RNA editing study under intense scrutiny : Nature News & Comment

RNA editing study under intense scrutiny 

The idea that RNA is often edited after being transcribed from DNA is a controversial one.

PASIEKA/SCIENCE PHOTO LIBRARY

Medscape: New Medical Admissions Test for New Generation of Physicians

New Medical Admissions Test for New Generation of Physicians

"People who have taken the MCAT see it as an exam that emphasizes physics, chemistry, and math, first and foremost, Darrell Kirch, MD, president and chief executive officer of the Association of American Medical Colleges, said in a video on the association's Web site."

OncoLink launches redesigned website based on search habits and feedback from patients, caregivers

OncoLink launches redesigned website based on search habits and feedback from patients, caregivers:

OncoLink, a free cancer information website developed by experts at the University of Pennsylvania's Abramson Cancer Center has launched a redesigned website based on the search habits and feedback from patients, caregivers and health care providers who use the site.

abstract: Shared Genetic Basis for Breast Cancer and Breast Density

Shared Genetic Basis for Breast Cancer and Breast Density:

" Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants."

Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer.

abstract: Phase 1 Dose-Escalation Study of Aflibercept Plus Docetaxel

Phase 1 Dose-Escalation Study of Aflibercept Plus Docetaxel:

Purpose: This phase I study cohort investigated aflibercept in combination with docetaxel in patients with advanced solid tumors.

Materials and Methods: Eligible patients had metastatic or nonresectable cancer for which docetaxel was considered appropriate. Patients received intravenous aflibercept (either 2, 4, 5, 6, 7, or 9 mg/kg) with docetaxel (75 mg/m²) on day 1 every 3 weeks until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLT) during cycle 1 and to determine the aflibercept recommended phase II trial dose (RP2D) for combination with docetaxel. Pharmacokinetics, tolerability, and antitumor activity were also investigated.

Results: Fifty-four patients (mean age, 56 y) were enrolled. Most had prior chemotherapy (96%) and most (24.1%) had breast cancer. In the dose-escalation phase (n = 34), there were three DLTs: grade 4 neutropenic infection (2 mg/kg), grade 3 dysphonia (7 mg/kg), and grade 2 hypertension (9 mg/kg). An excess of free-over-bound aflibercept was observed at doses of 5 mg/kg or more. The pharmacokinetics of aflibercept and docetaxel were not modified by coadministration. Aflibercept (6 mg/kg) was defined as the RP2D based on DLT and pharmacokinetic data.
Overall, the most frequent grade 3/4 adverse events (AE) were neutropenia (85.2%), leukopenia (74.1%), hypertension (18.5%), and stomatitis (16.7%). AEs associated with vascular endothelial growth factor blockade included epistaxis (all grades, 83.3%), proteinuria (68.5%), dysphonia (68.5%), and hypertension (53.7%). Seven patients had partial responses, and 32 patients had stable disease (>3 months in 18 patients).

Conclusion: On the basis of findings from this study, aflibercept (6 mg/kg) was the dose recommended for further clinical development. Clin Cancer Res; 18(6); 1743–50. ©2012 AACR.

abstract: Evaluation of Iniparib as a PARP Inhibitor (BRCA2....)

Evaluation of Iniparib as a PARP Inhibitor:

Purpose:

Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination (HR)-deficient tumors and ability to enhance the action of certain DNA-damaging agents. Compared with other PARP inhibitors in development, iniparib (4-iodo-3-nitrobenzamide) is notable for its simple structure and the reported ability of its intracellular metabolite 4-iodo-3-nitrosobenzamide to covalently inhibit PARP1 under cell-free conditions. The present preclinical studies were conducted to compare the actions iniparib with the more extensively characterized PARP inhibitors olaparib and veliparib.

Results:

Consistent with earlier reports, olaparib and veliparib selectively induced apoptosis and inhibited colony formation in cells lacking BRCA2 or ATM. Moreover, like earlier generation PARP inhibitors, olaparib and veliparib sensitized cells to the topoisomerase I poisons camptothecin and topotecan. Finally, olaparib and veliparib inhibited formation of pADPr in intact cells. In contrast, iniparib exhibited little or no ability to selectively kill HR-deficient cells, sensitize cells to topoisomerase I poisons, or inhibit pADPr formation in situ. In further experiments, iniparib also failed to sensitize cells to cisplatin, gemcitabine, or paclitaxel.


Conclusions:

While iniparib kills normal and neoplastic cells at high (>40 μmol/L) concentrations, its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors.  

Clin Cancer Res; 18(6); 1655–62. ©2012 AACR.

abstract: Impact of Preanalytic Factors on the Design and Application of Integral Biomarkers

Impact of Preanalytic Factors on the Design and Application of Integral Biomarkers:

Molecular assays have been routinely applied to improve diagnosis for the last 25 years. Assays that guide therapy have a similar history; however, their evolution has lacked the focus on analytic integrity that is required for the molecularly targeted therapies of today. New molecularly targeted agents require assays of greater precision/quantitation to predict the likelihood of response, i.e., to identify patients whose tumors will respond, while at the same time excluding and protecting those patients whose tumors will not respond or in whom treatment will cause unacceptable toxicity. The handling of tissue has followed a fit-for-purpose approach focused on appropriateness for diagnostic needs, which is less rigorous than the demands of new molecular assays that interrogate DNA, RNA, and proteins in a quantitative, multiplex manner. There is a new appreciation of the importance and fragility of tissue specimens as the source of analytes to direct therapy. By applying a total test paradigm and defining and measuring sources of variability in specimens, we can develop a set of specifications that can be incorporated into the clinical-care environment to ensure that a specimen is appropriate for analysis and will return a true result. 

abstract: Leveling the Playing Field: Bringing Development of Biomarkers and Molecular Diagnostics up to the Standards for Drug Development

Leveling the Playing Field: Bringing Development of Biomarkers and Molecular Diagnostics up to the Standards for Drug Development

 "....One way to accomplish this is to emphasize phase IV postmarketing, hypothesis-driven clinical trials with biological characterization that would permit an accurate definition of the association of low-prevalence gene alterations with toxicity or response in large cohorts."

Drug data reveal sneaky side effects : Nature News & Comment

Drug data reveal sneaky side effects : Nature 

 Mining of surveillance data highlights thousands of previously unknown consequences when drugs are taken together.

14 March 2012

An algorithm designed by US scientists to trawl through a plethora of drug interactions has yielded thousands of previously unknown side effects caused by taking drugs in combination.
The work, published today in Science Translational Medicine¹, provides a way to sort through the hundreds of thousands of 'adverse events' reported to the US Food and Drug Administration (FDA) each year. “It’s a step in the direction of a complete catalogue of drug–drug interactions,” says the study's lead author, Russ Altman, a bioengineer at Stanford University in California.........“Even if you show a drug is safe in a clinical trial, that doesn’t mean it’s going to be safe in the real world,” says Paul Watkins, director of the Hamner–University of North Carolina Institute for Drug Safety Sciences in Research Triangle Park, North Carolina, who was not involved in the work. “This approach is addressing a better way to rapidly assess a drug’s safety in the real world once it is approved.”.....

abstract: Cancer stem cells and metastasis

Cancer stem cells and metastasis
Publication year: 2012

Seminars in Cancer Biology


Cancer stem cells (CSCs) represent a subpopulation of tumour cells endowed with self-renewal and multi-lineage differentiation capacity but also with an innate resistance to cytotoxic agents, a feature likely to pose major clinical challenges towards the complete eradication of minimal residual disease in cancer patients. Operationally, CSCs are defined by their tumour-propagating ability when serially transplanted into immune-compromised mice and by their capacity to fully recapitulate the original heterogeneity of cell types observed in the primary lesions they are derived from. CSCs were first identified in hematopoietic malignancies and later in a broad spectrum of solid tumours including those of the breast, colon and brain. Notably, several CSC characteristics are relevant to metastasis, such as motility, invasiveness and, as mentioned above, resistance to DNA damage-induced apoptosis. Here, we have reviewed the current literature on the relation between CSCs and metastasis formation. Preliminary studies on cancer cell lines and patient-derived material suggest a rate-limiting role for stem-like cells in the processes of tumour cell dissemination and metastasis formation. However, additional studies are needed to deliver formal proof of their identity as the cell of origin of recurrences at distant organ sites. Nevertheless, several studies have already provided pre-clinical evidence of the efficacy of novel therapies directed against disseminated CSCs.

abstract: Cancer during pregnancy: perinatal outcome after in utero exposure to chemotherapy.

Cancer during pregnancy: perinatal outcome after in utero exposure to chemotherapy

Cancer during pregnancy: perinatal outcome after in utero exposure to chemotherapy.

Abstract

OBJECTIVES:

To study the outcome of pregnancies complicated by malignant disease, in particular neonatal morbidity and mortality after in utero exposure to chemotherapy.

METHODS:

This prospective study included 118 patients diagnosed with malignant disease for the first time during pregnancy over an 8-year period (March 2003-March 2011). Outcome of neonates born to mothers who received chemotherapy during pregnancy was studied and compared with a control group.

RESULTS:

The commonest cancer type diagnosed during pregnancy (56/118 = 47.45 %) was breast carcinoma followed by lymphoma/leukemia (32 = 27.12 %). Gynecological tumors (all ovarian) represented 10.16 %, soft tissue tumors 5.08 %, colorectal 4.23 %, thyroid 2.54 % and others 3.38 %. Sixty-one (51.64 %) women received chemotherapy (average 3 ± 2 cycles) during the second and third trimesters. The incidence of neonatal survival, preterm birth, small for gestational age and congenital malformations was not significantly different between women who received chemotherapy during pregnancy and the control group. Five (4.23 %) women with advanced disease died during or shortly after termination of pregnancy.

CONCLUSION:

In utero exposure to chemotherapy during the second and third trimesters of pregnancy carries minimal morbidity to the unborn fetus.

discussion (U.S.) : Clinical Pathways for Oncology: More Rigor Needed When Evaluating Models

Clinical Pathways for Oncology: More Rigor Needed When Evaluating Models

Wiley: Cochrane Review - Specialist cancer care may improve patient outcomes (ovarian/gyn cancers)

Wiley: Specialist cancer care may improve patient outcomes

The Cochrane Library

 More Press Releases related to this journal

Vol 2012 (4 Issues in 2012)

Specialist cancer care may improve patient outcomes

Survival rates for cancer patients may be improved by treatment in specialised cancer centres, according to Cochrane researchers. In a review of recent studies, they found that women diagnosed with gynaecological cancer lived longer when treated in specialist compared to non-specialist units.
In the past, cancer patients were often treated by non-specialist surgeons and hospitals. This is changing and in developed countries, most cancer care is now organised into networks of specialised centres, with on-site experts and specialised nursing staff. This centralised approach, although costly, may help improve outcomes for patients.
The review focused on data from five studies, altogether involving more than 62,000 women who were treated from the late 1990s onwards. Over 48,000 of the participants were involved in one study carried out in 2009, whilst the smallest study involved just 250. Due to clinical differences between the studies, the researchers combined the data in different ways. Incorporating three studies and over 50,000 women with gynaecological cancer, one analysis showed that women treated at teaching centres or regional cancer centres lived longer compared to those treated at community or general hospitals. An alternative combination of three of the studies, involving over 9,000 women with ovarian cancer, showed that those treated at institutions with on-site gynaecologists lived longer compared to those treated at community or general hospitals.
“We found consistent evidence for specialist treatment prolonging survival rates in women with gynaecological cancer,” said lead researcher, Professor Yin Ling Woo of the University of Malaya Cancer Research Institute, University of Malaya, in Kuala Lumpur, Malaysia. “The effect seemed to be strongest for ovarian cancer, although most evidence came from developed countries.”
The researchers estimate that survival rates could be improved by around 10%, although uncertainties in the data mean the actual figure could range between 1% and 18%. Better designed studies are needed to confirm the results. All five studies included in the review used electronic records to identify patients after they had received treatment, meaning it was difficult to be sure that the centralised and de-centralised treatment groups were similar.
“Ideally, women should be allocated to specialist and non-specialist treatment groups in advance to ensure that there is no bias in the data,” said Professor Woo. “These higher quality trials are needed to assess whether the extra cost is worthwhile, especially as many countries have limited resources for specialist care.”

interactive: First Ever Local Area Health System Scorecard Finds Significant Differences in Access, Costs, Quality, and Outcomes Within States and Among Nation's Biggest Cities

First Ever Local Area Health System Scorecard Finds Significant Differences in Access, Costs, Quality, and Outcomes Within States and Among Nation's Biggest Cities:

In the first scorecard measuring how 306 local U.S. areas are doing on key health care indicators such as insurance coverage, preventive care, and mortality rates, researchers at The Commonwealth Fund found significant differences between the best- and worst-performing localities.