Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial.

IMPORTANCE: The prognosis for patients with pancreatic cancer is poor, even after resection with curative intent. Gemcitabine-based chemotherapy is standard treatment for advanced pancreatic cancer, but its effect on survival in the adjuvant setting has not been demonstrated. OBJECTIVE: To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival. DESIGN, SETTING, AND PATIENTS: CONKO-001 (Charité Onkologie 001), a multicenter, open-label, phase 3 randomized trial to evaluate the efficacy and toxicity of gemcitabine in patients with pancreatic cancer after complete tumor resection. Patients with macroscopically completely removed pancreatic cancer entered the study between July 1998 and December 2004 in 88 hospitals in Germany and Austria. Follow-up ended in September 2012. INTERVENTIONS: After stratification for tumor stage, nodal status, and resection status, patients were randomly assigned to either adjuvant gemcitabine treatment (1g/m2 d 1, 8, 15, q 4 weeks) for 6 months or to observation alone. MAIN OUTCOMES AND MEASURES: The primary end point was disease-free survival. Secondary end points included treatment safety and overall survival, with overall survival defined as the time from date of randomization to death. Patients lost to follow-up were censored on the date of their last follow-up. RESULTS: A total of 368 patients were randomized, and 354 were eligible for intention-to-treat-analysis. By September 2012, 308 patients (87.0% [95% CI, 83.1%-90.1%]) had relapsed and 316 patients (89.3% [95% CI, 85.6%-92.1%]) had died. The median follow-up time was 136 months. The median disease-free survival was 13.4 (95% CI, 11.6-15.3) months in the treatment group compared with 6.7 (95% CI, 6.0-7.5) months in the observation group (hazard ratio, 0.55 [95% CI, 0.44-0.69]; P < .001). Patients randomized to adjuvant gemcitabine treatment had prolonged overall survival compared with those randomized to observation alone (hazard ratio, 0.76 [95% CI, 0.61-0.95]; P = .01), with 5-year overall survival of 20.7% (95% CI, 14.7%-26.6%) vs 10.4% (95% CI, 5.9%-15.0%), respectively, and 10-year overall survival of 12.2% (95% CI, 7.3%-17.2%) vs 7.7% (95% CI, 3.6%-11.8%). CONCLUSIONS AND RELEVANCE: Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN34802808.

Smoking increases the risk of pre- and postoperative complications in patients with pilonidal disease.

BACKGROUND: Smoking has a negative impact on the natural history and on treatment results of many dermatological conditions. However, there are no data demonstrating a similar effect in patients with pilonidal disease. PATIENTS AND METHODS: Consecutive patients undergoing surgery for pilonidal disease between 1/2004 and 3/2012 were analyzed retrospectively. Two surgical methods were used: a minimally invasive "pit-picking" surgery for smaller primary disease and Karydakis flap for patients presenting with larger primary disease or those who have been operated previously. The aim of the present study was to analyze the impact of smoking on the natural history and on treatment results. RESULTS: Six hundred and ten patients underwent 660 surgeries: 475 pit-picking operations and 185 Karydakis procedures. Smokers had developed a pilonidal abscess at least once during their disease significantly more often than non-smokers (48% vs. 26%, p = 0.00001). The recurrence rate following the pit-picking procedure was significantly increased in smokers (1-year recurrence rate: 36% vs. 21%, p = 0.008). After the Karydakis procedure, smokers developed more wound complications than non-smokers (29% vs. 10%, p = 0.005). The recurrence rate after the Karydakis flap was non-significantly increased in smokers (9% vs. 7% at 1 year, p = 0.07). CONCLUSIONS: Smoking has a detrimental effect on the natural history and on treatment results of pilonidal disease. Patients should be encouraged to cease smoking prior to pilonidal surgery.

[Incidentalomas of the liver and gallbladder. Evaluation and therapeutic procedure]. / Inzidentalome der Leber und der Gallenblase. Bewertung und therapeutisches Vorgehen.

The expanding use of ultrasound in general practice is leading to an ever increasing rate of detection of true hepatic incidentaloma. The correct diagnosis of hepatic incidentaloma may be made in over 90% with non-invasive means. The questionable diagnosis of "symptomatic" incidentaloma should undergo close scrutiny prior to a decision in favour of surgery. With regard to more recent literature, the former "absolute" requirement for surgical resection in all cases of liver cell adenoma may have to be reappraised. Final inability to rule out malignancy represents an unquestionable indication for surgery in the light of low rates of morbidity and lack of mortality in this otherwise healthy patient group. Percutaneous biopsies should not be performed due to oncological hazards, indeterminate results and potential for acute complications.The stage-oriented radical re-resection following diagnosis of an incidentally detected gallbladder cancer may lead to significantly improved long-term survival, especially in the early tumour stages T1b and T2, which represents the most common stage of gallbladder cancer in incidentaloma. Patients at elevated risk for incidental gallbladder cancer should undergo thorough instruction with regard to the potential hazards of laparoscopic cholecystectomy. Multimodal therapeutic strategies directed at advanced stages of incidentally detected gallbladder cancer should be evaluated in prospective multicentre studies.

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.

BACKGROUND: We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). METHODS: In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. RESULTS: Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). CONCLUSIONS: Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

Factors associated with disease progression in patients with gastrointestinal stromal tumors in the pre-imatinib era.

The aim of this study was to determine the predictors of survival in 38 patients with curatively resected gastrointestinal stromal tumors (GISTs). The tumor was located in the stomach in 23 cases, the small bowel in 13, and the colon in 2. In 23 patients (61%), a mutation in exon 11 of the kit gene was detected. In 7 cases, all small gastric tumors, a mutation in the platelet-derived growth factor receptor a (PDGFRA) gene was detected. The overall 5-year survival rate was 70%. In 9 patients, GISTs relapsed, leading to an actuarial 5-year disease-free survival of 78%. By multivariate analysis, the presence of distant metastases, the proliferative (MIB-1) index, and deletional mutation in codons 557 and/or 558 of kit exon 11 correlated significantly with poor outcome. None of the PDGFRA mutant GISTs relapsed. These findings suggest a strong relationship between various tyrosine kinase receptor mutations and survival outcome in patients with GISTs.

Validation of portal vein flow measurement by color flow Doppler sonography in a porcine model of septic shock.

OBJECTIVE: To compare portal vein flow values gained by color flow Doppler sonography with simultaneously derived data from an ultrasound transit time flow probe. DESIGN: Repeated, simultaneous flow measurements were performed in a prospective study investigating the effect of various drugs on hepatosplanchnic perfusion and energy balance in a long-term model of stable, hyperdynamic endotoxin shock. SETTING: Investigational animal laboratory. SUBJECTS: Domestic pigs. INTERVENTIONS: Alterations in respirator setting were studied with regard to their effect on the quality of color flow Doppler data in comparison to flow probe data. Additional experiments included variation in PEEP level in conjunction with volume resuscitation. MEASUREMENTS AND RESULTS: Respiratory rates of 14-18/min led to color Doppler flow values consistently 20-40% above simultaneously measured flow probe data. Temporary apnea led to enhanced agreement of data. Reduction in respiratory rate to 8/min with increase in tidal volume consistently led to color Doppler data within 10% of the corresponding flow probe values. CONCLUSIONS: A short-term period of respirator-dependent, constant portal vein inflow enables color Doppler sonography to detect correct values in a clinically relevant setting of hyperdynamic endotoxin shock.

Surgical management of bile duct injuries following laparoscopic cholecystectomy: analysis and follow-up of 28 cases.

BACKGROUND: Biliary tract lesions pose a dreaded complication of laparoscopic cholecystectomy. In a retrospective study we analyzed the clinical presentation, diagnostic and therapeutic management and outcome of 28 patients presenting with iatrogenic bile duct injuries. PATIENTS AND METHODS: Between 1994 and 2001 we treated 28 patients with bile duct lesions following laparoscopic cholecystectomy at our center. Operation notes and charts of all patients were reviewed systematically. A follow-up examination of each patient was performed after a median of 12 months (range 1-90). RESULTS: Twenty-two patients presented with major circumferential bile duct defect lesions. Less severe injuries (n=6) were two minor bile leaks, one bile duct stricture and three tangential lesions. Twenty-six patients were referred to our institution within 16 days (range 0-226 days). Six patients were treated by nonsurgical procedures: endoscopic stenting in four and percutaneous intervention in two. In one of the remaining patients a cystic duct leak was closed via laparotomy, and in 21 a hepaticojejunostomy was performed. Reconstruction of a hepaticojenunostomy was performed in two of these patients. Patients were dismissed from the hospital after a median of 13 days (range 4-156). Four patients presenting with generalized biliary peritonitis required prolonged intensive care. One or more episodes of cholangitis were seen in five patients during follow-up examinations. CONCLUSIONS: Major iatrogenic bile duct injuries are associated with high morbidity and prolonged hospitalization. Interdisciplinary cooperation and early referral to an experienced center is crucial in the management of patients suffering from this affliction. Cholangitis is a marked problem in the follow-up.

Cardiovascular risk factors and estimated risk for CAD in a randomized trial comparing calcineurin inhibitors in renal transplantation.

Cardiovascular morbidity and mortality is high in patients following renal transplantation. The present analysis assessed major cardiovascular risk factors and estimated the risk of coronary artery disease in the largest present-day comparative trial of tacrolimus vs. microemulsified cyclosporine A. In this 6-month study, 557 patients were randomly allocated to therapy with tacrolimus (n = 286) or cyclosporine A (n = 271) concomitantly with azathioprine and corticosteroids. The primary endpoint was the incidence of and time to acute rejection. Blood pressure, serum cholesterol, HDL cholesterol, triglycerides, and blood glucose were measured at baseline, and at months 1, 3, and 6. Ten-year risk of coronary heart disease was estimated according to the Framingham risk algorithm. Tacrolimus resulted in significantly lower summary measures (time-weighted average) of serum cholesterol (p = 0.0004) and mean arterial blood pressure (p = 0.0156), but in a higher summary measure of blood glucose (p = 0.0028) than cyclosporine. The summary measure of serum triglycerides was not different between treatment groups (p = 0.368). The mean 10-year coronary artery disease risk estimate was significantly lowered in men (p = 0.0032) treated with tacrolimus, but was unchanged in women. Tacrolimus and cyclosporine A microemulsion exert a compound-specific impact on cardiovascular risk factors and appear to affect the predicted rate of cardiovascular morbidity in different manners.

A Monocyte chemoattractant protein-1 (MCP-1) polymorphism and outcome after renal transplantation.

Among the factors modulating transplant rejection and cardiovascular disease, chemokines and their respective receptors deserve special attention. In this respect, increased expression of MCP-1 and the corresponding receptor CCR2 have been demonstrated in renal transplant rejection and coronary artery disease. The impact of the MCP-1-2518G and CCR2-64I genotypes on renal allograft function was investigated in 232 patients who underwent transplantation over an 11-yr period. Genomic DNA was genotyped using PCR with sequence-specific primers followed by restriction fragment length polymorphism analysis. Eighteen (7.8%) patients were homozygous for the MCP-1-2518G mutation. The G/G allele of MCP-1 -2518 behaved as a determinant for long-term allograft survival and resulted in reduction of the mean graft survival, as compared with the heterozygous (A/G) or wild-type (A/A) allele (67 +/- 14 versus 95 +/- 4 mo; Log rank P = 0.0052). The 64I mutation of CCR2 had no effect on kidney graft failure (93 +/- 6 and 91 +/- 5 mo, respectively; P = 0.81). None of the investigated polymorphisms showed a significant shift in gene frequency in acute rejection and rejection-free groups. In conjunction with these findings, peripheral blood mononuclear cells from kidney transplant recipients carrying the G-allele were characterized by a 2.5-fold higher MCP-1 secretion (P < 0.05). In conclusion, recipients of renal transplants homozygous for the -2518 G mutation of the MCP-1 gene are at risk for premature kidney graft failure. This variant of MCP-1 may be a future predictor for long-term kidney graft failure.

Early experience with the ET Senior Program "Old For Old"; better to be number one?

Eurotransplant offers a Senior Program to extend the donor pool for renal transplantation. The study comprised 14 patients of the ET Senior ("Old For Old") Program. Kidneys from five cadaveric donors were transplanted in pairs to ten recipients with a difference in cold ischemia time (CIT) of >4 h, and grouped according to CIT (group 1: patients that underwent transplantation first; group 2: patients that underwent transplantation second). CIT was shorter (5.5+/-2.0 h vs. 11.7+/-3.1 h, P<0.01), and the first day diuresis was higher (287.4 ml/h vs. 134.8 ml/h, P<0.05) in group 1 than in group 2. No patient in group 1 required dialysis, 3/5 patients in group 2. Rejection episodes occured more often in group 2 (5/5 vs. 3/5), and the hospital stay tended to be shorter in group 1 (33.0 days (27-43) vs. 54.2 days (27-112)). Our study confirms the positive effect of ultra-short CIT on early graft function in marginal donors, despite overall short CIT. The increase in delayed graft function (DGF) may lead to an extended hospital stay and dialysis requirements. Efforts to realize simultaneous transplantation in two recipients seem necessary to optimize results.