Probing the attenuation and protective efficacy of a candidate chikungunya virus vaccine in mice with compromised interferon (IFN) signaling.

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes explosive outbreaks of febrile illness associated with rash, and painful arthralgia. The CHIK vaccine strain 181/clone25 (181/25) developed by the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) was shown to be well-tolerated and highly immunogenic in phase I and II clinical trials although it induced transient arthralgia in some healthy adult volunteers. In an attempt to better understand the host factors that are involved in the attenuating phenotype of CHIK 181/25 vaccine virus we conducted studies in interferon (IFN)-compromised mice and also evaluated its immunogenic potential and protective capacity.

Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer.

Background: A previous dose-escalation trial of the vascular disrupting agent combretastatin A4 phosphate (CA4P) given before carboplatin, paclitaxel, or both showed responses in 7 of 18 patients with relapsed ovarian cancer.

Patients And Methods: Patients with ovarian cancer that had relapsed and who could start trial therapy within 6 months of their last platinum chemotherapy were given CA4P 63 mg/m(2) minimum 18 h before paclitaxel 175 mg/m(2) and carboplatin AUC (area under the concentration curve) 5, repeated every 3 weeks.

Results: Five of the first 18 patients' disease responded, so the study was extended and closed after 44 patients were recruited.

Cryptogenic colitis due to occult cytomegalovirus infection.

Colitis secondary to cytomegalovirus infection is well recognised and usually straightforward to diagnose. Here two cases are reported in whom all initial investigations failed to demonstrate the presence of virus, with potential adverse consequences for its treatment. A case is made for empirical antiviral therapy despite negative investigations if clinical suspicion is high.

Current academic clinical trials in ovarian cancer: Gynecologic Cancer Intergroup and US National Cancer Institute Clinical Trials Planning Meeting, May 2009.

Objective: To review the current status of large phase academic clinical trials for women with ovarian cancer, address cross-cutting issues, and identify promising areas for future collaboration.

Methods: In May 2009, the Gynecologic Cancer Intergroup, which represents 19 Cooperative Groups conducting trials for women with gynecologic cancer, and the US National Cancer Institute convened a Clinical Trials Planning Meeting.

Results: The topics covered included the impact of new developments in cancer biology upon molecular targets and novel agents, pharmacogenomics, advances in imaging, the potential benefit of diet and exercise to reduce the risk of recurrence, academic partnership with industry, statistical considerations for phases 2 and 3 trials, trial end points, and symptom benefit and health-related quality-of-life issues.

Primary chemotherapy: the future for the management of advanced ovarian cancer?

Primary surgery for advanced ovarian cancer has been the standard practice for more than 30 years. A survival benefit is principally seen in patients who have optimal cytoreduction with no or small-volume residual disease after surgery. In everyday clinical practice, many patients are not able to undergo optimal tumor debulking.

Optimal treatment for relapsing ovarian cancer.

The cure rate for women with ovarian cancer has not significantly changed over the past 10 years. However, overall survival from relapsed disease has shown improvement despite a lack of increase in progression-free survival. There are now many therapeutic options for women with relapsed disease.

Inhibition of carboplatin-induced DNA interstrand cross-link repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer.

Background: The potential of gemcitabine to interact with carboplatin was explored in a phase II trial in platinum-resistant ovarian cancer. Peripheral blood lymphocytes were sampled after drug administration to measure DNA interstrand cross-link formation and repair.

Patients And Methods: Forty patients received carboplatin target area under concentration-time curve (AUC 4) followed by gemcitabine 1,000 mg/m(2) with a second dose of gemcitabine on day 8.

Targeted trials in ovarian cancer.

The last five years has seen a major expansion in the number of clinical trials with molecular targeted agents in ovarian cancer. Most of the studies are with anti-angiogenic agents. This review discusses the rationale for molecular targeted therapy in ovarian cancer and the current randomized trials.

Treatment with cationic liposome-DNA complexes (CLDCs) protects mice from lethal Western equine encephalitis virus (WEEV) challenge.

Having recently characterized a CD-1 outbred mouse model of pathogenesis for Western equine encephalitis virus, we examined the possible protective effects of cationic liposome-DNA complexes (CLDCs) against encephalitic arboviral infection. In this investigation, mice were pre-treated, co-treated, or post-treated with CLDC then challenged with a subcutaneous or aerosol dose of the highly virulent WEEV-McMillan strain, lethal in mice 4-5 days after inoculation. Pre-treatment with CLDCs provided a significant protective effect in mice, which was reflected in significantly increased survival rates.

Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I).

Background: The first UKCCCR Anal Cancer Trial (1996) demonstrated the benefit of chemoradiation over radiotherapy (RT) alone for treating epidermoid anal cancer, and it became the standard treatment. Patients in this trial have now been followed up for a median of 13 years.

Methods: A total of 577 patients were randomised to receive RT alone or combined modality therapy using 5-fluorouracil and mitomycin C.

Virulence variation among isolates of western equine encephalitis virus in an outbred mouse model.

Little is known about viral determinants of virulence associated with western equine encephalitis virus (WEEV). Here, we have analysed six North American WEEV isolates in an outbred CD1 mouse model. Full genome sequence analyses showed < or =2.

Cdc7 kinase is a predictor of survival and a novel therapeutic target in epithelial ovarian carcinoma.

Purpose: There is a lack of prognostic and predictive biomarkers in epithelial ovarian carcinoma, and the targeting of oncogenic signaling pathways has had limited impact on patient survival in this highly heterogeneous disease. The origin licensing machinery, which renders chromosomes competent for DNA replication, acts as a convergence point for upstream signaling pathways. We tested the hypothesis that Cdc7 kinase, a core component of the licensing machinery, is predictive of clinical outcome and may constitute a novel therapeutic target in epithelial ovarian carcinoma.

Tracking epidemic Chikungunya virus into the Indian Ocean from East Africa.

The largest documented outbreak of Chikungunya virus (CHIKV) disease occurred in the Indian Ocean islands and India during 2004-2007. The magnitude of this outbreak led to speculation that a new variant of the virus had emerged that was either more virulent or more easily transmitted by mosquito vectors. To study this assertion, it is important to know the origin of the virus and how the particular strain circulating during the outbreak is related to other known strains.

Oxidation of ovarian epithelial cancer cells by hypochlorous acid enhances immunogenicity and stimulates T cells that recognize autologous primary tumor.

Purpose: Hypochlorous acid, a product of neutrophil myeloperoxidase, is a powerful enhancer of antigen processing and presentation. In this study, we examine whether ovarian epithelial cells (SK-OV-3) exposed to hypochlorous acid can stimulate T cells from patients with ovarian epithelial cancer that recognize common tumor antigens as well as autologous tumor.

Experimental Design: T cells from human leukocyte antigen (HLA)-A2(+) and HLA-A2(-) patients or healthy controls were stimulated with autologous dendritic cells cocultured with the generic ovarian tumor line SK-OV-3, previously exposed to hypochlorous acid.

Primary tumour resection and survival in the palliative management of metastatic colorectal cancer.

Aim: To examine whether surgical resection of the primary tumour confers a survival benefit and to identify the predictive factors of outcome in patients presenting with asymptomatic metastatic colorectal cancer (CRC).

Materials And Methods: A review of a hospital database in a tertiary institution over a 6-year period (1999-2005) revealed 70 patients with asymptomatic primary CRC and unresectable liver metastases treated initially by systemic chemotherapy. A multivariate regression analysis model was used to determine the relative influence of multiple tumours, single/multiple liver metastases, tumour site, differentiation, response of liver and primary tumour to chemotherapy, biochemical response to chemotherapy, age at presentation, performance status and surgical intervention for the CRC primary.

Setting up non-commercial clinical trials takes too long in the UK: findings from a prospective study.

Objective: To evaluate the specific components of setting up a simple multicentre clinical study four years after the new UK law on clinical trials was implemented in 2004.

Design: Timelines associated with activating a randomized multicentre trial in lung cancer patients using an investigational medicinal product (statins) were prospectively recorded.

Setting: 84 trial centres in the UK.

Lessons learned from a decade of clinical trials of high-dose chemotherapy in ovarian cancer.

Ovarian cancer is one of the most chemosensitive solid tumors and therefore a good example to explore high-dose chemotherapy (HDC). Interest in pursuing this treatment arose in the late 1980s following the success of HDC in treating hematological cancers and improvements in supportive care with peripheral blood stem cells. Experience from phase II trials and analysis of Bone Marrow Transplant Registry data led to the launch of several randomized phase III trials in the late 1990 s.

Why i.p. therapy cannot yet be considered as a standard of care for the first-line treatment of ovarian cancer: a systematic review.

A National Cancer Institute (NCI) clinical announcement recommended i.p. therapy for women with optimally debulked ovarian cancer.

DNA replication licensing factors and aurora kinases are linked to aneuploidy and clinical outcome in epithelial ovarian carcinoma.

Purpose: DNA replication licensing factors and Aurora kinases play critical roles in maintaining genomic integrity. We used multiparameter analyses of these cell cycle regulatory proteins to investigate their role in the progression of epithelial ovarian carcinoma (EOC).

Experimental Design: In a cohort of 143 patients, we linked the protein expression profiles of the proliferation marker Ki67, the replication licensing factors Mcm2 and geminin, and the Aurora A and B kinases to tumor DNA ploidy status and clinical outcome.

Enhanced repair of DNA interstrand crosslinking in ovarian cancer cells from patients following treatment with platinum-based chemotherapy.

Despite high tumour response rates to platinum-based chemotherapy in ovarian cancer survival is poor due to the emergence of drug resistance. Mechanistic studies in clinical material have been hampered by the unavailability of sensitive methods to detect the critical drug-induced effects in individual cells. A modification of the single cell gel electrophoresis (comet) assay allows the sensitive detection of DNA interstrand crosslinking in both tumour and normal cells derived directly from clinical material.

Phase III trial of high-dose sequential chemotherapy with peripheral blood stem cell support compared with standard dose chemotherapy for first-line treatment of advanced ovarian cancer: intergroup trial of the AGO-Ovar/AIO and EBMT.

Purpose: Although ovarian cancer is one of the most chemotherapy-sensitive solid tumors, cure after radical surgery and chemotherapy is uncommon. A randomized trial comparing high-dose sequential chemotherapy with peripheral blood stem cell (PBSC) support with platinum-based combination chemotherapy was conducted to investigate whether dose-intensification improves outcome.

Patients And Methods: One hundred forty-nine patients with untreated ovarian cancer were randomly assigned after debulking surgery to receive standard combination chemotherapy or sequential high-dose (HD) treatment with two cycles of cyclophosphamide and paclitaxel followed by three cycles of HD carboplatin and paclitaxel with PBSC support.

Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial.

Background: In the non-curative setting, the sequence in which anticancer agents are used, singly or in combination, may be important if patients are to receive the maximum period of disease control with the minimum of adverse effects. We compared sequential and combination chemotherapy strategies in patients with unpretreated advanced or metastatic colorectal cancer, who were regarded as not potentially curable irrespective of response.

Methods: We studied patients with advanced colorectal cancer, starting treatment with non-curative intent.