Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial.

Background: The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer.

Methods: In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada.

A randomized phase II study of pelareorep and docetaxel or docetaxel alone in men with metastatic castration resistant prostate cancer: CCTG study IND 209.

Background: Pelareorep is an oncolytic virus with activity in many cancers including prostate. It has synergism with microtubule-targeted agents. We undertook a clinical trial evaluating pelareorep in mCRPC patients receiving docetaxel.

Impact of resistance and aerobic exercise on sarcopenia and dynapenia in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial.

The purpose of this study was to conduct an exploratory analysis of the START examining the effects of resistance exercise training (RET) and aerobic exercise training (AET) on sarcopenia, dynapenia, and associated quality of life (QoL) changes in breast cancer (BC) patients receiving adjuvant chemotherapy. Participants were randomized to usual care (UC) (n = 70), AET (n = 64), or RET (n = 66) for the duration of chemotherapy. Measures of sarcopenia [skeletal muscle index (SMI)] and dynapenia [upper extremity (UE) and lower extremity (LE) muscle dysfunction (MD)] were normalized relative to age-/sex-based clinical cut-points.

Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial.

Purpose: To report the final efficacy findings and biomarker analysis from the NO16968 trial comparing bolus fluorouracil/folinic acid (FU/FA) with capecitabine plus oxaliplatin (XELOX) in resected stage III colon cancer.

Patients And Methods: After curative resection, patients were randomly assigned to receive XELOX, as oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1,000 mg/m(2) twice daily on days 1 to 14 every 3 weeks, or bolus FU/FA, as the Mayo Clinic or Roswell Park regimens, for 6 months. The primary end point was disease-free survival (DFS).

Using targeted virotherapy to treat a resistant Ewing sarcoma model: from the bedside to the bench and back.

Unlabelled: Metastatic Ewing sarcoma (EWS) is often resistant to current multimodal chemotherapeutic regimens. Oncolytic virus therapy (OV) is a novel therapeutic platform whereby viruses can selectively infect as well as replicate in and kill tumor cells, while sparing normal tissues. The purpose of this study is to investigate the efficacy of the biotherapeutic oncolytic agent, vesicular stomatitis virus (VSVΔM51), to kill EWS cells that are resistant to conventional therapy.

A Case of Appendiceal Adenocarcinoma with Clinical Benefit from FOLFOX and Bevacizumab.

A 44-year-old woman presented with lower abdominal pain and bilateral ovarian masses on ultrasound. Exploratory laparotomy revealed extensive peritoneal and intra-abdominal disease and an abnormal appendix. Bilateral salpingo-oophorectomy, infracolic omentectomy, ileocolic resection and primary anastomosis were performed.

Oncolytic Viruses: A New Weapon to Fight Cancer.

Remission from cancer after viral infection was first noted in the beginning of the 20th century, and with advances in virotherapy and genetic engineering, the advent of an approved viral therapeutic in North America is fast approaching. Mechanisms of tumour selectivity and killing, along with information obtained from clinical trials are reviewed here. Although oncolytic viruses are generally safe and well tolerated, their overall anti-tumour efficacy has varied.

Suitability of using multileaf collimator (MLC) for photon field matching.

This study evaluated and presented the results on the suitability of using a Siemens double-focused multileaf collimator (MLC) for photon field matching. The study was conducted using film-based dosimetry for measurements and a Theraplan Plus (version 3.8) treatment planning system (TPS) for planning comparisons and additional field matching investigations.

Activating transcription factor 4 is translationally regulated by hypoxic stress.

Hypoxic stress results in a rapid and sustained inhibition of protein synthesis that is at least partially mediated by eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation by the endoplasmic reticulum (ER) kinase PERK. Here we show through microarray analysis of polysome-bound RNA in aerobic and hypoxic HeLa cells that a subset of transcripts are preferentially translated during hypoxia, including activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response. Changes in mRNA translation during the unfolded protein response are mediated by PERK phosphorylation of the translation initiation factor eIF2alpha at Ser-51.

Dose-escalated 3D conformal radiotherapy in prostate cancer.

3D conformal radiotherapy involves the delivery of radiation to a defined 3D tumor volume while minimizing doses to adjacent critical tissues. The use of sophisticated imaging tools and advanced treatment planning software have allowed for better target definition enabling the oncologist to conform or shape radiation volume more closely around the target while minimizing dose to the rectum and bladder. 3D conformal radiotherapy has resulted in dramatic reductions in acute and late toxicity of radiation treatment in prostate cancer.

Is DNA polymerase beta important in thermal radiosensitization?

Thermal radiosensitization was tested in a pair of mouse cells (MB+ wild-type and MB-, DNA polymerase beta knockout cells) and in human breast carcinoma cells (MCF7 wild-type and C716 transfected to give elevated DNA polymerase beta expression). Results showed that neither reducing DNA polymerase beta (involved in base excision repair) nor increasing it had any significant effect on thermal radiosensitization. The data indicated that polymerase beta was not involved in thermal radiosensitization, and since hyperthermia is known as a radiation damage repair inhibitor, other repair pathways might be involved and need to be explored.

Stimulation of the murine Uchl1 gene promoter by the B-Myb transcription factor.

It has been reported that human lung cancers frequently overexpress both the ubiquitous cell cycle transcription factor B-myb and the ubiquitin carboxyterminal hydrolase UCHL1, an enzyme whose expression is normally limited to neurons and neuroendocrine cells in the lung. A possible explanation for the co-expression of these markers is that Uchl1 is subject to transcriptional regulation by B-Myb, and in tumors the ectopic expression of UCHL1 is a direct consequence of B-Myb overexpression. We have tested this hypothesis in the mouse model system by cloning the murine Uchl1 promoter and analyzing its regulation by murine B-Myb.

Cutting edge: MHC class II-restricted peptides containing the inflammation-associated marker 3-nitrotyrosine evade central tolerance and elicit a robust cell-mediated immune response.

Nitrotyrosine is widely recognized as a surrogate marker of up-regulated inducible NO synthase expression at sites of inflammation. However, the potential immunogenicity of autologous proteins containing nitrotyrosine has not previously been investigated. Herein, we used the I-E(K)-restricted T cell epitope of pigeon/moth cytochrome c (PCC/MCC(88-103)) to assess the ability of T cells to recognize ligands containing nitrotyrosine.

Multimodality management of locally recurrent colorectal cancer.

The combined management of locally recurrent colorectal cancer shows considerable promise, but the best way to incorporate the different treatment modalities and the potential benefits remain uncertain. The case series mentioned here were derived from highly selected groups from a much larger population of patients with recurrent disease; thus fully combined management may be only appropriate for a minority of people with recurrent disease. There is a need for multicenter randomized trials to better delineate the real benefits from the combined approach.

Barriers and facilitators to enrollment in cancer clinical trials: qualitative study of the perspectives of clinical research associates.

Background: The literature continues to report low rates of accrual to cancer clinical trials. Previous studies have examined principally physician-related or patient-related barriers. Clinical research associates (CRAs) have a unique perspective on enrollment that has been explored very little.

Examining the non-homologous repair process following cisplatin and radiation treatments.

Purpose: To investigate the extent of non-homologous end-joining (NHEJ) in the mechanism of cisplatin radiosensitization.

Materials And Methods: Ku80-deficient cells are deficient in the non-homologous DNA double-strand break repair process, while the wild-type MEF cells maintain full mammalian cell repair capabilities. Both cell lines were exposed to clinically applicable doses of cisplatin (1, 3 and 6 microg x ml(-1)) for 1 h immediately before exposure to 250 kV X-rays.

Brain metastases in Wilms' tumor: case report and literature review.

A 2-year-old girl who had a stage 2, favorable-histology Wilms tumor diagnosed when she was age 10 months presented with multiple brain metastases at second recurrence. She had been treated with combined radiotherapy, surgery, and chemotherapy; at 2 months after treatment, recurrent disease developed in the central nervous system and she died. Brain metastases are rare in the natural history of Wilms tumor.

Reexpression of a cluster of silenced transgenes is associated with their rearrangement.

Irreversible inactivation or silencing of tumor suppressor genes occurs frequently in the development of cancer. A similar process of silencing can occur after the integration of transfected or microinjected genes into the genomes of recipient cells. The inactivation of transfected genes seems particularly efficient in cells with stem cell characteristics.

Identification of XAF1 as an antagonist of XIAP anti-Caspase activity.

The inhibitors of apoptosis (IAPs) suppress apoptosis through the inhibition of the caspase cascade and thus are key proteins in the control of cell death. Here we have isolated the protein XIAP-associated factor 1 (XAF1) on the basis of its ability to bind XIAP, a member of the IAP family. XIAP suppresses caspase activation and cell death in vitro, and XAF1 antagonizes these XIAP activities.

Neoadjuvant chemotherapy before surgery for resectable carcinoma of the lower esophagus.

Neoadjuvant chemotherapy before surgery has been proposed to improve the outcome in patients with early lower esophageal cancer. To evaluate its effectiveness, we performed a systematic retrospective analysis of consecutive patients treated at the Ottawa Regional Cancer Center with prospective inclusion criteria. Between 1988 and 1992 patients were treated with surgery alone.

Cisplatin efflux, binding and intracellular pH in the HTB56 human lung adenocarcinoma cell line and the E-8/0.7 cisplatin-resistant variant.

Purpose: Many cell lines resistant to cisplatin (DDP) have reduced DDP accumulation. We postulated that reduced accumulation of DDP in resistant cells might be due to decreased intracellular DDP binding, leading to increased passive efflux.

Methods: The total cellular ([T-DDP]), intracellular ultrafiltrable ([F-DDP]) and precipitable cellular bound ([B-DDP]) DDP concentrations were all compared in the HTB56 human lung adenocarcinoma cell line and its E-8/0.

A myeloperoxidase-specific assay based upon bromide-dependent chemiluminescence of luminol.

Measurement of myeloperoxidase (MPO; EC 1.11.1.

A role for RNA processing in regulating expression from transfected genes.

We have examined the expression of cloned genes following their stable integration into the genome of pluripotent embryonal carcinoma stem cells. Transfected genes integrate into the genome as tandem arrays. Expression of reporter genes from these tandem arrays in embryonal carcinoma cells is inefficient probably because genes are subject to repeat-induced gene silencing.

Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR.

The interferon-inducible, double-stranded RNA-dependent protein kinase PKR has been implicated in anti-viral, anti-tumor, and apoptotic responses. Others have attempted to examine the requirement of PKR in these roles by targeted disruption at the amino terminal-encoding region of the Pkr gene. By using a strategy that aims at disruption of the catalytic domain of PKR, we have generated mice that are genetically ablated for functional PKR.