still not understood. To understand the molecular genetic underpinnings of this cancer and explore novel therapeutic targets for GBC, we examined the key genes and pathways involved in GBC using RNA sequencing. We performed gene expression analysis of 32 cases of surgically-resected GBC along with normal gallbladder tissue controls. We observed that 519 genes were differentially expressed between GBC and normal GB mucosal controls. The liver X receptor (LXR)/retinoid X receptor (RXR) and farnesoid X receptor (FXR) /RXR pathways were the top canonical pathways involved in GBC. Key genes in these pathways, including SERPINB3 and KLK1, were overexpressed in GBC, especially in female GBC patients. Additionally, ApoA1 gene expression suppressed in GBC as compared with normal control tissues. LXR and FXR genes, known to be important in lipid metabolism also function as tumor suppressors and their down regulation appears to be critical for GBC pathogenesis. LXR agonists may have therapeutic value and as potential therapeutic targets.

Mirizzi's syndrome: lessons learnt from 169 patients at a single center.

BACKGROUNDS/AIMS: Mirizzi's syndrome (MS) poses great diagnostic and management challenge to the treating physician. We presented our experience of MS cases with respect to clinical presentation, diagnostic difficulties, surgical procedures and outcome. METHODS: Prospectively maintained data of all surgically treated MS patients were analyzed. RESULTS: A total of 169 MS patients were surgically managed between 1989 and 2011. Presenting symptoms were jaundice (84%), pain (75%) and cholangitis (56%). Median symptom duration s was 8 months (range, <1 to 240 months). Preoperative diagnosis was possible only in 32% (54/169) of patients based on imaging study. Csendes Type II was the most common diagnosis (57%). Fistulization to the surrounding organs (bilio-enteric fistulization) were found in 14% of patients (24/169) during surgery. Gall bladder histopathology revealed xanthogranulomatous cholecystitis in 33% of patients (55/169). No significant difference in perioperative morbidity was found between choledochoplasty (use of gallbladder patch) (15/89, 17%) and bilio-enteric anastomosis (4/28, 14%) (p=0.748). Bile leak was more common with choledochoplasty (5/89, 5.6%) than bilio-enteric anastomosis (1/28, 3.5%), without statistical significance (p=0.669). CONCLUSIONS: Preoperative diagnosis of MS was possible in only one-third of patients in our series. Significant number of patients had associated fistulae to the surrounding organs, making the surgical procedure more complicated. Awareness of this entity is important for intraoperative diagnosis and consequently, for optimal surgical strategy and good outcome.

Platelet Derived Growth Factor-B and Human Epidermal Growth Factor Receptor-2 Polymorphisms in Gall Bladder Cancer.

Gall bladder cancer (GBC) is a gastro-intestinal cancer with high prevalence among north Indian women. Platelet derived growth factor-B (PDGFB) and human epidermal growth factor receptor-2 (HER2) may play roles in the etiology of GBC through the inflammation-hyperplasia-dysplasia-carcinoma pathway. To study the association of PDGFB and HER2 polymorphisms with risk of GBC, 200 cases and 300 controls were considered. PDGFB +286A>G and +1135A>C polymorphisms were investigated with an amplification refractory mutation system and the HER2 Ile655Val polymorphism by restriction fragment length polymorphism. Significant risk associations for PDGFB +286 GG (OR=5.25) and PDGFB +1135 CC (OR=3.19) genotypes were observed for GBC. Gender wise stratification revealed susceptibility for recessive models of PDGFB +1135A>C (OR=3.00) and HER2 Ile655Val (OR=2.52) polymorphisms among female GBC cases. GBC cases with gall stones were predisposed to homozygous +286 GG and +1135 CC genotypes. Significant risk associations were found for ACIle (OR=1.48), GAVal (OR=1.70), GAIle (OR=2.00) haplotypes with GBC cases and GCIle haplotype with female GBC cases (OR=10.37, P=<0.0001). Pair-wise linkage disequilibrium revealed negative associations among variant alleles. On multi-dimensional reduction analysis, a three factor model revealed significant gene-gene interaction for PDGFB +286A>G, PDGFB +1135A>C and HER2 Ile165Val SNPs with GBC. Protein-protein interaction showed significant association of PDGFB and HER2 with the epidermal growth factor receptor signaling pathway.

Indian Council of Medical Research consensus document for the management of gall bladder cancer.

The document is based on consensus among the experts and best available evidence pertaining to Indian population and is meant for practice in India.All postcholecystectomy gallbladder specimens should be opened and examined carefully by the operating surgeon and be sent for histopathological examination.All "incidental" gall bladder cancers (GBCs) picked up on histopathological examination should have an expert opinion.Evaluation of a patient with early GBC should include essential tests: A computed tomography (CT) scan (multi-detector or helical) of the abdomen and pelvis for staging with a CT chest or chest X-ray, and complete blood counts, renal and liver function tests. magnetic resonance imaging/positron emission tomography (PET)-CT are not recommended for all patients.For early stage disease (up to Stage IVA), surgery is recommended. The need for adjuvant treatment would be guided by the histopathological analysis of the resected specimen.Patients with Stage IVB/metastatic disease must be assessed for palliative e.g. endoscopic or radiological intervention, chemotherapy versus best supportive care on an individual basis. These patients do not require extensive workup outside of a clinical trial setting.There is an urgent need for multicenter trials from India covering various aspects of epidemiology (viz., identification of population at high-risk, organized follow-up), clinical management (viz., bile spill during surgery, excision of all port sites, adjuvant/neoadjuvant therapy) and basic research (viz., what causes GBC).

Gallbladder neck cancer and perihilar cholangiocarcinoma - siblings, cousins or look alikes?

The gallbladder neck cancer and perihilar cholangiocarcinoma present as painless progressive surgical obstructive jaundice. Sometimes it becomes difficult to differentiate between them even on cross-sectional imaging studies including computed tomography and magnetic resonance imaging. Staging laparoscopy and positron emission tomography may be useful in detecting metastases in gallbladder neck cancer, but are not recommended in perihilar cholangiocarcinoma. Most patients with gallbladder neck cancer and perihilar cholangiocarcinoma require preoperative biliary drainage. The differentiation is, however, important because their behavior and prognosis are totally different. Gallbladder neck cancer is biologically aggressive, thus long-term surviver are rare even after major resection. On the other hand, perihilar cholangiocarcinoma is often less aggressive and major proceduresresections are justified. Gallbladder neck cancer and perihilar cholangiocarcinoma, though not siblings, they tend to look alike sometimes.

Mutation profiling in gallbladder cancer in Indian population.

AIM: Gallbladder cancer is an aggressive malignancy usually diagnosed at late stage. The molecular genetics of this cancer is heterogeneous and not well established. Mutation profiling of gallbladder cancer was performed through massarray technology with an aim to identify molecular markers involved in the tumor pathogenesis that can be helpful as markers for early diagnosis and targets for therapy. MATERIALS AND METHODS: Forty nine cases of gallbladder cancer were screened through Sequenom Massarray technology for 390 mutations across 30 genes in formalin fixed paraffin embedded archived tissues and the results of mutation profiling was correlated with tumor characteristics. Mutations were observed in 9 of 49 cases across four genes--TP53 (four cases), CTNNB1 (two cases), PIK3CA (two cases), and KRAS (one case). Six of these cases were well differentiated but of eight of them belonged to stage II to IV disease. Six cases had associated gallstones. CONCLUSION: The mutation frequency found in gallbladder cancer is comparable to the data available in literature. Identification of PIK3CA and KRAS mutations would help in formulating more efficacious targeted approach for management. Studies with large number of cases would help in exploring more targets and better classification of these cancers at genetic level.

Vascular endothelial growth factor single-nucleotide polymorphism in gallbladder cancer.

BACKGROUND AND AIM: Angiogenesis plays a key role in growth, progression, and metastasis of various cancers. Vascular endothelial growth factor (VEGF) polymorphism has been associated with several cancers. Role of VEGF has not been reported in gallbladder cancer (GBC). Present study was designed to investigate the role of VEGF polymorphism in GBC and in other (benign) gallbladder diseases, that is chronic cholecystitis (CC) and xanthogranulomatous cholecystitis (XGC). METHODS: Blood samples were collected from 195 GBC, 140 CC, and 47 XGC patients and 300 normal healthy controls. VEGF polymorphisms were investigated using amplification refractory mutation system polymerase chain reaction for g.43737830A>G and g.3437A>C, polymerase chain reaction-restriction fragment length polymorphism for c.*237C>T, and g.43736418delTinsG amplified by polymerase chain reaction. RESULTS: At g.43737830A>G, GA genotype showed susceptibility (odds ratio [OR] = 1.65 and OR = 1.68) and GG genotype showed protective association (OR = 0.58 and OR = 0.50) with GBC and CC. Allele A of VEGF g.43737830A>G was risk associated with GBC and CC (OR = 1.48 and OR = 1.70), while G allele was risk protective for GBC and CC (OR = 0.67 and OR = 0.58). At g.3437A>C, genotype CA was risk protective for GBC (OR = 0.61). TT genotype of c.*237C>T was susceptible for GBC and CC (OR = 2.59 and OR = 3.48), while CC genotype was risk protective for GBC and CC (OR = 0.61 and OR = 0.34). T allele of c.*237C>T polymorphism was risk associated with GBC and CC (OR = 1.63 and OR = 2.90), while C allele was risk protective for GBC and CC (OR = 0.38 and OR = 0.28). Haplotype I-C-A-C was risk protective for GBC (OR = 0.27). CONCLUSION: The present study suggests that c.*237C>T and g.43737830A>G polymorphisms are useful markers of susceptibility to GBC.

Variations in biliary ductal and hepatic vascular anatomy and their relevance to the surgical management of choledochal cysts.

PURPOSE: An aberrant biliary ductal and vascular anatomy presents a technical challenge for choledochal cyst (CDC) surgery. Mismanagement may have unfavourable implications. This study highlights the spectrum, approach to their identification and management. METHODS: Forty of 117 (34 %) cases were identified to have an aberrant biliary ductal (n = 17) or arterial (n = 26) anatomy; 3 had both. The pancreaticobiliary anatomy was defined by an intraoperative cholangiogram (IOC) before January 2005 and a preoperative magnetic resonance cholangiopancreatogram (MRCP) subsequently. RESULTS: IOC missed 3 of 4 aberrant biliary ducts, while an MRCP accurately delineated 10 of 13 aberrant bile ducts. The significant biliary anomalies were: an aberrant right sectoral/segmental duct joining the common hepatic duct (CHD) or the cyst itself (n = 14), cystic duct (n = 1) and cystic duct-CHD junction (n = 1). The aberrant duct was incorporated into the biliary-enteric anastomosis (B-EA) by: (i) double ostia B-EA (n = 1), (ii) ductoplasty with single ostium B-EA for aberrant duct and CHD (n = 2), and (iii) transection of the CHD/cyst distal to the aberrant duct orifice with a single ostium B-EA (n = 13). The arterial anomalies were (i) replaced or accessory right hepatic artery (RHA) (n = 11) and (ii) RHA crossing anterior to the cyst (n = 15), which was repositioned posterior to the B-EA. CONCLUSION: It is important to consciously look for, appropriately identify and manage aberrant biliovascular anatomy. MRCP facilitates accurate preoperative delineation of aberrant duct anatomy. All major aberrant ducts need to be incorporated into the B-EA and aberrant arteries should not be ligated.

Risk factors for development of biliary stricture in patients presenting with bile leak after cholecystectomy.

BACKGROUND/AIMS: This study was aimed at determining the factors associated with the development of benign biliary stricture (BBS) in patients who had sustained a bile duct injury (BDI) at cholecystectomy and developed bile leaks. METHODS: A retrospective analysis of 214 patients with BDI who were referred to our center between January 1989 and December 2009 was done. RESULTS: One hundred fifty-three (71%) patients developed BBS (group I), and 61 (29%) were normal (group II). By univariate analysis, female gender (p=0.02), open cholecystectomy as the index operation (p=0.0001), delay in the referral from identification of injury (p=0.04), persistence of an external biliary fistula (EBF) beyond 4 weeks (p=0.0001), EBF output >400 mL (p=0.01), presence of jaundice (p=0.0001), raised serum total bilirubin level (p=0.0001), raised serum alkaline phosphatase level (p=0.0001), and complete BDI (p=0.0001) were associated with the development of BBS. Furthermore, open cholecystectomy as the index operation (p=0.04), delayed referral (p=0.02), persistent EBF (p=0.03), and complete BDI (p=0.001) were found to predict patient outcome in the multivariate analysis. CONCLUSIONS: For the majority of patients with BDI, the risk of developing BBS could have been predicted at the initial presentation.

Local recurrence and multi-organ metastasis of primary retroperitoneal leiomyosarcoma in unusual locations after surgical resection.

We report a case of retroperitoneal leiomyosarcoma in a 52-year-old woman, who developed local recurrence, pulmonary, hepatic, peritoneal, pancreatic, subcutaneous and intramuscular metastases two years after surgical resection of the primary tumor. Metastasis to the pancreas, subcutaneous or muscular tissue is very rare; however, presence of a lesion in these locations in a known case of leiomyosarcoma might indicate a metastatic tumor deposit.