Konrad Schoppmeyer

Surgical and palliative management and outcome in 184 patients with hilar cholangiocarcinoma: palliative photodynamic therapy plus stenting is comparable to r1/r2 resection.

Objective:First, to analyze the strategy for 184 patients with hilar cholangiocarcinoma seen and treated at a single interdisciplinary hepatobiliary center during a 10-year period. Second, to compare long-term outcome in patients undergoing surgical or palliative treatment, and third to evaluate the role of photodynamic therapy in this concept. Summary Background Data:Tumor resection is attainable in a minority of patients (<30%). When resection is not possible, radiotherapy and/or chemotherapy have been found to be an ineffective palliative option. Recently, photodynamic therapy (PDT) has been evaluated as a palliative and neoadjuvant modality. Methods:Treatment and outcome data of 184 patients with hilar cholangiocarcinoma were analyzed prospectively between 1994 and 2004. Sixty patients underwent resection (8 after neoadjuvant PDT); 68 had PDT in addition to stenting and 56 had stenting alone. Results:The 30-day death rate after resection was 8.3%. Major complications occurred in 52%. The overall 1-, 3-, and 5-year survival rates were 69%, 30%, and 22%, respectively. R0, R1, and R2 resection resulted in 5-year survival rates of 27%, 10%, and 0%, respectively. Multivariate analysis identified R0 resection (P < 0.01), grading (P < 0.05), and on the limit to significance venous invasion (P = 0.06) as independent prognostic factors for survival. PDT and stenting resulted in longer median survival (12 vs. 6.4 months, P < 0.01), lower serum bilirubin levels (P < 0.05), and higher Karnofsky performance status (P < 0.01) as compared with stenting alone. Median survival after PDT and stenting, but not after stenting alone, did not differ from that after both R1 and R2 resection. Conclusion:Only complete tumor resection, including hepatic resection, enables long-term survival for patients with hilar cholangiocarcinoma. Palliative PDT and subsequent stenting resulted in longer survival than stenting alone and has a similar survival time compared with incomplete R1 and R2 resection. However, these improvements in palliative treatment by PDT will not change the concept of an aggressive resectional approach.

Impact of capsule endoscopy on outcome in mid-intestinal bleeding: a multicentre cohort study in 285 patients.

Background Capsule endoscopy (CE) sensitively detects the bleeding source in the small bowel. However, the influence of CE on long-term outcome is not well established. Methods In five tertiary hospitals, all CE investigations were retrospectively identified dating back to 3 years. Patients with intestinal bleeding and negative bidirectional endoscopy were included, and relapse of bleeding was recorded. Results A bleeding source was detected in 219 of 285 patients (76.8%); CE provided the diagnosis in 175 of 219 (79.9%) and other, repeated investigations in 44 cases (20.1%). Follow-up (mean±SD=20.7±9.4 months) in 240 patients identified rebleeding in 65 (27.1%), and readmission to a hospital in 42 (17.5%). Hospital readmission was most frequent in patients with angiectasias (31.3%, relative risk (RR)=5.0; 95% confidence interval (CI)=2.4–10.4). Other risk factors included patients being older than 60 years of age (RR=3.8; 95% CI=1.5–9.5), and anticoagulant medication (RR=3.0; 95% CI=1.5–6.0). Therapeutic measures had a mean recurrence rate of 3.7% in surgical candidates (Meckels diverticulum, tumor), 40% in endoscopically treated and 16% in medically treated patients. In case all the detected angiectasias had been cauterized, the relapse rate was low (11.8%), but in incompletely treated patients, it was high (85.7%). Bleeding relapse was never lethal. Conclusion CE guides therapeutic measures and predicts the risk of recurrent bleeding in small intestinal bleeding. High risk of rebleeding in angiectasias is significantly reduced by the cauterization of all demonstrable lesions.

Irinotecan with 5-FU/FA in advanced biliary tract adenocarcinomas: a multicenter phase II trial.

Objectives:Biliary cancer has a poor prognosis and lacks a standard palliative chemotherapy. The purpose of this prospective single-arm phase II study was to determine the activity and tolerability of irinotecan, 5-fluorouracil, and folinic acid in advanced biliary cancer. Patients and Methods:Patients with inoperable intrahepatic cholangiocarcinoma (ICC) or gallbladder cancer (GBC) and no prior chemotherapy were eligible. Irinotecan 80 mg/m2, followed by folinic acid 500 mg/m2 and 5-FU 2000 mg/m2 infused over 24 hours (Fufiri) were administered weekly 6 times, every 8 weeks. The primary endpoint was response rate, and secondary endpoints were overall survival (OS), progression-free survival (PFS), and toxicity. Results:Seventeen patients with ICC and 13 patients with GBC were enrolled. All patients were evaluable for safety. WHO grade 3/4 drug-related adverse events occurred in 8 patients (27%), consisting of diarrhea and leukopenia in 5 and 3 patients, respectively. One patient with diarrhea grade 4 finally succumbed to sepsis. Objective response rate was 10% (95% confidence interval, 2.1%–26.5%), with an additional 10% of patients showing stable disease. Median overall survival was 166 days and 273 days, and median progression-free survival was 84 days and 159 days for ICC and GBC, respectively. Conclusions:Fufiri is a well-tolerated regimen in patients with ICC and GBC but has only modest activity in advanced biliary tract cancer.

Identification and Quantitation of the N-Acetyl-L-cysteine S-Conjugates of Bendamustine and Its Sulfoxides in Human Bile after Administration of Bendamustine Hydrochloride

We recently reported the detection of mercapturic acid pathway metabolites of bendamustine, namely, cysteine S-conjugates in human bile, which are supposed to subsequently undergo further metabolism. In this study, we describe the identification and quantitation of consecutive bendamustine metabolites occurring in human bile using authentic reference standards and the synthesis and structural confirmation of these compounds. Mass spectrometry data along with high-performance liquid chromatography retention data (fluorescence detection) of the synthetic reference standards were consistent with those of the metabolites found in human bile after administration of bendamustine hydrochloride to cancer patients. Analysis of the purified synthetic reference compounds showed a purity of at least 95%. Structural confirmation was achieved by one- and two-dimensional proton as well as carbon-13 NMR spectroscopy and mass spectrometry. A total of 16 bendamustine-related compounds were detected in the bile of patients, 11 of them were recovered as conjugates. Eight conjugates have been structurally confirmed as novel mercapturic acids and sulfoxides. Biliary excretion of the sulfoxides was twice that of the mercapturate precursors. Glutathione S-conjugates of bendamustine have not been detected in bile samples, indicating rapid enzymatic cleavage in humans. Both the lack of glutathione (GSH) conjugates and occurrence of diastereomeric sulfoxides emphasize species-related differences in the GSH conjugation of bendamustine between humans and rats. The total amount recovered in the bile as the sum of all conjugates over the period of 24 h after dosing averaged 5.2% of the administered dose. The question of whether the novel metabolites contribute to urinary excretion should be a target of future investigations.

Imatinib Mesylate for Palliative Second-Line Treatment of Advanced Biliary Tract Cancer: A Bicentric Phase II Study

inclusion criteria were age between 18 and 75 years, Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2, a life expectancy of > 3 months, and adequate bone marrow, hepatic and renal function. Primary endpoints of this study were objective response rate (complete remission (CR) and partial remission (PR) according to World Health Organization (WHO) criteria) and progression-free survival (PFS); secondary endpoints included imatinib pharmacokinetics (PK), rate of disease control (CR, PR, and stable disease (SD)) and time to tumor progression (TTP), frequency and severity of adverse events, and overall survival (OS). All patients received the following regimen: imatinib mesylate 400 mg/day orally for 1 week followed by a dose escalation to 600 mg/day if tolerable. CT scans or MRI for tumor measurement were performed at baseline and every 12 weeks, Ffluorodeoxyglucose positron emission tomography ([F]FDG-PET) scans at baseline, week 1 and week 12. The plasma concentrations of imatinib mesylate and N-demethylated piperazine derivative (CGP74588) were determined by a high-performance liquid chromatography method on day 1, according to a specified time schedule and in weeks 2, 4, 6, 18, 30, and 42 of the study prior to the morning dosage administration. Immunohistochemical staining was carried out at the end of our study since c-kit-R positivity was no criterion for study enrollment. To be of interest for further studies, imatinib mesylate would have to produce a response rate (RR) of at least 25%. Based on previous studies, a number of 40 patients was needed to generate a 95% confidence interval with a range of 28 percent points. Nine patients were enrolled between 05/2006 and 08/2009 (table 1) and the study was stopped prematurely due to poor recruitment. Treatment was continued for at least 3 months in 5 patients. However, all of these patients required intermittent dose reductions due to (serious) adverse events. No objective responses were observed in an intention-to-treat analysis. 5 patients experienced disease progression (PD), with a median TTP of 79 days (range 38–116 days). 4 patients

Thymostimulin versus placebo for palliative treatment of locally advanced or metastasised hepatocellular carcinoma: a phase III clinical trial.

BackgroundThymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess the efficacy of thymostimulin in a phase III trial.MethodsThe study was designed as a prospective randomised, placebo-controlled, double-blind, multicenter clinical phase III trial. Between 10/2002 and 03/2005, 135 patients with locally advanced or metastasised HCC (Karnofsky ≥60%/Child-Pugh ≤ 12) were randomised to receive thymostimulin 75 mg s.c. 5×/week or placebo stratified according to liver function. Primary endpoint was twelve-month survival, secondary endpoints overall survival (OS), time to progression (TTP), tumor response, safety and quality of life. A subgroup analysis according to liver function, KPS and tumor stage (Okuda, CLIP and BCLC) formed part of the protocol.ResultsTwelve-month survival was 28% [95%CI 17-41; treatment] and 32% [95%CI 19-44; control] with no significant differences in median OS (5.0 [95% CI 3.7-6.3] vs. 5.2 [95% CI 3.5-6.9] months; p = 0.87, HR = 1.04 [95% CI 0.7-1.6]) or TTP (5.3 [95%CI 2.0-8.6] vs. 2.9 [95%CI 2.6-3.1] months; p = 0.60, HR = 1.13 [95% CI 0.7-1.8]). Adjustment for liver function, Karnofsky status or tumor stage did not affect results. While quality of life was similar in both groups, fewer patients on thymostimulin suffered from accumulating ascites and renal failure.ConclusionsIn our phase III trial, we found no evidence of any benefit to thymostimulin in the treatment of advanced HCC and there is therefore no justification for its use as single-agent treatment. The effect of thymostimulin on hepato-renal function requires further confirmation.Trial RegistrationCurrent Controlled Trials ISRCTN64487365.

A pilot study of bendamustine in advanced bile duct cancer

We performed a pilot study to evaluate the safety and tolerability of bendamustine in patients with advanced hilar bile duct cancer and impaired liver function. Six patients with histologically proven, unresectable adenocarcinoma of the hilar bile duct were treated with bendamustine 140 mg/m2 intravenously on day 1 of the first cycle and with bendamustine 100 mg/m2 on days 1 and 2 of the second to fourth cycle. Treatment cycles were repeated every 21 days. Primary endpoint was the safety and tolerability of the treatment; secondary endpoints were response rate, time to progression and overall survival. Transient lymphopenia grade 3 occurred in all six patients. No other grade 3 or 4 toxicities were present. The most common nonhematologic toxicity was mouth dryness grade 2 in six patients. Three patients had stable disease. No partial or complete responses were observed. Median time to progression was 3.3 months; median overall survival was 6 months. Our study demonstrates that bendamustine can be safely administered in patients with hilar bile duct cancer and impaired liver function. A potential role of bendamustine in combination therapies for bile duct cancer will be a subject of further trials.

Radiochemotherapy followed by gemcitabine and capecitabine in extrahepatic bile duct cancer: a phase I/II trial.

Objective:Both radiotherapy and chemotherapy with gemcitabine and capecitabine have efficacy in biliary cancer. Our aim was to determine the toxicity and efficacy of a postoperative regimen combining both treatment modalities in extrahepatic bile duct cancer. Methods:Patients were eligible after surgery for extrahepatic bile duct adenocarcinoma. Surgery included resection of lymph node positive cancer, incomplete resections and diagnostic laparotomy in unresectable tumors. Patients received a fractionated radiotherapy of 49.6 Gy accompanied by gemcitabine once a week. After a 2-week rest, patients were treated with gemcitabine and capecitabine on a 3-week cycle. The treatment continued for 6 cycles in nonmeasurable disease or until disease progression or intolerable toxicity. Results:There were 18 patients (resection/laparotomy 7/11) enrolled between August 2003 and April 2005. Radiotherapy was completed in all patients and a total of 66 cycles of chemotherapy was applied. Fatigue and nausea were the most common mild adverse events. Grade 3 and 4 toxicity was rare after resection but frequent in unresectable disease and consisted of fatigue, nausea, duodenal ulcer, cachexia, and cholangitis in 1, 2, 2, 4, and 4 patients, respectively. We observed a 50% disease stabilization rate in patients with measurable disease. Median overall survival was 7.9 months in patients with unresectable tumors. Median overall survival in patients after resection has not been reached at a median follow-up of 19.5 months. Conclusions:Radiochemotherapy using gemcitabine followed by gemcitabine and capecitabine is an active regimen with manageable toxicity after resection of extrahepatic bile duct cancer but has significant toxicity in unresectable disease.

Predictive value of heparanase expression in the palliative therapy of pancreatic cancer

Background/Aims: Patients with pancreatic ductal adenocarcinoma (PDA) have a median survival of less than six months from diagnosis. Palliative chemotherapy with the current standard gemcitabine does only marginally improve median survival. There may be subgroups of patients receiving palliative therapy that have a better prognosis. Factors predicting response to palliative therapy are ill-defined, though. Heparanase, an endoglycosidase degrading components of the extracellular matrix, promotes cell invasion, is involved in angiogenesis and plays a role in tumor metastases. It is expressed in PDA and its expression is associated with shorter postoperative survival after pancreatic resections. Methods: 58 patients with inoperable PDA were treated with gemcitabine therapy. Tissue sections from primary or metastatic tumor were used for immunohistochemical analysis. Heparanase expression was determined and correlated to tumor response, time to progression and survival. Results: Heparanase expression was detectable by immunohistochemistry in 36 out of 58 (62%) patients analyzed. Overall survival was 7.4 vs. 13.3 months (p = 0.006) in heparanase-positive and -negative tumors, respectively. Progression-free survival was 1.3 vs. 3.4 months, respectively (p = 0.47). Conclusion: Heparanase expression may be a useful marker to predict response to palliative therapy with gemcitabine in PDA.

A 79-Year-Old Patient With Yellow Sputum

C uestion: A 79-year-old woman was admitted with a -day history of vomiting, malaise, and nocturnal yellowsh stained cough. She denied having fever or pain. One onth earlier she has had an episode of Escherichia coli neumonia and sepsis. Her history included a cholecysectomy 9 months ago. Postoperatively, a benign bile uct stenosis had caused recurrent episodes of cholangiis and was treated by repeated endoscopic stenting. Furhermore, paroxysmal atrial fibrillation, coronary artery isease, and type 2 diabetes mellitus were present. On physical examination, she had slightly icteric clerae and basal pulmonary rales. Laboratory results howed elevated alanine aminotransferase (160 U/L), asartate aminotransferase (110 U/L), alkaline phosphatase 58 U/L, -glutamyl transferase (1514 U/L), and biliruin (4.4 U/L). The leukocyte count was 15,000/ L. A putum specimen was positive for Citrobacter freudii, E coli, nd Enterococcus gallinarum. Blood culture was also posiive for E coli. Chest radiograph showed a left-sided pulmonary infilrate. Because the laboratory results suggested a cholanitis, endoscopic retrograde cholangiography was perormed. The cholangiogram is illustrated in Figure A and hows an uncommon finding. What is the diagnosis? See the GASTROENTEROLOGY web site (www.gastrojournal. rg) for more information on submitting your favorte image to Clinical Challenges and Images in GI. SEBASTIAN WEIS, MD JOACHIM MÖSSNER, MD KONRAD SCHOPPMEYER, MD Department of Medicine and Dermatology Division of Gastroenterology and Rheumatology University of Leipzig Leipzig, Germany