Mutational and Immunophenotypic Profiling of a Series of 8 Tubo-ovarian Carcinosarcomas Revealed a Monoclonal Origin of the Disease.

Carcinosarcomas are rare, highly aggressive neoplasms composed of a combination of carcinomatous and sarcomatous elements. These tumors represent a paradigmatic field for the study of intratumor heterogeneity. A series of 8 tubo-ovarian carcinosarcomas was characterized for the following: (i) immunohistochemical expression of MNF116, epithelial membrane antigen, vimentin, S100, chromogranin, synaptophysin, desmin, myogenin (MYF4), and p53; (ii) mutational profiling of KRAS, BRAF, PIK3CA, NRAS, TP53, and DICER1 genes. Heterologous differentiation was present in 6 of 8 tumors. Cytokeratin MNF116 and epithelial membrane antigen were positive in all the carcinomatous components and in 87.5% and 50.0% of the sarcomatous components, respectively. The sarcomatous components showed positive staining for vimentin in all cases. Two cases demonstrated positivity for neuroendocrine markers in their carcinomatous components. All rhabdomyosarcomas were positive for desmin and MYF-4. Chondrosarcomas were positive for S100. All but one tumor showed similar p53 immunoreactivity in both the carcinomatous and sarcomatous components, and one case showed cytoplasmic p53 expression. Three of 8 cases (37.5%) showed TP53 mutations, and, in 2 cases, the TP53 mutation was shared by both epithelial and mesenchymal components. DICER1 mutation was found in all components of one case. Mutations in KRAS, NRAS, BRAF, and PIK3CA genes were not found in the study cohort. Our results highlight the heterogeneity of ovarian carcinosarcomas at the phenotypic level. A common mutational signature was observed in both components in 3 of 4 informative tumors. More studies are required to dissect different levels of ovarian carcinosarcomas' heterogeneity in order to define the best therapeutic approaches to these aggressive neoplasms.

Second-line therapy for refractory renal-cell carcinoma.

In the last 5 years inhibitors of the VEGF/VEGFR and mTOR pathways have dramatically changed the therapeutic approach to metastatic renal cancer. Randomized controlled trials have shown that six targeted agents--sorafenib, sunitinib, temsirolimus, bevacizumab, everolimus and pazopanib--are able to improve patient outcome. Even if the choice of drug for first-line therapy is quite well defined, to date it is not easy to characterize and evaluate the efficacy of new therapies in second-line treatment. It is not clear whether, after first-line therapy with a VEGF/VEGFR inhibitor, use of mTOR or a second TKI inhibitor should be recommended. In this review we report on current evidence supporting the use of targeted agents in second-line therapy. Therefore we try to combine current clinical results with a practical clinical approach, with the goal of evaluating the best clinical decision for different clinical situations.

An update on targeted therapy in metastatic renal cell carcinoma.

An improved understanding of the biological pathways deregulated in renal cell carcinoma has led to the development of various targeted agents, changing dramatically the therapeutic options for this disease. However, despite numerous opinions and guidelines, the optimal treatment still remains uncertain. In this review, we analyze the most recent published reports regarding the agents sunitinib, bevacizumab, sorafenib, temsirolimus, and everolimus. Moreover, we assess the novel targeted drugs pazopanib and axitinib. In addition, given the likely lack of cross-resistance between these targeting agents, we discuss sequential and combination targeted therapy in metastatic renal cell carcinoma, analyzing the most recent data.

Clinical experience and critical evaluation of the role of sorafenib in renal cell carcinoma.

Renal cell carcinoma (RCC) is a common malignancy worldwide with approximately 95,000 new cases per year and ranks as the sixth cause of cancer deaths. Until recently, the slightly active and very toxic cytokines were available for patients with advanced RCC. Advances have been made in understanding the molecular biology of renal cancer. The introduction of targeted agents has led to promising possibilities for treating these highly vascularized tumors. Angiogenesis inhibition is likely to represent the main potential therapeutic target. Sorafenib is an oral multikinase inhibitor with activity against tyrosine kinase receptors that are responsible for blood vessel development and has shown to be active in treating advanced RCC. In this review, we summarize the pharmacology, mode of action, pharmacokinetics, and safety of sorafenib use in therapy for advanced RCC.

Bevacizumab and glioblastomas, a single-centre experience: how disease history and characteristics may affect clinical outcome.

BACKGROUND: In 2009, bevacizumab, a monoclonal antibody to vascular endothelial growth factor, received accelerated approval by the United States Food and Drug Administration for the treatment of glioblastoma, based on its high response rate (RR) and 6-month progression-free survival (PFS-6). However, time to progression and overall survival (OS) were disappointing. Since 2008 have been data collected evaluating the safety and efficacy of bevacizumab in patients with relapsed malignant gliomas. PATIENTS AND METHODS: This is a retrospective review of adult patients with recurrent malignant gliomas treated with bevacizumab at a dose of 10 mg/kg every 14 days; some patients were also treated with irinotecan at a dose of 125 mg/m(2) every 14 days. Patients were evaluated for side-effects and clinical outcomes of response, progression and survival. RESULTS: Ten patients received bevacizumab and nine patients received the combination with irinotecan. Both single-agent bevacizumab and combination treatment were well-tolerated. RR was of 28% with no complete responses, PFS-6 was 20% and OS was 4.5 months (95% confidence interval: 3.07-5.98 months). CONCLUSION: Although well-tolerated, the efficacy of bevacizumab was somewhat disappointing, possibly due to the high rate of secondary high-grade gliomas in the studied patient cohort and the late use of bevacizumab in the course of the disease.

Good response to second-line bevacizumab and interferon-alpha in a sunitinib-refractory patient with metastatic renal cell carcinoma.

In recent years with the development of targeted agents such as bevacizumab, sunitinib, sorafenib, temsirolimus, and everolimus, the treatment of metastatic renal cell carcinoma has changed dramatically. In clinical practice, sunitinib and bevacizumab are reserved for first-line treatment, but despite various guidelines, optimal treatment is still uncertain. We present, for the first time, a case of a good response to second-line bevacizumab and interferon-alpha in a patient who failed classical sunitinib treatment.

A phase II study of gemcitabine at fixed infusion rate of 10 mg/m2/min with or without immunotherapy in advanced renal cancer.

BACKGROUND: Advanced renal cancer remains a challenge for oncologists since no treatment other than surgery has demonstrated a clear survival advantage. PATIENTS AND METHODS: Gemcitabine was given to suitable patients at a fixed infusion rate of 10 mg/m2/min. Eighteen patients received concomitant immunotherapy, mostly low doses of interleukin 2 (IL2). RESULTS: Thirty patients were enrolled. The overall response rate was 14% (22% in the subset of patients treated with both chemotherapy and immunotherapy) with a median progression-free survival time of 4.1 + months. Toxicity was not mild, mostly fatigue, nausea and anaemia, even though not life threatening. CONCLUSION: Gemcitabine at the fixed infusion rate of 10 mg/m2/min with concomitant low doses of IL2 could be useful in the palliative treatment of symptomatic patients with renal carcinoma progressing after tyrosine kinases inhibitor.

Establishment and characterization of xenografts and cancer cell cultures derived from BRCA1 -/- epithelial ovarian cancers.

The BRCA1 gene is responsible for a high number of hereditary breast and ovarian cancers that cluster in families with a strong genetic predisposition. Despite intense investigation, the accumulating findings on BRCA1 biological functions have not yet been translated into specific therapeutic approaches, also due to the lack of suitable experimental models. The purpose of this study was to establish and characterize cell cultures and xenografts from patients with BRCA1 -/- ovarian cancers. We derived two ovarian cancer cell lines, termed PD-OVCA1 and PD-OVCA2, both from patients previously treated with chemotherapy, that propagate in SCID mice as well as in vitro for a limited number of passages. Both cell lines expressed cytokeratins and the CA125 tumour marker. A detailed molecular characterization highlighted both constitutive and somatic genetic events that abrogate BRCA1 gene function. Both cell lines were shown to lose the wild type BRCA1 allele; intriguingly, these deletions were apparently accompanied by gain of one or more copies of the mutant alleles. Finally, a genomic profile of major chromosomal aberrations was obtained by the Multiplex Ligation-dependent Probe Amplification (MLPA) technique, which disclosed chromosomal imbalances targeting specific genes in each cell line. The PD-OVCA1 and PD-OVCA2 ovarian cancer cell lines will provide a valuable tool for new experimental models for the study of BRCA1-associated tumour biology.