Treatment inferred from mutations identified using massive parallel sequencing leads to clinical benefit in some heavily pretreated cancer patients.

Molecular portraits of numerous tumors have flooded oncologists with vast amounts of data. In parallel, effective inhibitors of central pathways have shown great clinical benefit. Together, this promises potential clinical benefits to otherwise end-stage cancer patients. Here, we report a clinical service offering mutation detection of archived samples using the ion Ampliseq cancer panel coupled with clinical consultation.A multidisciplinary think tank consisting of oncologists, molecular-biologists, genetic counselors, and pathologists discussed 67 heavily pretreated, advanced cancer patient cases, taking into account mutations identified using ion Ampliseq cancer panel, medical history, and relevant literature.The team generated a treatment plan, targeting specific mutations, for 41 out of 64 cases. Three patients died before results were available. For 32 patients, the treating oncologists chose not to include the panel recommendation in the treatment plan for various reasons. Nine patients were treated as recommended by the panel, 5 with clinical benefit, and 4 with disease progression.This study suggests that routine use of massive parallel tumor sequencing is feasible and can judiciously affect treatment decisions when coupled with multidisciplinary team-based decision making. Administration of personalized based therapies at an earlier stage of disease, expansion of genetic alterations examined, and increased availability of targeted therapies may lead to further improvement in the clinical outcome of metastatic cancer patients.

Radical cystectomy vs. chemoradiation in T2-4aN0M0 bladder cancer: a case-control study.

BACKGROUND: Muscle-invasive bladder cancer is most commonly treated by radical cystectomy. Patients who are too sick to go through this surgery or who are unwilling to accept the mutilation associated with it are referred to chemoradiation. We compared the results of these 2 modalities using age-matched populations. PARTICIPANTS AND METHODS: Between 1998 and 2008, 33 patients were treated with chemoradiation for biopsy-proven T2-4aN0M0 urothelial bladder cancer. For every patient treated with chemoradiation, an age-matched patient who underwent radical cystectomy on the same year was selected for comparison. Mean radiotherapy dose was 62 Gy (standard deviation = 8.4) and median follow-up of both groups was approximately 36 months. RESULTS: The groups were similar in age, proportion of men, and length of follow-up. However, the Charlson comorbidity index was significantly lower for operated patients (3.45 vs. 4.36, P = 0.01). Furthermore, 2 patients (6%) in the chemoradiation group had salvage cystectomy (one for disease recurrence and another for bladder shrinkage). The 2- and 5-year overall survival rates after surgery were 74.4% and 54.8%, respectively, and after chemoradiation were 70.2% and 56.6% (P = 0.8), respectively. The 2- and 5-year disease-free survival rates after surgery were 67.8% and 63.2%, respectively, and after chemoradiation were 63% and 54.3% (P = 0.89), respectively. Side effects were mild in both groups, with grade 3+toxicity seen in only 2 operated and 4 irradiated patients. CONCLUSIONS: Despite having a significantly higher comorbidity index, patients treated with chemoradiation had similar overall and disease-free survival rates with low toxicity. Treatment with chemoradiation should be considered in patients with T2-4aN0M0 bladder cancer.

Integration of PET/CT into the preoperative evaluation of patients with early cervical cancer does not decrease the proportion of patients with positive lymph nodes found after surgery.

PURPOSE: The aim of this study was to evaluate whether preoperative positron emission tomography/computed tomography (PET/CT) in patients with early-stage cervical carcinoma reduced the proportion of patients with metastatic lymph nodes identified after surgery. PATIENTS AND METHODS: This is a multicenter case-control study of 599 patients with early cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy at 1 of 10 gynecological oncology units in Israel. The patients were divided into 2 groups according to whether or not they underwent a preoperative PET/CT. The primary outcome was the proportion of patients with nodal involvement. The 2 groups were compared with regard to the clinical and histological variables. RESULTS: Of the 599 patients who underwent surgery, 180 (36%) had preoperative PET/CT study. There were no significant differences between the PET/CT and control groups with regard to clinical and histological risk factors. The proportion of patients with involved nodes was similar in the control and PET/CT groups (20.8% vs 19%; P = 0.73) as well as the proportion of patients receiving adjuvant radiotherapy/chemoradiation (58.3% vs 55.1%; P = 0.55). CONCLUSIONS: Preoperative PET/CT in patients with early cervical cancer does not reduce proportion of patients with metastatic nodal involvement and the employment of multimodality treatment. Prospective clinical trials comparing management based on PET/CT findings are warranted.

Significance of heparanase in cancer and inflammation.

Heparan sulfate proteoglycans (HSPGs) are primary components at the interface between virtually every eukaryotic cell and its extracellular matrix. HSPGs not only provide a storage depot for heparin-binding molecules in the cell microenvironment, but also decisively regulate their accessibility, function and mode of action. As such, they are intimately involved in modulating cell invasion and signaling loops that are critical for tumor growth, inflammation and kidney function. In a series of studies performed since the cloning of the human heparanase gene, we and others have demonstrated that heparanase, the sole heparan sulfate degrading endoglycosidase, is causally involved in cancer progression, inflammation and diabetic nephropathy and hence is a valid target for drug development. Heparanase is causally involved in inflammation and accelerates colon tumorigenesis associated with inflammatory bowel disease. Notably, heparanase stimulates macrophage activation, while macrophages induce production and activation of latent heparanase contributed by the colon epithelium, together generating a vicious cycle that powers colitis and the associated tumorigenesis. Heparanase also plays a decisive role in the pathogenesis of diabetic nephropathy, degrading heparan sulfate in the glomerular basement membrane and ultimately leading to proteinuria and kidney dysfunction. Notably, clinically relevant doses of ionizing radiation (IR) upregulate heparanase expression and thereby augment the metastatic potential of pancreatic carcinoma. Thus, combining radiotherapy with heparanase inhibition is an effective strategy to prevent tumor resistance and dissemination in IR-treated pancreatic cancer patients. Also, accumulating evidence indicate that peptides derived from human heparanase elicit a potent anti-tumor immune response, suggesting that heparanase represents a promising target antigen for immunotherapeutic approaches against a broad variety of tumours. Oligosaccharide-based compounds that inhibit heparanase enzymatic activity were developed, aiming primarily at halting tumor growth, metastasis and angiogenesis. Some of these compounds are being evaluated in clinical trials, targeting both the tumor and tumor microenvironment.

Small cell (neuroendocrine) carcinoma of the prostate: etiology, diagnosis, prognosis, and therapeutic implications--a retrospective study of 30 patients from the rare cancer network.

Within the framework of the Rare Cancer Network Study, we examined 30 patients suffering from small cell neuroendocrine prostate cancer, either in an early/localized or an advanced/metastatic stage. Patients were treated with cisplatin-based chemotherapy, with or without pelvic radiotherapy. Two patients with early disease achieved complete remission for a duration of 19 and 22 months. Three patients with advanced disease achieved complete remission for 6, 7, and 54 months, respectively. Twenty-five patients succumbed to massive local and/or distant failure. No patient presented with brain metastases as the initial site of relapse. Small cell neuroendocrine prostate carcinoma is a very aggressive disease with a poor prognosis, even in its localized form. Despite initial response, the common cisplatin-based chemotherapy plus radiotherapy failed to improve outcome markedly. Improvement will come from understanding the biology of the disease and integrating new targeted therapies into the treatment of this rare and aggressive tumor.