Pramod Kumar Garg

A randomized controlled trial of antioxidant supplementation for pain relief in patients with chronic pancreatitis.

BACKGROUND & AIMS Oxidative stress has been implicated in the pathophysiology of chronic pancreatitis (CP). We evaluated the effects of antioxidant supplementation on pain relief, oxidative stress, and antioxidant status in patients with CP. METHODS In a placebo-controlled double blind trial, consecutive patients with CP were randomized to groups that were given placebo or antioxidants for 6 months. The primary outcome measure was pain relief, and secondary outcome measures were analgesic requirements, hospitalization, and markers of oxidative stress (thiobarbituric acid-reactive substances [TBARS]) and antioxidant status (ferric-reducing ability of plasma [FRAP]). RESULTS Patients (age 30.5+/-10.5 years, 86 male, 35 alcoholic, and 92 with idiopathic CP) were assigned to the placebo (n=56) or antioxidant groups (n=71). After 6 months, the reduction in the number of painful days per month was significantly higher in the antioxidant group compared with the placebo group (7.4+/-6.8 vs 3.2+/-4, respectively; P< .001; 95% CI, 2.07, 6.23). The reduction in the number of analgesic tablets per month was also higher in the antioxidant group (10.5+/-11.8 vs 4.4+/-5.8 respectively; P= .001; 95% CI, 2.65, 9.65). Furthermore, 32% and 13% of patients became pain free in the antioxidant and placebo groups, respectively (P= .009). The reduction in the level of TBARS and increase in FRAP were significantly higher in the antioxidant group compared with the placebo group (TBARS: placebo 1.2+/-2.7 vs antioxidant 3.5+/-3.4 nmol/mL; P= .001; 95% CI 0.96, 3.55; FRAP: placebo -5.6+/-154.9 vs antioxidant 97.8+/-134.9 microMFe(+2) liberated, P= .001, 95% CI 44.98, 161.7). CONCLUSIONS Antioxidant supplementation was effective in relieving pain and reducing levels of oxidative stress in patients with CP.

Typhoid carriers among patients with gallstones are at increased risk for carcinoma of the gallbladder

OBJECTIVE:The aim of this study was to identify risk factors for carcinoma of the gallbladder (CaGB) among patients with gallstones (GS) with special reference to role of chronic Salmonella typhi carrier state.METHODS:A prospective case-control study was conducted in a tertiary care center in India. Cases were defined as consecutive patients with CaGB and GS, whereas controls were patients with GS alone. All were assessed clinically and their demographic data, diet, and smoking history recorded. Patients were detected to be typhoid carriers on the basis of Vi serology by enzyme linked immunosorbent assay. Cases (n = 37) and controls (n = 80) were compared by univariate and logistic regression analysis.RESULTS:The mean age of the cases and the controls were 53.4 ± 11 yr and 43.5 ± 14 yr, respectively. Among the cases, six (16%) patients were detected to be typhoid carriers, in contrast to two (2.5%) among controls (p = 0.01). Compared to controls, cases were more often older (p = 0.0002), of a lower socioeconomic status (p = 0.0005), and smokers (p = 0.0002). Stepwise logistic regression analysis identified typhoid carrier state (OR = 14; CI 2–92), age ≥47 yr (OR = 5; CI 2–14) and smoking (OR = 11; CI 2–71) as the three independent risk factors for development of CaGB among patients with GS.CONCLUSION:Chronic typhoid carrier state was the most important risk factor among patients with CaGB and gallstones.

Best Supportive Care Compared With Chemotherapy for Unresectable Gall Bladder Cancer: A Randomized Controlled Study

PURPOSE We designed this study to evaluate efficacy of modified gemcitabine and oxaliplatin (mGEMOX) over best supportive care (BSC) or fluorouracil (FU) and folinic acid (FA) in unresectable gall bladder cancer (GBC). PATIENTS AND METHODS Patients with unresectable GBC were enrolled for single center randomized study. Arm A, BSC; arm B, FU 425 mg/m(2) and FA 20 mg/m(2) intravenous (IV) bolus weekly for 30 weeks (FUFA); arm C, gemcitabine 900 mg/m(2) and oxaliplatin 80 mg/m(2) IV infusion on days 1 and 8 every 3 weeks for maximum of six cycles. Eighty-one patients were randomly assigned, arms A (n = 27), B (n = 28), and C (n = 26). RESULTS Complete response plus partial response in the three groups was 0 (0%), four (14.3%), and eight (30.8%) respectively (P < .001). Two patients in the mGEMOX arm and one patient in the FUFA arm underwent curative resection after chemotherapy. One patient in the mGEMOX arm had complete pathologic response. Median overall survival (OS) was 4.5, 4.6, and 9.5 months for the BSC, FUFA, and mGEMOX arms (P = .039), respectively. Progression-free survival (PFS) was 2.8, 3.5, and 8.5 months for the three groups (P < .001). There was no difference in grade 3/4 toxicities in the chemotherapy arms except transaminitis, which was more prevalent in mGEMOX arm (P = .04). Two patients in the FUFA arm and 10 patients in the mGEMOX arm had grade 3 or 4 myelosuppression. Two patients in the mGEMOX group had neutropenic fever that resolved with antibiotics. CONCLUSION This randomized controlled trial confirmed the efficacy of chemotherapy (mGEMOX) compared with BSC and FUFA in improving OS and PFS in unresectable GBC.

Association of extent and infection of pancreatic necrosis with organ failure and death in acute necrotizing pancreatitis

BACKGROUND & AIMS Organ failure is the usual cause of death in acute necrotizing pancreatitis. Our objective was to study whether the extent and infection of pancreatic necrosis correlate with organ failure and mortality. METHODS All consecutive patients with acute pancreatitis were prospectively studied. They underwent a detailed clinical and investigative evaluation. Pancreatic necrosis, diagnosed on a computed tomography scan, was graded as <30%, 30%-50%, and >50% necrosis and characterized as either sterile or infected. Logistic regression analysis was done to find out the association of the extent and infection of pancreatic necrosis with organ failure and mortality. RESULTS Of 276 patients (mean age, 41.25 years; 172 men), 104 had pancreatic necrosis: 30 had <30% necrosis, 37 had 30%-50% necrosis, and 37 had >50% necrosis; 74 had sterile necrosis, and 30 had infected necrosis. Of them, 37 (35%) patients developed organ failure. Two significant factors were associated with the development of organ failure, the extent of necrosis (<30% necrosis vs 30%-50% necrosis: P = .03; odds ratio [OR], 5.82; 95% confidence interval [CI], 1.15-29.45; <30% necrosis vs >50% necrosis: P = .0004; OR, 18.86; 95% CI, 3.75-94.92) and infected pancreatic necrosis (P = .02; OR, 3.29; 95% CI, 1.17-9.24). The overall mortality was 22%. Infected pancreatic necrosis (P = .006; OR, 4.99; 95% CI, 1.56-16.02) and Acute Physiology, Age, and Chronic Healthy Evaluation II score (P = .004; OR, 1.28; 95% CI, 1.08-1.52) were 2 independent predictors of mortality. CONCLUSIONS Extent of necrosis and infected pancreatic necrosis were associated with the development of organ failure in patients with acute necrotizing pancreatitis. Infected pancreatic necrosis was the most significant predictor of mortality.

Survey on chronic pancreatitis in the Asia–Pacific region

Background and Aims:  A survey was conducted of chronic pancreatitis (CP) in different countries in the Asia–Pacific region. The main objective of the survey was to generate a database containing information regarding the prevalence, etiology, clinical presentation, diagnostic work‐up, and management of CP in the Asia–Pacific region.

Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis.

BACKGROUND & AIMS The role of trypsinogen activation in the pathogenesis of acute pancreatitis (AP) has not been clearly established. METHODS We generated and characterized mice lacking trypsinogen isoform 7 (T7) gene (T(-/-)). The effects of pathologic activation of trypsinogen were studied in these mice during induction of AP with cerulein. Acinar cell death, tissue damage, early intra-acinar activation of the transcription factor nuclear factor κB (NF-κB), and local and systemic inflammation were compared between T(-/-) and wild-type mice with AP. RESULTS Deletion of T7 reduced the total trypsinogen content by 60% but did not affect physiologic function. T(-/-) mice lacked pathologic activation of trypsinogen, which occurs within acinar cells during early stages of AP progression. Absence of trypsinogen activation in T(-/-) mice led to near complete inhibition of acinar cell death in vitro and a 50% reduction in acinar necrosis during AP progression. However, T(-/-) mice had similar degrees of local and systemic inflammation during AP progression and comparable levels of intra-acinar NF-κB activation, which was previously shown to occur concurrently with trypsinogen activation during early stages of pancreatitis. CONCLUSIONS T7 is activated during pathogenesis of AP in mice. Intra-acinar trypsinogen activation leads to acinar death during early stages of pancreatitis, which accounts for 50% of the pancreatic damage in AP. However, progression of local and systemic inflammation in AP does not require trypsinogen activation. NF-κB is activated early in acinar cells, independently of trypsinogen activation, and might be responsible for progression of AP.

Predictors of unsuccessful mechanical lithotripsy and endoscopic clearance of large bile duct stones.

BACKGROUND Mechanical lithotripsy is used to break large bile duct stones. This study investigated the predictors of unsuccessful mechanical lithotripsy. METHODS Consecutive patients with bile duct stones underwent endoscopic retrograde cholangiography, sphincterotomy, and basket removal of stones. Mechanical lithotripsy was performed for stones of large size (>15 mm diameter) that precluded extraction intact. Success was defined as complete clearance of the duct. Various predictive factors, including size and number of stones, stone impaction, serum bilirubin, presence of cholangitis, and bile duct diameter were analyzed in relation to the success or failure of lithotripsy. RESULTS A total of 669 patients underwent endoscopic retrograde cholangiography for suspected choledocholithiasis, which was found in 401 patients. Of the latter patients, 87 had large stones that required mechanical lithotripsy. Lithotripsy was successful in 69 (79%) patients. Impaction of the stone(s) in the bile duct was the only significant factor that predicted failure of lithotripsy and consequent failure of bile duct clearance. Other factors, including stone size, were not significant. CONCLUSIONS Mechanical lithotripsy is successful in about 79% of patients with large bile duct stones. The only significant factor that predicts failure of mechanical lithotripsy is stone impaction in the bile duct.

Idiopathic chronic pancreatitis in India: phenotypic characterisation and strong genetic susceptibility due to SPINK1 and CFTR gene mutations.

Objective To study the genetic predisposition, phenotype and prognosis of idiopathic chronic pancreatitis (CP). Design Prospective observational and case–control study. Setting Tertiary care academic centre. Patients Consecutive patients with CP. Interventions Detailed mutational analysis was done for the cationic trypsinogen, SPINK1 and CFTR genes with single-strand conformational polymorphism or restricted fragment length polymorphism, and sequencing. Clinical and disease characteristics of idiopathic versus alcoholic CP, and early onset versus late onset idiopathic CP were compared. Response to multimodality treatment (medical, endoscopic and/or surgical) and prognosis were analysed. Main outcome measures Genetic mutations, phenotypic characterisation and prognosis of idiopathic CP. Results Of the 411 patients with CP, 242 had idiopathic aetiology (age 27.50±11.85 years; 154 men). Malnutrition and cassava were not risk factors. SPINK1 N34S mutation was present in 42% of patients with idiopathic CP (vs 4% controls, p<0.001) and 17% of patients with alcoholic CP (p=0.016 compared with controls). In the CFTR gene, nine patients with idiopathic CP had mutations and 41 patients had polymorphisms (50% vs 10% controls, p<0.001). Diabetes developed in 35.53% of patients with idiopathic CP. About 85% of patients had significant pain relief with therapy. The probability of surviving for 35 years after onset of idiopathic CP was 83%. The typical features of tropical calcific pancreatitis were seen only in 5.8% of patients. Conclusion Strong genetic susceptibility due to SPINK1 and CFTR gene mutations, and comparative phenotype of idiopathic CP in India suggest that the term ‘tropical calcific pancreatitis’ is a misnomer.

Efficacy of Conservative Treatment, Without Necrosectomy, for Infected Pancreatic Necrosis: A Systematic Review and Meta-analysis

BACKGROUND & AIMS Conservative treatment (intensive care, a combination of antimicrobial agents, and nutritional support, with or without drainage of the infected fluid) has recently been shown to be effective for patients with infected pancreatic necrosis (IPN), but the data from individual studies are not robust enough to recommend it as the standard of care. We performed a systematic review and meta-analysis of studies related to primary conservative management for IPN. METHODS We performed a literature search of MEDLINE/PubMed from January 1990 to March 2012 for studies of a priori protocols for primary conservative treatment, without necrosectomy, for consecutive patients with IPN. We analyzed data from 8 studies, comprising 324 patients with IPN who received primary conservative management. We then analyzed an additional 4 studies (comprising 157 patients) that reported the efficacy of percutaneous drainage in nonconsecutive patients with IPN. Outcome measures were the success of conservative management strategy, need for necrosectomy, and mortality. RESULTS There was significant heterogeneity in results among the studies. Based on a random effects model, conservative management was successful for 64% of patients (95% confidence interval [CI], 51%-78%); mortality was 12% (95% CI, 6%-18%), and 26% of patients required necrosectomy or additional surgery for complications (95% CI, 15%-37%). A separate analysis of 4 studies that reported outcomes of nonconsecutive patients with IPN following percutaneous drainage had comparable results; 50% had successful outcomes (95% CI, 43%-58%), mortality was 18% (95% CI, 6%-30%), and 38% of patients required surgery (95% CI, 20%-56%). CONCLUSIONS Conservative management without necrosectomy is a successful approach for 64% of patients with IPN. This approach has low mortality and prevents surgical necrosectomy.

Chronic pancreatitis: Asia–Pacific consensus report

Abstract   Current knowledge about chronic pancreatitis (CP) is limited and there is a particular dearth of information about the entity known as tropical pancreatitis. A consensus working party was convened by the Trustees of the Journal of Gastroenterology and Hepatology Foundation to conduct a systematic investigation into available evidence about the epidemiology, etiopathogenesis, diagnosis and management of CP. A literature search and formal survey of international experts in the field were used to assemble reliable evidence about these issues. The present review summarizes the results of the working party’s findings and presents a series of practice guidelines to improve diagnosis, investigation and treatment of patients with CP, particularly those in the Asia–Pacific region. Areas for further research have also been identified.