A phase II clinical trial of neoadjuvant ketoconazole and docetaxel chemotherapy before radical prostatectomy in high risk patients.

PURPOSE: Patients with high risk prostate cancer (prostate specific antigen greater than 20 ng/ml, Gleason score greater than 7, or clinical stage T2b or greater) have been shown to have a 30% to 40% biochemical recurrence rate after definitive local therapy. Looking for improvement on these outcomes, we conducted a phase II clinical trial examining the combination of ketoconazole and docetaxel in the neoadjuvant setting before radical prostatectomy. MATERIALS AND METHODS: A total of 22 patients with clinically localized, high risk prostate cancer were enrolled in the study. For 12 weeks they were treated with neoadjuvant docetaxel and ketoconazole, with dosing based on phase I data. Patients were monitored for tolerance of therapy and dosing adjustments were made for significant toxicities. Radical prostatectomy with extended lymph node dissection was subsequently performed and patients were followed postoperatively for biochemical recurrence. RESULTS: At a median followup of 18 months 8 patients remained biochemically free of recurrence after surgery alone. An additional 6 patients received salvage therapy and had an undetectable prostate specific antigen. Of the 22 patients 16 experienced National Cancer Institute grade 3 or 4 toxicity at some point during the therapy. However, 16 patients completed all 4 cycles of chemotherapy. CONCLUSIONS: Neoadjuvant ketoconazole combined with docetaxel has appreciable but acceptable toxicity with 73% of the patients completing all 4 courses of therapy. Of those who underwent radical prostatectomy 36% remained continuously biochemically free of recurrence at a median followup of 18 months.

2-methoxyestradiol inhibits Barrett's esophageal adenocarcinoma growth and differentiation through differential regulation of the beta-catenin-E-cadherin axis.

The purpose of this study was to evaluate whether 2-methoxyestradiol (2-ME(2)), a promising anticancer agent, modulates Barrett's esophageal adenocarcinoma (BEAC) cell growth and behavior through a cellular pathway involving beta-catenin in partnership with E-cadherin, which seems to play a critical role in the induction of antitumor responses in cancer cells. We found that 2-ME(2) markedly reduced the BEAC cell proliferation through regulating apoptotic machinery such as Bcl-2 and Bax. It may nullify the aggressive behavior of the cells by reducing the migratory behavior. Expressions of beta-catenin and E-cadherin and binding of these two proteins is activated in a 2-ME(2)-dependent fashion in Bic-1 cells. Moreover, overexpressions of these two proteins may be due to the stabilization of these proteins by 2-ME(2). We found that 2-ME(2)-induced antimigratory effects are mediated through the beta-catenin-E-cadherin signaling pathways. In view of these results, we determined whether 2-ME(2) reduces BEAC tumor growth. Administration of 2-ME2 significantly decreased the growth of BEAC cells xenografted on the flank of nude mice. The evidence presented points out that the effect of 2-ME(2) on beta-catenin-orchestrated signal transduction plausibly plays a multifaceted functional role to inhibit the proliferation and cell migration of 2-ME(2)-treated malignant cells and it could be a potential candidate in novel treatment strategies for Barrett's esophageal adenocarcinoma.

Leiomyosarcoma of the inferior vena cava: a case report and review of the literature.

A 68-year-old white female presented with two years of progressively worsening dyspnea. Echocardiography revealed a large right atrial mass and partial obstruction of the inferior vena cava. Further imaging revealed a cystic dense mass in the inferior vena cava and right atrium. Immunohistochemical stains were consistent with leiomyosarcoma. Intraoperatively, the tumor was noted to originate from the posterior aspect of the inferior vena cava. The patient underwent successful resection of the mass. Adjuvant radiation therapy was completed. The patient's dyspnea gradually improved and she continues to remain disease free five years post-resection.

Gain of oncogenic function of p53 mutants induces invasive phenotypes in human breast cancer cells by silencing CCN5/WISP-2.

CCN5/WISP-2 is overexpressed in noninvasive breast cancer cells and tissue samples, whereas its expression is minimal or undetected in invasive conditions. CCN5/WISP-2 has been considered as an antiinvasive gene because CCN5/WISP-2 silencing augments the invasive phenotypes in vitro. However, the mechanism of silencing of CCN5 during the progression of the disease has been elusive. Because p53 mutations are associated with breast cancer progression and have been shown to correlate inversely with CCN5/WISP-2 expression in other cancer cell types, the objective of this study was to explore whether p53 mutants suppress CCN5 expression in breast tumor cells resulting in the progression of this disease. We found CCN5 expression is inversely correlated with the mutational activation of p53 in human breast tumor cells. The ectopic expression of p53 mutants in ER-positive noninvasive breast tumor cells silenced the CCN5/WISP-2 expression and enhanced invasive phenotypes, including the induction of morphologic changes from the epithelial-to-mesenchymal type along with the alterations of hallmark proteins of these cell types and an augmentation of the migration of these cells. The suppression of CCN5 by the p53 mutants can be nullified by estrogen signaling in these cells through the transcriptional activation of the CCN5 gene. Moreover, the invasive changes can be imitated by blocking the CCN5/WISP-2 expression through RNA interference or can be reversed by the addition of CCN5/WISP-2 recombinant protein in the culture. Thus, these studies suggest that CCN5 inactivation could be an essential molecular event for p53 mutant-induced invasive phenotypes.

Biclonal post-transplant B-cell lymphoma: report of a case with two distinct cell populations, XX,t(14;18) and XY,t(11;14).

Lymphoproliferative disorders are more likely to occur in transplant patients compared to the general population. Typically in these patients, lymphomas occur within 6-10 months following transplant and are Epstein-Barr virus (EBV) positive. We report a biclonal apparently EBV negative lymphoma occurring in a patient ten years after renal transplant, with karyotypes XX,t(14;18) and XY,t(11;14). Though the biclonal populations also had different sex chromosome compositions, complete evaluation showed that both clones most likely evolved from the patient's native lymphocytes.

Gemcitabine and cisplatin for patients with metastatic or recurrent esophageal carcinoma: a Southwest Oncology Group Study.

PURPOSE: Experimental data, both in vivo and in vitro, suggest that the combination of gemcitabine and cisplatin acts synergistically. Within the Southwest Oncology Group, we designed a Phase II trial to test this chemotherapy combination for patients with esophageal cancer. EXPERIMENTAL DESIGN: Patients with metastatic or recurrent esophageal cancer were treated with gemcitabine 1000 mg/m(2) on days 1, 8, and 15, and cisplatin 100 mg/m(2) on day 15. Cycles were repeated every 28 days. The statistical endpoint was overall survival. RESULTS: Sixty-four eligible patients were accrued from 37 institutions. Twenty-six percent of patients had prior chemotherapy. The treatment was generally well-tolerated, with the most common toxicity being neutropenia in 31% of patients. All 64 patients have died. Survival at 3 months was 81%, and at 1 year was 20%. Median survival was 7.3 months. CONCLUSIONS: This regimen is tolerable palliative option for patients with metastatic esophageal cancer.

Differential expression of neuropilin-1 in malignant and benign prostatic stromal tissue.

Neuropilin-1 (NRP-1), a co-receptor for VEGF165, is overexpressed in various prostate cancer cell lines and in advanced prostate tumors. However, distribution of the NRP-1 in prostate tumors has not yet been evaluated. Using immunohistochemical analysis, we evaluated 21 archival prostate tumors and 5 benign glands for the expression of NRP-1. In addition, we utilized a quantitative RT-PCR method to examine mRNA expression in 9 additional prostate tumors obtained from radical prostatectomy specimens and compared this expression to the adjacent normal tissue. The RT-PCR analyses demonstrated overexpression of NRP-1 mRNA in malignant tissue samples by 10.0-fold as compared to adjacent normal tissue. By immunohistochemistry, NRP-1 protein was undetected or minimally detected in the epithelial tumor cells. However, NRP-1 immuno-reaction was detected in the surrounding tumor stroma. Variable immuno-reaction for NRP-1 was also seen in the adjacent normal tumor stroma and the stroma of the benign prostate samples. These observations suggest that neuropilin-1 is expressed in the prostatic stromal cells, not epithelial tumor cells, and this expression is significantly increased in the malignant phenotype.