Wolfgang Lamm

Hypothyroidism in patients with renal cell carcinoma: blessing or curse?

Sunitinib and sorafenib are tyrosine kinase inhibitors that have important antitumor activity in metastatic renal cell carcinoma (mRCC). Hypothyroidism constitutes a commonly reported side effect of both drugs, and particularly of sunitinib. The objective of this analysis was to investigate whether the occurrence of hypothyroidism during treatment with sunitinib and sorafenib affects the outcome of patients with mRCC.

Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma

Background Bortezomib belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma. Preclinical studies suggest that bortezomib has synergistic activity with rituximab, which provides a rationale for the exploration of treatment combinations. Design and Methods The activity and safety of bortezomib in combination with rituximab and dexamethasone were investigated in patients with relapsed or chemotherapy-refractory mantle cell lymphoma. A treatment cycle consisted of bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11; six 21-day cycles), rituximab (375 mg/m2, day 1) and dexamethasone (40 mg orally, days 1 to 4). Responding patients received four consolidating doses of rituximab. Sixteen patients with progressive mantle cell lymphoma after a median of three prior lines of therapy were enrolled. Results The overall response rate was 81.3% (13 patients), with seven patients achieving a complete response (43.8%). Six of these patients were also negative for disease activity by positron emission tomography scanning. The median progression-free survival and overall survival were 12.1 and 38.6 months, respectively. In patients achieving a complete response, the median progression-free survival and overall survival have not yet been reached. Adverse events (greater than grade II) included thrombocytopenia (37.5%), fatigue (18.8%) and peripheral neuropathy (12.5%). Two patients discontinued bortezomib because of grade III neuropathy. Conclusions Bortezomib combined with rituximab and dexamethasone has promising activity and manageable toxicity in patients with heavily pretreated mantle cell lymphoma. Achievement of complete response emerged as an important factor for sustained disease control. This trial was registered at www.clinicaltrials.gov as #NCT00261612.

Extracellular Matrix Remodeling by Bone Marrow Fibroblast-like Cells Correlates with Disease Progression in Multiple Myeloma

The pathogenesis of multiple myeloma (MM) is regarded as a multistep process, in which an asymptomatic stage of monoclonal gammopathy of undetermined significance (MGUS) precedes virtually all cases of MM. Molecular events characteristic for the transition from MGUS to MM are still poorly defined. We hypothesized that fibroblast-like cells in the tumor microenvironment are critically involved in the pathogenesis of MM. Therefore, we performed a comparative proteome profiling study, analyzing primary human fibroblast-like cells isolated from the bone marrow of MM, of MGUS, as well as of non-neoplastic control patients. Thereby, a group of extracellular matrix (ECM) proteins, ECM receptors, and ECM-modulating enzymes turned out to be progressively up-regulated in MGUS and MM. These proteins include laminin α4, lysyl-hydroxylase 2, prolyl 4-hydroxylase 1, nidogen-2, integrin α5β5, c-type mannose receptor 2, PAI-1, basigin, and MMP-2, in addition to PDGF-receptor β and the growth factor periostin, which are likewise involved in ECM activities. Our results indicate that ECM remodeling by fibroblast-like cells may take place already at the level of MGUS and may become even more pronounced in MM. The identified proteins which indicate the stepwise progression from MGUS to MM may offer new tools for therapeutic strategies.

Targeting of VEGF-dependent transendothelial migration of cancer cells by bevacizumab

Cancer progression is often associated with the formation of malignant effusions. Vascular endothelial growth factor (VEGF) is a major regulator of vascular permeability and has been implicated as mediator of tumor progression.

Extracerebral metastases determine the outcome of patients with brain metastases from renal cell carcinoma

BackgroundIn the era of cytokines, patients with brain metastases (BM) from renal cell carcinoma had a significantly shorter survival than patients without. Targeted agents (TA) have improved the outcome of patients with metastatic renal cell carcinoma (mRCC) however, their impact on patients with BM is less clear. The aim of this analysis was to compare the outcome of patients with and without BM in the era of targeted agents.MethodsData from 114 consecutive patients who had access to targeted agent were analyzed for response rates (ORR), progression free survival (PFS) and overall survival (OS). All patients diagnosed with BM underwent local, BM-specific treatment before initiation of medical treatment.ResultsData of 114 consecutive patients who had access to at least one type of targeted agents were analyzed. Twelve out of 114 renal cell carcinoma (RCC) patients (10.5%) were diagnosed with BM. Systemic treatment consisted of sunitinib, sorafenib, temsirolimus or bevacizumab. The median PFS was 8.7 months (95% CI 5.1 - 12.3) and 11.4 months (95% CI 8.7 - 14.1) for BM-patients and non-BM-patients, respectively (p = 0.232). The median overall survival for patients with and without BM was 13.4 (95% CI 1- 43.9) and 33.3 months (95% CI 18.6 - 47.0) (p = 0.358), respectively. No patient died from cerebral disease progression. ECOG Performance status and the time from primary tumor to metastases (TDM) were independent risk factors for short survival (HR 2.74, p = 0.001; HR: 0.552, p = 0.034).ConclusionsAlthough extracerebral metastases determine the outcome of patients with BM, the benefit from targeted agents still appears to be limited when compared to patients without BM.

Pulmonary metastasectomy for soft tissue sarcoma--report from a dual institution experience at the Medical University of Vienna.

BACKGROUND Pulmonary metastasectomy when possible has become therapeutic standard in soft tissue sarcoma patients. However, published reports frequently describe mixed series of patients with bone or soft tissue sarcoma. We report the outcome of 46 soft tissue sarcoma (STS) patients who underwent pulmonary metastasectomy (PM). METHODS This current analysis includes retrospective survival data from 46 consecutive STS patients with pulmonary metastases who underwent PM at the Medical University of Vienna between January 2003 and December 2013. RESULTS In total 72 pulmonary metastasectomies were performed. 322 metastatic nodules were resected with a median number of four nodules per intervention and the R0 resection rate was 97.2%. The postoperative complication rate as documented was low. Median follow-up (mFU) was 31.8 months (range 3.7-127.4). Median overall survival as calculated from first detection of metastatic disease was 47.1 months (95% confidence interval (CI)=36.2-58.1 months) and 45.3 months (95% CI=33.3-57.4 months) when calculated from first PM until death or last follow-up (n=46). Five-year overall survival calculated from primary diagnosis was 62% and 32% when estimated from first PM. Previous disease free interval (DFI) as calculated from date of surgery of the primary tumour until the date of diagnosis of lung metastasis was 12.2 months (range 0-140.1 months). Median relapse-free survival (mRFS) after first PM to the date of recurrence of lung metastasis, death or last follow-up was 13.4 months (95% CI=3-23.8 months). CONCLUSION Median overall survival in this selected patient cohort is 45.3 months. Despite the lack of prospective randomised controlled trials, PM is a reasonable treatment strategy in selected patients.

Synergistic effect of Sorafenib and Sunitinib with Enzastaurin, a selective protein kinase C inhibitor in renal cell carcinoma cell lines

Enzastaurin (LY317615.HCl) is an oral selective PKC-beta inhibitor with antiproliferative efficacy in various tumor models. This study was designed to investigate whether combination therapy with Enzastaurin and other targeted agents including Sorafenib and Sunitinib enhanced anti-tumor efficacy in renal cell carcinoma cell lines. Enzastaurin alone presented not active in renal cell carcinoma cell lines. Both Sorafenib and Sunitinib with Enzastaurin at concentrations feasible in vivo showed a synergistic reduction of viable RCC cells by inhibiting cell growth through inhibition of phospho-S6-kinase and GSK3-beta. The combination of Enzastaurin with Sorafenib and Sunitinib seems highly encouraging and warrants further investigation in vivo.

Safety and efficacy of temsirolimus in heavily pretreated patients with metastatic renal cell carcinoma

Background. First line treatment with temsirolimus is considered standard of care in poor risk patients with metastatic renal cell carcinoma. The role of temsirolimus in pretreated patients with any risk profile is unclear. The aim of this retrospective analysis was to investigate the impact of temsirolimus in patients who had progressed on various treatment lines. Material and methods. From April 2007 to July 2009, all patients who had progressed on receptor-tyrosine kinase-inhibitors, VEGF-antibodies and other agents were treated with temsirolimus (25 mg weekly). Physical examination, white blood cell count and chemistry were obtained weekly and tumor response was assessed every 12 weeks. Results. Thirty patients with a median age of 68 years range (44–81) received treatment with temsirolimus. Most patients were categorized intermediate risk (60%) and the majority had three or more metastatic sites (56.7%). Temsirolimus was median the fourth (range 2–5) systemic treatment line. Grade 3 and 4 toxicities were rare and consisted of anemia, thrombocytopenia and hyperglycemia. Objective remission and stable disease were achieved in 13.3% and 60% of the patients, respectively. The median progression free survival was 4.9 months (2.93–6.81 95% CI). Conclusion. Temsirolimus appears feasible, safe and active in heavily pretreated patients.

Elevated serum creatinine and low albumin are associated with poor outcomes in patients with liposarcoma.

Low serum albumin levels and impaired kidney function have been associated with decreased survival in patients with a variety of cancer types. In a retrospective cohort study, we analyzed 84 patients with liposarcoma treated at from May 1994 to October 2011. Uni‐ and multivariable Cox proportional hazard models and competing risk analyses were performed to evaluate the association between putative biomarkers with disease‐specific and overall survival. The median age of the study population was 51.7 (range 19.6–83.8) years. In multivariable analysis adjusted for AJCC tumor stage, serum creatinine was highly associated with disease‐specific survival (Subdistribution Hazard ratio (SHR) per 1 mg/dl increase = 2.94; 95%CI 1.39–6.23; p = 0.005). High albumin was associated with improved overall and disease‐specific survival (Hazard Ratio (HR) per 10 units increase = 0.50; 95%CI 0.26–0.95; p = 0.033 and SHR = 0.64; 95%CI 0.42–1.00; p = 0.049). The serum albumin‐creatinine‐ratio emerged to be associated with both overall and disease‐specific survival after adjusting for AJCC tumor stage (HR = 0.95; 95%CI 0.92–0.99; p = 0.011 and SHR = 0.96; 95%CI 0.93–0.99; p = 0.08). Our study provides evidence for a tumor‐stage‐independent association between higher creatinine and lower albumin with worse disease‐specific survival. Low albumin and a high albumin‐creatinine‐ratio independently predict poor overall survival. Our work identified novel prognostic biomarkers for prognosis of patients with liposarcoma.

Distinctive outcome in patients with non-uterine and uterine leiomyosarcoma

BackgroundLeiomyosarcomas represent the largest subtype of soft tissue sarcomas. Two subgroups can be distinguished, non-uterine (NULMS) and uterine leiomyosarcomas (ULMS). The aim of this retrospective study was to evaluate differences in clinical features and outcome between these two subgroups.MethodsOutcome and clinical-pathological parameters between 50 patients with NULMS and 45 patients with ULMS were assessed, and compared between both groups. Univariate and multivariable survival analyses were performed.ResultsPatients with ULMS presented with larger tumors when compared to patients with NULMS (p < 0.001). More patients with ULMS initially presented with metastatic disease (67% vs. 36%, p = 0.007). Most common metastatic site was lung for both subtypes (28% and 38%). Five-year overall survival (OS) rates of 82.6% and 41.2% and median OS times of 92.6 (range: 79.7-105.4) and 50.4 (range: 34.8-66.0) months were observed in patients with NULMS and ULMS, respectively (p = 0.006). In multivariate analysis, initial metastatic disease remained an independent prognostic factor in terms of OS (p < 0.0001).ConclusionAt time of diagnosis ULMS were larger and more often metastasized. Therefore patients with ULMS showed unfavorable outcome when compared to NULMS. Later diagnosis might be caused by differences in symptoms and clinical presentation or a more aggressive biological tumor behavior.