Bertram Wiedenmann

Sunitinib malate for the treatment of pancreatic neuroendocrine tumors

BACKGROUND The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials. METHODS We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety. RESULTS The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue. CONCLUSIONS Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).

ENETS consensus guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary

ENETS Consensus Guidelines for the Management of Patients with Liver and Other Distant Metastases from Neuroendocrine Neoplasms of Foregut, Midgut, Hindgut, and Unknown Primary

Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands.

We report here the in vivo diagnostic use of a peptide–dye conjugate consisting of a cyanine dye and the somatostatin analog octreotate as a contrast agent for optical tumor imaging. When used in whole-body in vivo imaging of mouse xenografts, indotricarbocyanine-octreotate accumulated in tumor tissue. Tumor fluorescence rapidly increased and was more than threefold higher than that of normal tissue from 3 to 24 h after application. The targeting conjugate was also specifically internalized by primary human neuroendocrine tumor cells. This imaging approach, combining the specificity of ligand/receptor interaction with near-infrared fluorescence detection, may be applied in various other fields of cancer diagnosis.

Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors-the international lanreotide and interferon alfa study group

PURPOSE Somatostatin analogs and interferon alfa control hormone-active/functional neuroendocrine gastroenteropancreatic tumors. In addition to hormonal control, variable degrees of antiproliferative effects for both agents have been reported. Until now, however, no prospective, randomized studies in therapy-naive patients have compared somatostatin analogs or interferon alfa alone with a combination of the two. METHODS Eighty therapy-naive patients with histologically verified neuroendocrine tumor disease (primary localization: foregut, n = 36; midgut, n = 30; hindgut, n = 3; unknown, n = 11; functional, n = 29; nonfunctional, n = 51) were randomly treated either with lanreotide (1 mg three times a day administered subcutaneously [SC]) or interferon alfa (5 x 106 U three times a week SC) or both. All patients had disease progression in the 3 months before study entry, verified with imaging procedures. RESULTS Twenty-five patients were treated with lanreotide, 27 patients were treated with interferon alfa, and 28 patients were treated with the combination. Partial tumor remission was seen in four patients (one patient who received lanreotide, one patient who received interferon alfa, and two patients who received the combination). During the 12 months of therapy, stable disease was observed in 19 patients (seven patients who received lanreotide, seven patients who received interferon alfa, and five patients who received the combination), whereas tumor progression occurred in 14 of 25 patients (lanreotide), 15 of 27 patients (interferon alfa), and 14 of 28 patients (combination). Side effects leading to an interruption of therapy were more frequent in the combination group than in the monotherapy arms. CONCLUSION This prospective, randomized, multicenter study shows for the first time that somatostatin analogs, interferon alfa, or the combination of the two had comparable antiproliferative effects in the treatment of metastatic neuroendocrine gastroenteropancreatic tumors. Response rates were lower compared with those published in previous, nonrandomized studies. The antiproliferative effect of the tested substances was similar for functional and nonfunctional neuroendocrine tumors.

Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS).

Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS).

Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection.

Adefovir dipivoxil was recently approved for the treatment of wild‐type and lamivudine‐resistant hepatitis B virus (HBV) infection. Tenofovir disoproxil fumarate, a congender of adefovir that is used in the treatment of HIV infected patients, has recently been shown to also be effective in patients with lamivudine‐resistant HBV infection. We therefore compared the two substances in a study of 53 patients defined by high HBV DNA (>6 log10 copies/mL) levels and genotypic evidence of lamivudine resistance. Thirty‐five patients received tenofovir for 72 to 130 weeks, and 18 received adefovir for 60 to 80 weeks. Changes in HBV DNA levels were followed for the complete period of 48 weeks. Early viral kinetics were compared on matched subgroups of 5 patients each. Individually, all tenofovir‐treated patients showed a strong and early suppression of HBV DNA within a few weeks whether they were coinfected with HIV or were without comorbidity. In contrast, considerable individual variations in HBV DNA decline were observed in the adefovir group. Thus at week 48, only 44% of these patients had HBV DNA levels below 105 copies/mL in contrast to 100% of the tenofovir‐treated patients (P = .001). No severe side effects were noticed in either group. No evidence of phenotypic viral resistance could be demonstrated in the tenofovir‐treated patients in the long term (up to 130 weeks). In conclusion, tenofovir may become an effective alternative for the treatment of patients with lamivudine‐resistant HBV infection. (HEPATOLOGY 2004;40:1421–1425.)

Differentiation of pluripotent embryonic stem cells into the neuronal lineage in vitro gives rise to mature inhibitory and excitatory neurons.

Embryonic stem (ES) cells represent a suitable model to analyze cell differentiation processes in vitro. Here, we report that pluripotent ES cells of the line BLC 6 differentiate in vitro into neuronal cells possessing the complex electrophysiological and immunocytochemical properties of postmitotic nerve cells. In the course of differentiation BLC 6-derived neurons differentially express voltage-dependent (K+, Na+, Ca2+) and receptor-operated (GABAA, glycine, AMPA, NMDA receptors) ionic channels. They generate fast Na(+)-driven action potentials and are functionally coupled by inhibitory (GABAergic) and excitatory (glutamatergic) synapses as revealed by measurements of postsynaptic currents. Moreover, BLC 6-derived neurons express neuron-specific cytoskeletal, cell adhesion and synaptic vesicle proteins and exhibit a Ca(2+)-dependent GABA secretion. Thus, the ES cell model enables the investigation of cell lineage determination and signaling mechanisms in the developing nervous system from a pluripotential stem cell to a differentiated postmitotic neuron. The in vitro differentiation of neurons from ES cells may be an excellent approach to study by targeted gene disruption a variety of neuronal functions.

Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy†‡§

Incomplete virological response to adefovir dipivoxil (ADV) has been observed in patients with lamivudine‐resistant hepatitis B virus (HBV) infection and may be associated with developing resistance and disease progression. We therefore investigated whether the efficacy of viral suppression could be improved by replacing ADV with tenofovir disoproxil fumarate (TDF). Twenty patients with chronic HBV infection (18 HBeAg+), viral breakthrough during lamivudine therapy, and persistent viral replication (>10 4 copies/mL) after 15 months of ADV monotherapy (range 4‐28 months) were treated with TDF 300 mg daily and were retrospectively analyzed. A screening for nucleoside/nucleotide analogue resistance mutations within the HBV polymerase gene was performed in all patients by direct sequencing. Within a median of 3.5 months, application of TDF led to undetectable HBV DNA in 19 of 20 patients, as demonstrated by suppression of HBV DNA below the detection limit of 400 copies/mL. Initially elevated ALT levels had normalized in 10 of 14 patients by the end of follow‐up (median 12 months, range 3‐24 months). Four patients lost HBeAg, after 3, 4, 5, and 16 months, and one patient seroconverted to anti‐HBs after 16 months of TDF therapy. Lamivudine‐associated mutations (rtV173L, rtL180M, rtM204V/I) could be detected in 6 patients at baseline of TDF, but this obviously did not influence the response. ADV‐resistant mutations were not detected. No side effects were reported. In conclusion, these preliminary observations strongly suggest that TDF might be a highly effective rescue drug for HBV‐infected patients with altered responsiveness to treatment with lamivudine and ADV. (HEPATOLOGY 2006;44:318–325.)

Long‐term efficacy of tenofovir monotherapy for hepatitis B virus‐monoinfected patients after failure of nucleoside/nucleotide analogues

Tenofovir disoproxil fumarate (TDF) has demonstrated high antiviral efficacy in treatment‐naive patients with chronic hepatitis B virus (HBV) infection but experience in nucleoside/nucleotide analogue (NA)‐experienced patients is limited. In this retrospective multicenter study we therefore assessed the long‐term efficacy of TDF monotherapy in patients with prior failure or resistance to different NA treatments. Criteria for inclusion were HBV DNA levels >4.0 log10 copies/mL at the start and a minimum period of TDF therapy for at least 6 months. In all, 131 patients (mean age 42 ± 12 years, 95 male, 65% hepatitis B e antigen [HBeAg]‐positive) were eligible. Pretreatment consisted of either monotherapy with lamivudine (LAM; n = 18), adefovir (ADV; n = 8), and sequential LAM‐ADV therapy (n = 73), or add‐on combination therapy with both drugs (n = 29). Three patients had failed entecavir therapy. Resistance analysis in 113 of the 131 patients revealed genotypic LAM and ADV resistance in 62% and 19% of patients, respectively. The mean HBV DNA level at TDF baseline was 7.6 ± 1.5 log10 copies/mL. The overall cumulative proportion of patients achieving HBV DNA levels <400 copies/mL was 79% after a mean treatment duration of 23 months (range, 6–60). Although LAM resistance did not influence the antiviral efficacy of TDF, the presence of ADV resistance impaired TDF efficacy (100% versus 52% probability of HBV DNA <400 copies/mL, respectively). However, virologic breakthrough was not observed in any of the patients during the entire observation period. Loss of HBeAg occurred in 24% of patients and HBsAg loss occurred in 3%. No significant adverse events were noticed during TDF monotherapy. Conclusion: TDF monotherapy induced a potent and long‐lasting antiviral response in NA‐experienced patients with previous treatment failure. Our data may have implications for current add‐on strategies. (HEPATOLOGY 2009.)

Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis.

Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6–8.0; P = 1.3 × 10−7). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2–15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7–109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.