Effective downsizing but enhanced intratumoral heterogeneity following neoadjuvant sorafenib in patients with non-metastatic renal cell carcinoma.

OBJECTIVES: To evaluate the safety and feasibility of sorafenib prior to surgery for downsizing tumors in patients with non-metastatic cT1-3 renal tumors together with a characterization of functional intratumoral heterogeneity (ITH). MATERIALS AND METHODS: The effects of 4-week sorafenib prior to curative surgery were assessed in a prospective, single-center, randomized, placebo-controlled, double-blinded, pilot trial in patients with T1-3N0M0 renal cell carcinoma (RCC). Patients received sorafenib or placebo for 28 days prior to surgery. MRI was performed at baseline and prior to surgery to calculate tumor volume. The clinical responses were further characterized on the molecular level by immunohistochemical stainings for Ki-67, cleaved caspase-3, and CD31. RESULTS: After enrolling 20 patients into the study, 14 patients were randomized, of which 12 patients were available for analysis. While no significant change in tumor volume was seen for placebo (range = -24.2-0.2%) a reduction of 29.0% (range = -4.9-61.1%) was detected for sorafenib (p < 0.05). Primary renal tumor diameter changed from 10.6 cm (range = 6.5-10.8) to 10.7 cm (range = 6.7-11.1) in the placebo group, and from 5.4 cm (range = 4.3-7.3) to 4.4 cm (range = 3.5-6.8) for the sorafenib group, at baseline vs. 28 days of treatment. Correlative assessment of proliferation, apoptosis, and microvessel density revealed an enhanced degree of functional ITH in treated patients suggesting adaptive and/or regenerative processes with potential relevance for the development of drug resistance. CONCLUSIONS: Sorafenib in standard dosage, given preoperatively for 28 days, was clinically active in downsizing tumors in patients with locally confined, non-metastatic RCC together but led to an enhanced functional ITH in the residual tumor tissue.

Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol.

BACKGROUND: The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany. METHODS: ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months. DISCUSSION: This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application of an oncolytic virus. Due to its study design the trial will not only generate data on the local effect of H-1PV but it will also investigate the penetration of H-1PV into the tumor after systemic delivery and obtain safety data from systemic delivery possibly supporting clinical trials with H-1PV in other, non-CNS malignancies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01301430.

New resampling method for evaluating stability of clusters.

BACKGROUND: Hierarchical clustering is a widely applied tool in the analysis of microarray gene expression data. The assessment of cluster stability is a major challenge in clustering procedures. Statistical methods are required to distinguish between real and random clusters. Several methods for assessing cluster stability have been published, including resampling methods such as the bootstrap. We propose a new resampling method based on continuous weights to assess the stability of clusters in hierarchical clustering. While in bootstrapping approximately one third of the original items is lost, continuous weights avoid zero elements and instead allow non integer diagonal elements, which leads to retention of the full dimensionality of space, i.e. each variable of the original data set is represented in the resampling sample. RESULTS: Comparison of continuous weights and bootstrapping using real datasets and simulation studies reveals the advantage of continuous weights especially when the dataset has only few observations, few differentially expressed genes and the fold change of differentially expressed genes is low. CONCLUSION: We recommend the use of continuous weights in small as well as in large datasets, because according to our results they produce at least the same results as conventional bootstrapping and in some cases they surpass it.

Role of the eNOS Glu298Asp variant on the GNB3825T allele dependent determination of alpha-adrenergic coronary constriction.

The 825T allele of a polymorphism at GNB3, encoding the G protein beta(3) subunit, is associated with an enhanced coronary blood flow (CBF) reduction in response to alpha(2)-, but not to alpha(1)-adrenoceptor activation. Because the regulation of vascular tone by alpha(2)-adrenoceptors includes direct vasoconstriction as well as vasodilatation by endothelial release of nitric oxide, the eNOS Glu298Asp variant might further contribute to explain the variability of CBF reduction in response to alpha-adrenoceptor activation. Genotyping at the GNB3 and the eNOS gene was performed on 48 individuals receiving either the alpha(1)-adrenoceptor agonist methoxamine (5 mg i.c.) and/or the alpha(2)-adrenoceptor agonist BHT 933 (5 mg i.c.). CBF was calculated from quantitative coronary angiography and intracoronary Doppler flow velocity measurement. To analyse the impact of genotypes and coronary artery disease, a linear regression model was used, including cholesterol levels, heart rate, smoking and mean aortic blood pressure. An initial, univariate analysis suggested an impact of the eNOS Glu298Asp variant on alpha(2)-adrenoceptor-induced coronary constriction (CBF reduction 53.4 ch006.1 TT/TG versus 30.7 ch006.9% GG; P = 0.003). However, multifactorial analysis showed that the GNB3825T allele was associated exclusively with the CBF reduction on alpha(2)-adrenoceptor activation (58.2 +/- 4.4% TT/TC versus 27.9 +/- 4.3% CC; P < 0.0001). Contrary to the initial analysis, the Glu298Asp variant of the eNOS gene provides no additional information on the genetic basis of alpha(2)-adrenoceptor-induced coronary vasoconstriction, which appears exclusively associated to the 825T allele at GNB3. Analysis of modifying genes appears crucial for the understanding of genetic associations.

Long-term outcome of psychodynamic therapy and cognitive-behavioral therapy in social anxiety disorder.

OBJECTIVE: Relatively few studies have examined the long-term outcome of psychotherapy in social anxiety disorder. The authors previously reported findings of a clinical trial comparing cognitive-behavioral therapy (CBT), psychodynamic therapy, and a wait-list control. The purpose of the present study was to follow the participants' status over the ensuing 24 months. METHOD: Outpatients with social anxiety disorder who were treated with CBT (N=209) or psychodynamic therapy (N=207) in the previous trial were assessed 6, 12, and 24 months after the end of therapy. Primary outcome measures were rates of remission and response. RESULTS: For both CBT and psychodynamic therapy, response rates were approximately 70% by the 2-year follow-up. Remission rates were nearly 40% for both treatment conditions. Rates of response and remission were stable or tended to increase for both treatments over the 24-month follow-up period, and no significant differences were found between the treatment conditions after 6 months. CONCLUSIONS: CBT and psychodynamic therapy were efficacious in treating social anxiety disorder, in both the short- and long-term, when patients showed continuous improvement. Although in the short-term, intention-to-treat analyses yielded some statistically significant but small differences in favor of CBT in several outcome measures, no differences in outcome were found in the long-term.

Psychodynamic therapy and cognitive-behavioral therapy in social anxiety disorder: a multicenter randomized controlled trial.

OBJECTIVE Various approaches to cognitive-behavioral therapy (CBT) have been shown to be effective for social anxiety disorder. For psychodynamic therapy, evidence for efficacy in this disorder is scant. The authors tested the efficacy of psychodynamic therapy and CBT in social anxiety disorder in a multicenter randomized controlled trial. METHOD In an outpatient setting, 495 patients with social anxiety disorder were randomly assigned to manual-guided CBT (N=209), manual-guided psychodynamic therapy (N=207), or a waiting list condition (N=79). Assessments were made at baseline and at end of treatment. Primary outcome measures were rates of remission and response, based on the Liebowitz Social Anxiety Scale applied by raters blind to group assignment. Several secondary measures were assessed as well. RESULTS Remission rates in the CBT, psychodynamic therapy, and waiting list groups were 36%, 26%, and 9%, respectively. Response rates were 60%, 52%, and 15%, respectively. CBT and psychodynamic therapy were significantly superior to waiting list for both remission and response. CBT was significantly superior to psychodynamic therapy for remission but not for response. Between-group effect sizes for remission and response were small. Secondary outcome measures showed significant differences in favor of CBT for measures of social phobia and interpersonal problems, but not for depression. CONCLUSIONS CBT and psychodynamic therapy were both efficacious in treating social anxiety disorder, but there were significant differences in favor of CBT. For CBT, the response rate was comparable to rates reported in Swedish and German studies in recent years. For psychodynamic therapy, the response rate was comparable to rates reported for pharmacotherapy and cognitive-behavioral group therapy.

Effect of CD34 cell dose on hematopoietic reconstitution and outcome in 508 patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation.

BACKGROUND: We analyzed the hematopoietic reconstitution and outcome of 508 patients with multiple myeloma (MM) with respect to the number of CD34+ cells reinfused at our center. PATIENTS AND METHODS: Each cohort of 390 patients (unselected CD34+ cell transplant) and 118 patients (CD34+ selected transplant) was divided into four subgroups. Among the 390 transplantations, 86 patients received a high dose (HD-) of > or =6.50 x 10(6) unselected CD34+ cells/kg, 116 patients a low dose (LD-) of <3.00 x 10(6) CD34+ cells/kg. Among the patients treated with CD34+ selected PBSC, 34 received > or =6.50 x 10(6) CD34+ cells/kg (HD+) and 16 <3.00 x 10(6) CD34+ cells/kg (LD+). RESULTS: HD- patients experienced a reduced median time to leukocyte (13 d vs. 14 d) (P < 0.001) and platelet reconstitution >20 x 10(9)/L (10 d vs. 12 d) (P < 0.001). Similarly, HD+ showed a reduced median time to leukocyte (12 d vs. 15 d) (P < 0.001) and platelet recovery >20 x 10(9)/L (10 d vs. 11 d) (P = 0.058). CD34+ cell-dose was significant for long-term platelet recovery at day 360 (unselected transplant P = 0.015, selected transplant P = 0.023). Number of transplanted CD34+ cells had no significant impact on transplant related mortality, overall survival or CR/PR rates within 100 d. In terms of supportive care the differences of high-/low-dose grafts were minimal. CONCLUSIONS: These results confirm that high doses of CD34+ PBSC shorten hematopoietic reconstitution and reduce hospitalization. Nevertheless secure engraftment results from transplantation of 2.00-3.00 x 10(6) CD34+ cells/kg. As 60% of our pretreated patients are able to collect > or =5.00 x 10(6) CD34+ cells/kg within a single leukapheresis, division into two or more freezing bags allows safe tandem transplantation in the majority of MM patients.