Original Paper
Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes†
Article first published online: 6 JUN 2012
Original Paper
Article first published online: 6 JUN 2012
Issue 8, 2012 of The Cochrane Library is now available! New and updated reviews available on interventions for health-related quality of life for cancer survivors, weight loss and maintenance, and high blood pressure.
Mol Cancer Res. 2012 Aug 15. [Epub ahead of print]
University of Toronto.
Epithelial ovarian cancer (EOC) is the leading cause of death among gynaecological malignancies in North American women. Given that EOC encompasses a broad class of tumors consisting of a variety of different histological and molecular subtypes, which generates genetically and etiologically distinct tumors, several challenges arise during treatment of patients with this disease. Overlaying this complexity is the contribution of supporting cells, particularly stromal components such as fibroblasts and immune infiltrates that collectively create a microenvironment that promotes and enhances cancer progression. A notable example is the induction of angiogenesis, which occurs through the secretion of pro-angiogenic factors by both tumor and tumor-associated cells. The recent development of angiogenic inhibitors targeting tumor vasculature, which have been shown to improve patient outcome when combined with standard therapy, has launched a paradigm shift on how cancer patients should be treated. It is evident that future clinical practices will focus on the incorporation of therapies that antagonize the pro-tumoral effects of such microenvironment contributors. Herein, an overview of the varying tumor-host interactions that influence tumor behaviour will be discussed, in addition to the recent efforts undertaken to target these interactions and their potential to revolutionize EOC patient care.
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Biologic rationale and clinical activity of mTOR inhibitors in gynecological cancer.
Cancer Treat Rev. 2012 Oct;38(6):767-75
Authors: Diaz-Padilla I, Duran I, Clarke BA, Oza AM
Abstract
Advanced recurrent gynecological malignancies have a poor prognosis despite systemic treatment, which is usually cytotoxic chemotherapy. Responses are generally short-lived and more effective treatments are needed. Rationally designed molecularly targeted therapy is an emerging and important option in this setting. The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase of the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway with a critical role in controlling cancer cellular growth, metabolism and cell cycle progression. Aberrant PI3K-dependent signaling occurs frequently in a wide range of tumor types, including ovarian, endometrial and cervical cancer. Early clinical studies of first-generation mTOR inhibitors have shown promising clinical activity in endometrial cancer. However, the molecular basis of sensitivity and resistance to these agents remains largely unknown. In this review, we will update the clinical and biological data underlying the development of first generation mTOR inhibitors in the treatment of gynecological tumors. The role of potential new combination regimens with mTOR inhibitors in gynecological cancers will also be discussed.
PMID: 22381585 [PubMed - indexed for MEDLINE]
Genetics, Inheritance and Strategies for Prevention in Populations at High Risk of Colorectal Cancer (CRC).
Recent Results Cancer Res. 2012;191:157-83
Authors: Burn J, Mathers J, Bishop DT
Abstract
Hereditary forms of colorectal cancer account for less than 5 % of colorectal cancer but attract disproportionate attention because they offer an opportunity for effective surgical prophylaxis, influence the health of the wider family and give insight into the critical pathways of carcinogenesis. Familial Adenomatous Polyposis (FAP) due to loss of the APC gene and Lynch syndrome or Hereditary Non-Polyposis Colon Cancer (HNPCC) due to breakdown in MisMatch Repair are the principal syndromes of broader interest and both have been the subject of chemoprevention trials. There has been a longstanding interest in non-steroidal anti inflammatories in FAP where trials have shown regression of polyps with the "pro drug"sulindac and the selective COX2 inhibitors though impact on long-term cancer risk is not confirmed. The CAPP1 trial focused on two interventions in a factorial design, aspirin and resistant starch or fermentable fibre. Resistant starch is not absorbed in the small intestine and undergoes colonic fermentation to short-chain fatty acids including butyrate which have anti-cancer effects. Polyposis registry clinicians across Europe recruited adolescents with FAP to receive aspirin (600 mg as 2 tablets/d) and/or 30 g as 2 sachets/d in a 1:1 blend of potato starch and high amylose maize starch [Hylon VII]) with placebo control for at least a year or until surgery before age 21. Fifty-nine percent (133/227) of recruits had a baseline and at least one other endoscopy. After a median of 17 months , the primary endpoint of a risk of an increased polyp number in the rectum and sigmoid colon was not significantly reduced in either treatment group with relative risks of 0.77 (aspirin; 95 % CI, 0.54-1.10;) and 1.05 (RS; 95 % CI, 0.73-1.49. The diameter of the largest polyp detected tended to be smaller in the aspirin arm. The planned subgroup analyses of patients who elected to continue on study for more than one year found a significant reduction in the size of the largest polyp in the aspirin versus non-aspirin group (p = 0.02), Mean crypt length decreased significantly over time on study in the two combined RS groups, compared with the two combined non-RS groups (p < 0.0001 for interaction), in a model of the interaction between intervention and time. In CAPP2, 1009 Lynch syndrome gene carriers were recruited from 43 international centres. 937 commenced intervention: 600mg enteric coated aspirin and/or 30grams of the resistant starch Novelose in a 2 by 2 factorial placebo controlled design. After a mean of 29 months, intervention, there was no evidence that either agent influenced ...
CALGARY, Aug. 16, 2012 /PRNewswire/ - Oncolytics Biotech Inc. ("Oncolytics") (TSX:ONC) (NASDAQ:ONCY) today announced that it has completed patient enrollment in its U.K. Phase I clinical trial using intravenously-administered REOLYSIN in combination with cyclophosphamide in patients with advanced malignancies (REO 012).
"We are pleased to complete enrollment of this technical study examining cyclophosphamide's potential to modulate the immune system's response to REOLYSIN," said Dr. Matt Coffey, COO of Oncolytics. "Studies of this type help to advance our understanding of the interaction between the immune system and our product."
The primary objective of the open label, dose-escalating, non-randomized, 36-patient study is to determine the Minimum Effective Immunomodulatory Dose (MED) of cyclophosphamide necessary to obtain successful immune modulation. Secondary objectives of the trial include assessing the safety profile of the combination and gathering any evidence of antitumor activity.
Eligible patients include those who have been diagnosed with advanced or metastatic solid tumors, including pancreatic, lung and ovarian cancers that are refractory to standard therapy, or for which no standard curative therapy exists.
The principal investigators for the study are Dr. James Spicer of King's College, London, Dr. Johann de Bono and Dr. Kevin Harrington of the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London, and Professor Hardev Pandha of the Royal Surrey County Hospital NHS Trust, Surrey and Mount Alvernia Hospitals.
About Oncolytics Biotech Inc.
Oncolytics is a Calgary-based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics' clinical program includes a variety of human trials including a Phase III trial in head and neck cancers using REOLYSIN, its proprietary formulation of the human reovirus. For further information about Oncolytics, please visit: www.oncolyticsbiotech.com.
This press release contains forward-looking statements, within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements, including the Company's expectations related to the U.K. Phase I clinical trial with REOLYSIN in combination with cyclophosphamide , and the Company's belief as to the potential of REOLYSIN as a cancer therapeutic, involve known and unknown risks and uncertainties, which could cause the Company's actual results to differ materially from those in the forward-looking statements. Such risks and uncertainties include, among others, the availability of funds and resources to pursue research and development projects, the efficacy of REOLYSIN as a cancer treatment, the tolerability of REOLYSIN outside a controlled test, the success and timely completion of clinical studies and trials, the Company's ability to successfully commercialize REOLYSIN, uncertainties related to the research and development of pharmaceuticals and uncertainties related to the regulatory process. Investors should consult the Company's quarterly and annual filings with the Canadian and U.S. securities commissions for additional information on risks and uncertainties relating to the forward-looking statements. Investors are cautioned against placing undue reliance on forward-looking statements. The Company does not undertake to update these forward-looking statements, except as required by applicable laws.
SOURCE Oncolytics Biotech Inc.
Recent studies suggest that thromboprophylaxis is beneficial in preventing venous thromboembolism (VTE) in cancer outpatients, but this is not widely adopted because of incomplete understanding of the contemporary incidence of VTE and concerns about bleeding. Therefore, the authors examined the incidence and predictors of VTE in ambulatory patients with bladder, colorectal, lung, ovary, pancreas, or gastric cancers.
Data were extracted from a large health care claims database of commercially insured patients in the United States between 2004 and 2009. Demographic and clinical characteristics of the cancer cohort (N = 17,284) and an age/sex-matched, noncancer control cohort were evaluated. VTE incidence was recorded during a 3-month to 12-month follow-up period after the initiation of chemotherapy. Multivariate analyses were conducted to identify independent predictors of VTE and bleeding.
The mean age of the study population was 64 years, and 51% of patients were women. VTE occurred in 12.6% of the cancer cohort (n = 2170) over 12 months after the initiation of chemotherapy versus 1.4% of controls (n = 237; P < .0001); incidence ranged by cancer type from 19.2% (pancreatic cancer) to 8.2% (bladder cancer). Predictors of VTE included type of cancer, comorbidities (Charlson Comorbidity Index score or obesity), and commonly used specific antineoplastic or supportive care agents (cisplatin, bevacizumab, and erythropoietin).
This large, contemporary, real-world analysis confirmed high rates of VTE in select patients with solid tumors and suggested that the incidence of VTE is high in the real-world setting. Awareness of the benefits of targeted thromboprophylaxis may result in a clinically significant reduction in the burden of VTE in this population. Cancer 2012. © 2012 American Cancer Society.
Following the publication of 'Medicine, morality and health care social media' in BMC Medicine, author Farris Timimi (Medical Director, Mayo Clinic Center for Social Media, @FarrisTimimi) and his colleague Lee Aase (Director, Mayo Clinic Center for Social Media, @LeeAase) joined BMC Medicine Editor Sabina Alam (@BMCMedicine) in a twitter chat to discuss the ideas raised in Timimi's commentary.
It was apparent there was consensus amongst the contributors of the twitter chat – social media should be used as a tool by healthcare providers to interact with patients. Some systems are already in place, but more work is required to develop the right kind of social media platforms, and perhaps more importantly, more physicians should be encouraged to learn how to use social media to engage with the general public. Whether the medical institutions should make this a requirement remains to be determined.
A summary of the discussion with a selection of the contributions can be viewed at Storify.
Following the success of this chat we are considering having more in the future. If you feel there are any topics that should be discussed please get in touch via email, or of course tweet at us ! (@BMCMedicine)
Patients with Lynch Syndrome Mismatch Repair Gene Mutations Are at Higher Risk for Not Only Upper Tract Urothelial Cancer but Also Bladder Cancer.
Eur Urol. 2012 Aug 2;
Authors: Skeldon SC, Semotiuk K, Aronson M, Holter S, Gallinger S, Pollett A, Kuk C, van Rhijn B, Bostrom P, Cohen Z, Fleshner NE, Jewett MA, Hanna S, Shariat SF, Van Der Kwast TH, Evans A, Catto J, Bapat B, Zlotta AR
Abstract
BACKGROUND: Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused by mutations in mismatch repair (MMR) genes. An increased risk for upper tract urothelial carcinoma (UTUC) has been described in this population; however, data regarding the risk for bladder cancer (BCa) are sparse. OBJECTIVE: To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations. DESIGN, SETTING, AND PARTICIPANTS: Cancer data from 1980 to 2007 were obtained from the Familial Gastrointestinal Cancer Registry in Toronto for 321 persons with known MMR mutations: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Standardized incidence ratios from the Ontario Cancer Registry, using the Surveillance Epidemiology and End Results public database, were used to compare cancer risk in patients with MMR mutations with the Canadian population. Microsatellite instability analysis and immunohistochemistry (IHC) of the MMR proteins were also performed and the results compared with matched sporadic bladder tumors. RESULTS AND LIMITATIONS: Eleven of 177 patients with MSH2 mutations (6.21%, p<0.001 compared with the Canadian population) were found to have BCa, compared with 3 of 129 patients with MLH1 mutations (2.32%, p>0.05). Of these 11 tumors, 81.8% lacked expression of MSH2 on IHC, compared with the matched sporadic cases, which all displayed normal expression of MSH2 and MLH1. The incidence of UTUC among MSH2 carriers was 3.95% (p<0.001), and all tumors were found to be deficient in MSH2 expression on IHC. Mutations in the intron 5 splice site and exon 7 of the MSH2 gene increased the risk of urothelial cancer. Limitations include possible inflated risk estimates due to ascertainment bias. CONCLUSIONS: LS patients with MSH2 mutations are at an increased risk for not only UTUC but also BCa and could be offered appropriate screening.
PMID: 22883484 [PubMed - as supplied by publisher]
[Ovarian cancer--modern approach to its origin and histogenesis].
Abstract
Ovarian cancers (OC) belong to a heterogeneous group of pathologies and are traditionally classified with regard to histological type and degree of differentiation. OC was hypothesized to originate from ovarian surface epithelium (OSE) and inclusion cysts epithelium (IC). Unfortunately this theory was never supported by any clinical or molecular evidence linking carcinogenesis with OSE and was refuted. OC subtypes demonstrate morphologic features that resemble MĂĽllerian duct-derived epithelia of the genital tract. Investigations of the HOX gene family MĂĽllerian epithelial differentiation markers, confirmed the HOX genes expression in many subtypes of OC but not in OSE. The first step towards connecting OC origin with other than OSE genital tract structures were epidemiological observations indicating a minor OC risk after tubal ligation in women with the BRCA mutation. The first in situ carcinoma was found in the Fallopian tube fimbriae. Further research confirmed the same mechanism in sporadic OC. Endometriosis and endometrium cells may be a highly probable place of endometrioid OC initiation. Mucinous types share common futures with gastrointestinal tract cancers and there one needs to search for their precursors. Clear cell carcinoma may arise from glandular epithelium of endocervix or from endometrioid foci. The new classification of OC was proposed in 2004, suggesting to divide all OC into two types: I and II. Type II includes serous and endometrioid G3 subtypes, carcinosarcomas and undifferentiated OC. They are responsible for 75% of OC morbidity identified usually in FIGO stages Ill or IV, have poor prognosis and relapse early The remaining hystiotypes, with better prognosis and earlier FIGO stages at time of diagnosis, were classified as type I. Serous and endometrioid poorly differentiated ovarian cancers demonstrate mutation in TP53 gene (type II) and highly differentiated ones, generally in BRAS and KRAS genes (type I). The differences in molecular pathways also confirm different patterns of carcinogenesis of both OC types. Modern approach to OC histogenesis and origin emphasizes the necessity to verify OC screening, detection and treatment methods.
PMID: 22880466 [PubMed - in process]
Clear Cell Carcinoma of the Female Genital Tract (Not Everything Is as Clear as it Seems).
Adv Anat Pathol. 2012 Sep;19(5):296-312
Abstract
Clear cell carcinoma has a storied history in the female genital tract. From the initial designation of ovarian clear cell adenocarcinoma as "mesonephroma" to the linkage between vaginal clear cell carcinoma and diethylstilbestrol exposure in utero, gynecologic tract clear cell tumors have puzzled investigators, posed therapeutic dilemmas for oncologists, and otherwise presented major differential diagnostic challenges for pathologists. One of the most common errors in gynecologic pathology is misdiagnosis of clear cell carcinoma, on both frozen section and permanent section. Given the poor response to platinum-based chemotherapy for advanced-stage disease and increased risk of thromboembolism, accurate diagnosis of clear cell carcinoma is important in the female genital tract. This review (1) presents the clinical and pathologic features of female genital tract clear cell carcinomas; (2) highlights recent molecular developments; (3) identifies areas of potential diagnostic confusion; and (4) presents solutions for these diagnostic problems where they exist.
PMID: 22885379 [PubMed
After more than six years of funding exclusive projects in forestry and agriculture, Genome Canada has now announced a $67.5 million funding competition for large-scale genomics projects in human health, with focus on personalised medicine.i The human genomics community of this country understandably rejoiced at this long overdue announcement that gives them, for the first time in years, the means to compete internationally (http://www.genomecanada.ca/en/portfolio/research/2012-competition.aspx). Canada has been fairly generous in funding human-health related research but mostly through the Canadian Institutes of Health Research (CIHR) or the Canada Foundation for Innovation, neither of which has within its mandate to fund the type of specific multimillion-dollar project that is usually thought of as genomics. The typical CIHR grant, for example, rarely exceeds $1 million (200 000 over 5 years) in direct costs.
The elation over the announcement of this funding opportunity in late 2011 soon gave way to sober...
Postmenopausal hormone (PMH) therapy may reduce colorectal cancer (CRC) risk, but existing data are inconclusive.
To evaluate associations between PMH therapy and incident CRC, overall and by molecularly defined subtypes, in the population-based Iowa Women's Health Study of older women.
Exposure data were collected from Iowa Women's Health Study participants (55–69 years) at baseline (1986). Archived, paraffin-embedded tissue specimens for 553 CRC cases were collected and analysed to determine microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive) and BRAF mutation (BRAF-wildtype or BRAF-mutated) status. Multivariable Cox regression models were fit to estimate RRs and 95% CIs.
PMH therapy (ever vs never use) was inversely associated with incident CRC overall (RR=0.82; 95% CI 0.72 to 0.93), with a significantly lower risk for MSI-L/MSS tumours (RR=0.75; 95% CI 0.60 to 0.94), and borderline significantly lower risks for CIMP-negative (RR=0.79; 95% CI 0.63 to 1.01) and BRAF-wildtype (RR=0.83; 95% CI 0.66 to 1.04) tumours. For PMH therapy >5 years, the subtype-specific risk estimates for MSI-L/MSS, CIMP-negative and BRAF-wildtype tumours were: RR=0.60, 95% CI 0.40 to 0.91; RR=0.68, 95% CI 0.45 to 1.03; and RR=0.70, 95% CI 0.47 to 1.05, respectively. PMH therapy was not significantly associated with the MSI-H, CIMP-positive or BRAF-mutated CRC subtypes.
In this prospective cohort study, PMH therapy was inversely associated with distinct molecularly defined CRC subtypes, which may be related to differential effects from oestrogen and/or progestin on heterogeneous pathways of colorectal carcinogenesis.
by Suzanne Moffatt, Emma Noble, Martin White
The onset, treatment and trajectory of cancer is associated with financial stress among patients across a range of health and welfare systems and has been identified as a significant unmet need. Welfare rights advice can be delivered effectively in healthcare settings, has the potential to alleviate financial stress, but has not yet been evaluated. We present an evaluation of a welfare rights advice intervention designed to address the financial consequences of cancer.
MethodsDescriptive study of welfare outcomes among 533 male and 641 female cancer patients and carers aged 4–95 (mean 62) years, who accessed the welfare rights advice service in North East England between April 2009 and March 2010; and qualitative interview study of a maximum variation sample of 35 patients and 9 carers.
ResultsOver two thirds of cancer patients and carers came from areas of high socio-economic deprivation. Welfare benefit claims were successful for 96% of claims made and resulted in a median increase in weekly income of £70.30 ($109.74, €84.44). Thirty-four different types of benefits or grants were awarded. Additional resources were perceived to lessen the impact of lost earnings, help offset costs associated with cancer, reduce stress and anxiety and increase ability to maintain independence and capacity to engage in daily activities, all of which were perceived to impact positively on well-being and quality of life. Key barriers to accessing benefit entitlements were knowledge, system complexity, eligibility concerns and assumptions that health professionals would alert patients to entitlements.
ConclusionsThe intervention proved feasible, effectively increased income for cancer patients and was highly valued. Addressing the financial sequelae of cancer can have positive social and psychological consequences that could significantly enhance effective clinical management and suitable services should be routinely available. Further research is needed to evaluate health outcomes definitely and assess cost-effectiveness.
Safety, cost-effectiveness and feasibility of daycase paracentesis in the management of malignant ascites with a focus on ovarian cancer.
Br J Cancer. 2012 Aug 9;
Authors: Harding V, Fenu E, Medani H, Shaboodien R, Ngan S, Li HK, Burt R, Diamantis N, Tuthill M, Blagden S, Gabra H, Urch CE, Moser S, Agarwal R
Abstract
Background:Paracentesis for malignant ascites is usually performed as an in-patient procedure, with a median length of stay (LoS) of 3-5 days, with intermittent clamping of the drain due to a perceived risk of hypotension. In this study, we assessed the safety of free drainage and the feasibility and cost-effectiveness of daycase paracentesis.Method:Ovarian cancer admissions at Hammersmith Hospital between July and October 2009 were audited (Stage 1). A total of 21 patients (Stage 2) subsequently underwent paracentesis with free drainage of ascites without intermittent clamping (October 2010-January 2011). Finally, 13 patients (19 paracenteses, Stage 3), were drained as a daycase (May-December 2011).Results:Of 67 patients (Stage 1), 22% of admissions and 18% of bed-days were for paracentesis, with a median LoS of 4 days. In all, 81% of patients (Stage 2) drained completely without hypotension. Of four patients with hypotension, none was tachycardic or symptomatic. Daycase paracentesis achieved complete ascites drainage without complications, or the need for in-patient admission in 94.7% of cases (Stage 3), and cost £954 compared with £1473 for in-patient drainage.Conclusions:Free drainage of malignant ascites is safe. Daycase paracentesis is feasible, cost-effective and reduces hospital admissions, and potentially represents the standard of care for patients with malignant ascites.British Journal of Cancer advance online publication, 9 August 2012; doi:10.1038/bjc.2012.343 www.bjcancer.com.
PMID: 22878372 [PubMed - as supplied by publisher]
Psychological treatment outcomes for cancer patients: what do meta-analyses tell us about distress reduction?
Psychooncology. 2012 Apr;21(4):343-50
Abstract
OBJECTIVE: The effectiveness of psychological treatment for distress reduction in cancer patients has been frequently studied and reviewed in systematic reviews but reviewer conclusions vary considerably. Clear and consistent evidence is needed to assist clinicians and administrators with their decision-making. We hypothesized that uneven handling of confounding methodological features are at least partly the reason for disagreements and reviewed the literature in this light.
METHOD: A systematic review of 14 published meta-analyses was conducted to determine whether due consideration of moderating variables in psycho-oncological treatments permits clearer recommendations. Quality of the reviews, treatment type, dosage, therapist qualities, outcomes at follow-up, and screening versus not screening for elevated distress were examined as moderator variables.
RESULTS: Treatment effects are consistently positive but also vary greatly in magnitude. There is lacking evidence for many important questions, in particular, differential treatment effects for different cancer types and stages. Regarding moderators of outcome, quality of review had no impact on results for depression but including lower quality reviews actually lead to underestimation of treatment effects for anxiety. The most potent negative moderator variable, however, is a floor effect that arises when patients are recruited for treatment studies without being selected for high levels of distress. Such indiscriminate recruitment is very frequent in psycho-oncology and leads to small reported treatment effects; when, however, patients are first screened for elevated distress, the ratio of observed treatment effects sizes is roughly three times greater.
CONCLUSION: Sweeping judgments about the effectiveness of psycho-oncological treatments for distress reduction are somewhat misleading and counter-productive. Among moderator variables, floor effects are particularly pervasive and have a large suppressor effect on observed outcomes.
PMID: 21882287 [PubMed - indexed for MEDLINE]