RNOP-09: Pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma - a phase II study

BACKGROUND: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for. METHODS: In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx, PEG-Dox) and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy) and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression. RESULTS: The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison. CONCLUSION: Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data

Precision oncology in surgery: patient selection for operable pancreatic cancer

Objective: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection. Background: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease. Method: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram. Results: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables. Conclusions: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease

Google Goes Cancer: Improving Outcome Prediction for Cancer Patients by Network-Based Ranking of Marker Genes

Predicting the clinical outcome of cancer patients based on the expression of marker genes in their tumors has received increasing interest in the past decade. Accurate predictors of outcome and response to therapy could be used to personalize and thereby improve therapy. However, state of the art methods used so far often found marker genes with limited prediction accuracy, limited reproducibility, and unclear biological relevance. To address this problem, we developed a novel computational approach to identify genes prognostic for outcome that couples gene expression measurements from primary tumor samples with a network of known relationships between the genes. Our approach ranks genes according to their prognostic relevance using both expression and network information in a manner similar to Google's PageRank. We applied this method to gene expression profiles which we obtained from 30 patients with pancreatic cancer, and identified seven candidate marker genes prognostic for outcome. Compared to genes found with state of the art methods, such as Pearson correlation of gene expression with survival time, we improve the prediction accuracy by up to 7%. Accuracies were assessed using support vector machine classifiers and Monte Carlo cross-validation. We then validated the prognostic value of our seven candidate markers using immunohistochemistry on an independent set of 412 pancreatic cancer samples. Notably, signatures derived from our candidate markers were independently predictive of outcome and superior to established clinical prognostic factors such as grade, tumor size, and nodal status. As the amount of genomic data of individual tumors grows rapidly, our algorithm meets the need for powerful computational approaches that are key to exploit these data for personalized cancer therapies in clinical practice

Molekularbiologie und Molekularpathologie des kolorektalen Karzinoms

Mit einer für das Jahr 2000 geschätzten Inzidenz von 945.000 Neuerkrankungen und 492.000 Todesfällen rangiert das kolorektale Karzinom (KRK) nach dem Bronchial- und Mammakarzinom an 3. Stelle der weltweiten Krebsstatistik. In Deutschland erkranken jährlich ca. 50.000 Personen. Das durchschnittliche Erkrankungsalter liegt bei den sporadischen KRK (ca. 50–60% aller KRK) mit unauffälliger Familienanamnese bei ca. 65 Jahren, bei den autosomal-dominant monogenetisch bedingten hereditären Krebsprädispositionssyndromen (<10% aller KRK) in der Regel vor dem 45. Lebensjahr. Dabei sind ca. 3% der erblichen KRK dem hereditären nichtpolypösen kolorektalen Karzinom (HNPCC) mit einer Penetranz von 80–85% zuzuordnen, weitere ca. 1% der klassischen oder attenuierten Form der familiären adenomatösen Polyposis (FAP) mit einer 100%igen Penetranz. Daneben gibt es noch weitere, seltene autosomaldominante Krebssyndrome wie familiäre juvenile Polypose und Peutz- Jeghers-Syndrom (<1% der KRK) sowie hereditär polygen verursachte KRK (ca. 30–40%). Da die den jeweiligen familiären Krebsprädispositionserkrankungen zugrunde liegenden molekulargenetischen Defekte weitgehend bekannt sind, kann heute bereits vor Ausprägung des nur bei der klassischen FAP charakteristischen Phänotyps bei auffälliger Familienanamnese oder frühem Erkrankungsalter der Verdacht auf eine hereditäre Tumordisposition durch den molekularen Nachweis der auslösenden Keimbahnmutation gesichert werden. Diese prädiktive Diagnostik ermöglicht zwar zum einen eine neue Dimension der Krebsprävention und Früherkennung, wirft jedochneben möglichen psychosozialen Problemen und Gefahr der Diskriminierung auch zahlreiche ethische und nicht zuletzt versicherungsrechtliche Fragen auf. Diese sind in ihrer Konsequenz nicht unumstritten

Ochronosis--a rare cause of secondary gonarthrosis Ochronose--eine seltene Ursache der sekundären Gonarthrose

Ochronosis is a manifestation of the rare disease alkaptonuria. The most common presentations include pain in the lumbar spine region starting during the 3rd decade, spreading over the large joints. There exists no curative therapy for the disease at the moment. In the long-term the patients will be dependent on total joint arthroplasty