Healthnewsreviews blog: The marketing of anemia drugs - a story we shouldn't forget (including comments)

The marketing of anemia drugs - a story we shouldn't forget

 "In an opinion piece on TheScientist.com, Daniel W. Coyne writes, “Amgen’s incomplete report on an early major trial of epoetin misled the medical community about the anemia drug’s risks and benefits—and helped make Amgen rich.”
In the book, “How We Do Harm,” Otis Brawley, MD, chief medical and scientific officer of the American Cancer Society, writes quite a bit about hemoglobin-building drugs.  He discusses:.....

FAQ: Adverse Events(search by drug name)

FAQ: Adverse Events

About Us

Adverse Events, Inc. (AEI) is a provider of up-to-the-minute, critical, potentially life-saving information regarding side effects associated with FDA-approved prescription medications. AEI has created a unique set of online tools that are optimized to provide un-paralleled access to adverse event information on over 4,000 drugs, in an easy to understand and navigate format. AEI’s tools give control over treatment plans back to patients and their doctors, while providing an immediate view of potential trends and problems in the drug industry to pharmaceutical, healthcare, insurers, financial institutions and media.
RxFilter™ is a proprietary 17-step data refinement process developed by AdverseEvents, Inc. that standardizes and normalizes the Federal Drug Administration (FDA) Adverse Events Reporting System (AERS) database. Combining complex computer algorithms with hands-on data analysis by highly trained researchers, the RxFilter process is the most thorough optimization procedure ever applied to the FDA's drug safety database. It accurately measures and tracks adverse events associated with medications reported to the FDA.

Top 10 Drugs with the Highest Number of Adverse Events Reported

Browse all by letter: example: Cisplatin    5,107 (number of adverse events reported)

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Oxaliplatin-related thrombocytopenia

Oxaliplatin-related thrombocytopenia

Oxaliplatin is a third generation platinum compound that inhibits DNA synthesis, mainly through intrastrandal cross-links in DNA. Most of the experience with the clinical use of this drug is derived from colorectal cancer but it is also used in other tumor types such as ovary, breast, liver and non-Hodgkin's lymphoma. Thrombocytopenia is a frequent toxicity seen during oxaliplatin treatment, occurring at any grade in up to 70 % of patients and leading to delays or even discontinuation of the chemotherapy. Although myelossupression is recognized as the main cause of oxaliplatin-related thrombocytopenia, new mechanisms for this side-effect have emerged, including splenic sequestration of platelets related to oxaliplatin-induced liver damage and immune thrombocytopenia. These new pathophysiology pathways have different clinical presentations and evolution and may need specific therapeutic maneuvers. This article attempts to review this topic and provides useful clinical information for the management of oxaliplatin-related thrombocytopenia...........

Seth's blog: Dedicating the merit

Dedicating the merit:

For an author, one of the nicest parts of the traditional book is the dedication page. The dedication is far more than an acknowledgement to someone who helped you write the book, it's a permanent signpost, a capstone to the work of a year or more.
Even if the person you've dedicated the book to can't read it, the writer benefits from the knowledge that a connection was made and that a memory was preserved.
Here's the thing: you can dedicate just about anything. A project, a meeting, a tweet. You don't have to tell anyone but yourself. This blog post, like all the posts before it, has a dedication page, at least in my head.
When you start creating for and in honor of those that have made a difference to you, your work changes.

paywalled: MR Imaging of Malignancies Arising in Endometriomas and Extraovarian Endometriosis

MR Imaging of Malignancies Arising in Endometr... [Radiographics. 2012] - PubMed - NCBI

Radiographics. 2012 May

Abstract: 

Cancers that arise in ovarian or extraovarian endometriosis are a distinct disease category with a histologic profile different from that of the more common epithelial ovarian cancers and with a better prognosis.

Because the malignant transformation of endometriomas is rarely associated with lymphadenopathy or peritoneal carcinomatosis, a high index of suspicion on the part of the radiologist is necessary to establish a timely diagnosis of endometriosis-related ovarian cancers and allow appropriate oncologic management. Although imaging is not currently performed for surveillance of endometriosis, magnetic resonance (MR) imaging is often performed when surgical treatment is under consideration................. For definitive diagnosis, histopathologic analysis is required.

paywalled: Treatment of Chemotherapy-Induced Anemia in Ovarian Cancer Patients: Does the Use of Erythropoiesis-Stimulating Agents Worsen Survival?

Treatment of Chemotherapy-Induced Anemia in Ovarian Cancer P... : International Journal of Gynecological Cancer

Abstract

Objective: 

Considering the paucity of data relating erythropoiesis-stimulating agent (ESA) use to ovarian cancer survival, our objective was to evaluate the effect of ESA as used for the treatment of chemotherapy-induced anemia (CIA) on survival in ovarian cancer patients.

Materials and Methods:  

A multi-institution retrospective chart review was performed on ovarian cancer patients. Data collection included patient demographic, surgicopathologic, chemotherapy, ESA, and survival data. Patients were stratified by ever-use of ESA and were compared using appropriate statistical methods.

Results: A total of 581 patients were eligible for analysis with 39% (n = 229) patients with ever-use of ESA (ESA-YES) and 61% (n = 352) never-use ESA (ESA-NO). Mean age was 60.4 years with most patients having stage IIIC (60%) of papillary serous histological diagnosis (64%) with an optimal cytoreduction (67%). Median follow-up for the cohort was 27 months. Both ESA-YES and ESA-NO groups were similar regarding age, body mass index, race, stage, histological diagnosis, and debulking status. Compared with the ESA-NO group, ESA-YES patients were significantly more likely to experience recurrence (56% vs 80%, P < 0.001) and death (46% vs 59%, P = 0.002). Kaplan-Meier curves demonstrated a significant reduction in progression-free survival for ESA-YES patients (16 vs 24 months, P < 0.001); however, overall survival was statistically similar between the 2 groups (38 vs 46 months, P = 0.10). When stratifying by ever experiencing a CIA, ESA-YES patients demonstrated a significantly worse progression-free survival (17 vs 24 months, P = 0.02) and overall survival (37 vs 146 months, P < 0.001).

Conclusions: 

Our data evaluating the use of ESA as a treatment of CIA in ovarian cancer patients are similar to reports in other tumor sites. Considering that patients who used ESA were more likely to experience recurrence and death and to have decreased survival, the use of ESA in ovarian cancer patients should be limited.

paywalled: Differential diagnosis of a pelvic mass: improved algorithms and novel biomarkers.

Differential diagnosis of a pelvic mass: improved algorithms and novel biomarkers.:


ABSTRACT:

More than 200,000 women undergo exploratory surgery for a pelvic mass in the United States each year and 13%-21% of pelvic lesions are found to be malignant. Individual reports and meta-analysis indicate better outcomes when cancer surgery is performed by gynecologic oncologists. Despite the advantages provided by more thorough staging and cytoreductive surgery, only 30%-50% of women with ovarian cancer are referred to surgeons with specialized training in the United States. Imaging, menopausal status and biomarkers can aid in distinguishing malignant from benign pelvic masses to inform decisions regarding appropriate referral. The risk of malignancy index (RMI) uses ultrasound, menopausal status and CA125 and has been utilized in the United Kingdom for two decades, providing sensitivity that has ranged from 71%-88% and specificity it from 97%-74% for identifying patients with malignant disease. Criteria have been established by the Society of Gynecology Oncology and American College of Obstetrics and Gynecology for referral to a gynecologic oncologist, but these have lower sensitivity and specificity than the RMI.

Recently, two new algorithms have been developed to identify women at sufficiently high risk to prompt referral to a specialized surgeon. The OVA1 multivariate index incorporates imaging, menopausal status, CA125 and four other proteomic biomarkers. Use of OVA1 provides 85%-96% sensitivity at 28%-40% specificity depending upon menopausal status. The negative predictive value for women judged to be at low risk is 94%-96%.

The risk of malignancy algorithm (ROMA) includes CA125, human epididymal protein 4 and menopausal status, but not imaging results.

paywalled: Intraperitoneal and intravenous chemotherapy in peritoneal carcinomatosis.

Intraperitoneal and intravenous chemotherapy in peritoneal carcinomatosis.:

Intraperitoneal and intravenous chemotherapy in peritoneal carcinomatosis.

Hepatogastroenterology. 2012 Jul-Aug

Abstract
Background/Aims:
We conducted a phase I trial of IP oxaliplatin and paclitaxel with IV paclitaxel and bevacizumab in patients with peritoneal carcinomatosis.

Methodology:
Patients received IV bevacizumab (2.5mg/kg) over 1 hour (day 1), then IV paclitaxel (110mg/m2) 24-hr-infusion (day 1) and IP oxaliplatin (25-40mg/m2) (day 2), and IP paclitaxel (30-60mg/m2) (day 8 from cycle 2 onwards). A '3+3' design was used.

Results:
Nineteen patients were treated (median age 60 years; 10 women, 9 men; median number of prior therapies 3). Primary tumors were colorectal (n=9), signet ring carcinoma (n=2), gastric (n=2), ovarian (n=2) and others (n=4). The maximum tolerated doses (MTD) of IP oxaliplatin and IP paclitaxel were 25mg/m2 and 60mg/ m2, respectively. Nine (47%) patients reported no toxicities >grade 2. Two patients receiving IP oxaliplatin 40mg/m2 and IP paclitaxel 60mg/m2 had dose limiting toxicities (DLT) of grade 3 diarrhea/dehydration and febrile neutropenia. Toxicities included abdominal pain (n=14), nausea (n=10) and constipation (n=7). Of 12 patients restaged at 2 months, 7 (58%) had stable disease (SD) including 2 (17%) who had SD for >4 months.

Conclusions: 
IP paclitaxel and IP oxaliplatin can be given safely at 60mg/m2 and 25mg/m2, respectively.

PMID: 22580643 [PubMed - in process]

paywalled: Recurrent and founder mutations in the PMS2 gene - Clinical Genetics

Recurrent and founder mutations in the PMS2 gene - Tomsic - Clinical Genetics

Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer.

Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However some mutations are observed repeatedly, across individuals not known to be related, due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations.

Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations, one (c.903G>T) a probable founder, and one (c.1A>G) where founder mutation status could not be evaluated. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2.

paywalled: Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients - Kantelinen - Human Mutation - Wiley Online Library

Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients - Kantelinen - Human Mutation

Abstract

Mismatch repair (MMR) malfunction causes the accumulation of mismatches in the genome leading to genomic instability and cancer. The inactivation of an MMR gene (MSH2, MSH6, MLH1 or PMS2) with an inherited mutation causes Lynch syndrome (LS), a dominant susceptibility to cancer. MMR gene variants of uncertain significance (VUS) may be pathogenic mutations which cause LS, may result in moderately increased cancer risks, or may be harmless polymorphisms. Our study suggests that an inherited MMR VUS individually assessed as proficient may, however, in a pair with another MMR VUS found in the same colorectal cancer (CRC) patient have a concomitant contribution to the MMR deficiency. Here, eight pairs of MMR gene variants found in cancer patients were functionally analyzed in an in vitro MMR assay. Although the other pairs do not suggest a compound deficiency, the MSH2 VUS pair c.380A>G/c.982G>C (p.Asn127Ser/p.Ala328Pro), which nearly halves the repair capability of the wild type MSH2 protein, is presumed to increase the cancer risk considerably. Moreover, two MSH6 variants, c.1304T>C (p.Leu435Pro) and c.1754T>C (p.Leu585Pro), were shown to be MMR deficient. The role of one of the most frequently reported MMR gene VUS, MSH2 c.380A>G (p.Asn127Ser), is especially interesting, since its concomitant defect with another variant could finally explain its recurrent occurrence in CRC patients.

Increased Expression of PITX2 Transcription Factor Contributes to Ovarian Cancer Progression

PLOS Increased Expression of PITX2 Transcription Factor Contributes to Ovarian Cancer Progression:

Principal Findings
.....Clinicopathological correlation showed that the upregulated PITX2 was significantly associated with high-grade (P = 0.023) and clear cell subtype (P = 0.011) using Q-PCR and high-grade (P<0.001) ovarian cancer by IHC analysis. Functionally, enforced expression of PITX2 could promote ovarian cancer cell proliferation, anchorage-independent growth ability, migration/invasion and tumor growth in xenograft model mice. Moreover, enforced expression of PITX2 elevated the cell cycle regulatory proteins such as Cyclin-D1 and C-myc. Conversely, RNAi mediated knockdown of PITX2 in PITX2-high expressing ovarian cancer cells had the opposite effect.

Conclusion
Our findings suggest that the increased expression PITX2 is involved in ovarian cancer progression through promoting cell growth and cell migration/invasion. Thus, targeting PITX2 may serve as a potential therapeutic modality in the management of high-grade ovarian tumor.

paywalled: Recording patient preferences for end-of-life care as an incentivized quality indicator: What do general practice staff think?

Recording patient preferences for end-of-life care as an incentivized quality indicator: What do general practice staff think?:

Introduction: Since April 2009, indicators for the UK Quality and Outcomes Framework pilot have been developed and piloted across a nationally representative sample of practices. In October 2009 a single palliative care indicator was piloted for 6 months that looked at, ‘the percentage of patients on the palliative care register who have a preferred place to receive end-of-life care documented in the records’.

Aim: The aim of this study was to gain the views and experiences of general practice staff on whether the inclusion of a single incentivized indicator to record the preferred place to receive end-of-life care would improve the quality of palliative care. Any issues arising from its implementation in a pay-for-performance scheme were also explored.

Methods: Interviews took place with 57 members of staff in 24 practices: 21 GPs, 16 practice managers, 12 nurses and eight others (mostly information technology experts).

Results: The indicator was not deemed appropriate for incentivization due to concerns about incentivizing an isolated, single issue within a multi-faceted, multi-disciplinary and complex topic. Palliative care was seen to be too sensitive and patient specific to be amenable to population-level quality measurement. In implementation, the indicator would pose potential harm to patients who may be asked about their end-of-life care at an inappropriate time and by a member of staff who may not be best placed to address this sensitive topic.

Conclusions: The most appropriate time to ask a patient about end-of-life care is subjective and patient specific and therefore does not lend itself to an inflexible single indicator. Focusing on one isolated question simplifies and distracts from a multi-faceted and complex issue and may lead to patient harm.

American Society for Clinical Pathology: Molecular Testing in Colorectal Cancer (Lynch Syndrome/MLH1, MSH2, MSH6, PMS2/MSI-H/KRAS/BRAF.....)

Blogger's Note: focus (obviously) on colorectal cancer, however, the cancer spectrum of Lynch Syndrome is noted in this paper as well as the shortcomings of the Bethesda Guidelines

 Molecular Testing in Colorectal Cancer

Conclusion

In summary, current standard-of-care molecular testing of CRC is aimed at detecting Lynch syndrome and KRAS mutations. However, with recent rapid development of biological agents targeted against components of the EGFR signaling cascade in the treatment of CRCs, mutational analysis of the genes in the EGFR signaling pathway may become a standard of care for patients with CRC in the near future. Ideally, identifying molecular prognostic and predictive factors may allow us to identify high-risk patients with stage II CRC who will benefit from chemotherapy after surgery. In addition, this may allow us to determine patients’ eligibility for targeted biological therapies.

A benign multicystic peritoneal mesothelioma mimicking recurrence of ovarian borderline tumor: a case report

A benign multicystic peritoneal mesothelioma mimicking recurrence of ovarian borderline tumor: a case report:

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

 Introduction
Benign multicystic peritoneal mesothelioma (BMPM) is an extremely rare tumor that occurs mainly in women in their reproductive age. Its preoperative diagnosis and adequate treatment are quite difficult to attain.

Case presentation
The case was 23 years-old Japanese woman and had a history of right oophorectomy and left ovarian cystectomy for an ovarian tumor at 20 years of age. The left ovarian tumor had been histologically diagnosed as mucinous borderline tumor. Two years and 9 months after the initial operation, multiple cysts were found in the patient. Laparotomy was performed, and the uterus, left ovary, omentum, and pelvic lymph nodes were removed due to suspicion of recurrence of the borderline tumor. Histological examination, however, revealed that the cysts were not a recurrence of the borderline tumor but rather BMPM. There were no residual lesions, and the patient was followed up with ultrasonography. She remains free from recurrence 9 months after treatment.

Conclusion:
We report a case of BMPM mimicking recurrence of ovarian borderline tumor. BMPM should be suspected when a multicystic lesion is present in the pelvis as in the case presented here, especially in patients with previous abdominal surgery.

paywalled - Unravelling the two entities of endometrioid ovarian cancer: A single center clinical experience

Unravelling the two entities of endometrioid ovarian cancer: A single center clinical experience

Purchase

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Abstract

Objective

Due to the increasing prevalence of the benign condition, ovarian carcinoma arising from endometriosis is emerging as a relevant clinical entity with an unclear biological signature. We have investigated clinical and histologic features of endometriosis-associated endometrioid ovarian cancer using an institutional retrospective database.

Methods

Patients diagnosed with endometrioid ovarian cancer at our institution were divided into two groups according to the fulfillment or not of Sampson's and Scott's criteria for the detection of endometriosis-associated ovarian cancer. Clinical and histological data were reported and compared. Survival analysis was obtained using the log-rank test in an unadjusted Kaplan-Meier method. Multivariate analysis was performed using the Cox proportional hazards regression model to establish independent factors associated with endometriosis-associated endometrioid ovarian cancer and to identify predictors of survival.

Results

Patients with endometriosis-associated endometrioid ovarian cancer were significantly younger, had a lower disease stage (77% vs 38%; p = 0.003), a less prevalent high grade tumor (38% vs 82%; p = 0.002) and a higher prevalence of squamous and mucinous metaplasia. 

The rate of endometrial cancer diagnosis was significantly higher in women with endometriosis-associated endometrioid ovarian cancer (33%) than in other patients (11%) (p = 0.04) with a 92% concordance between ovarian and endometrial histologic tumor grade. A significant difference in survival rate could not be demonstrated between patients with or without endometriosis.

Conclusions

The analysis of a retrospective endometrioid ovarian cancer database may allow to suggest a molecular, morphological and clinical parallelism between endometrial and endometrioid ovarian cancer.

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Highlights

► Endometriosis-associated endometrioid ovarian tumors possess a different biologic signature when compared to cancers not associated with the disease.
► Clinical course and molecular alterations of type I and type II endometrial tumors are similar to those detected respectively in endometriosis-associated and non-associated endometrioid ovarian tumor.

Journal of Ovarian Research May 15th: Tubal ligation, hysterectomy and ovarian cancer: A meta-analysis

 Blogger's Note: included in the study are references to hereditary ovarian cancer - BRCA's but not Lynch Syndrome
                                      ~~~~~~~~~~~~~~~

Journal of Ovarian Research Tubal ligation, hysterectomy and ovarian cancer: A meta-analysis

Introduction
Ovarian cancer is the fifth leading cause of cancer death in US women [1], yet primary prevention recommendations are limited. Gynecological surgeries including tubal ligation and hysterectomy may alter ovarian cancer risk by protecting the ovary from ascending carcinogens or damaging the utero-ovarian artery altering hormonal function. In addition, tubal ligation may increase immunity against the surface glycoprotein human mucin 1 (MUC1) [2-4]. While tubal ligation and hysterectomy generally have been found to be inversely associated with ovarian cancer, effect estimates vary between studies and little is
known about potential effect modifiers of these associations. Therefore, we conducted a meta-analysis of the association between ovarian cancer and tubal ligation as well as hysterectomy.

Results
......In secondary analyses, the association between tubal ligation and ovarian cancer risk was stronger for endometrioid tumors compared to serous tumors.

Conclusion

Observational epidemiologic evidence strongly supports that tubal ligation and hysterectomy are associated with a decrease in the risk of ovarian cancer, by approximately 26-30%. Additional research is needed to determine whether the association between tubal ligation and hysterectomy on ovarian cancer risk differs by individual, surgical, and tumor characteristics.

pdf

What Did You Know, and When Did You Stop Knowing It? - Forbes

What Did You Know, and When Did You Stop Knowing It? - Forbes

Recently, a story (Analytical Trend Troubles Scientists) appeared in The Wall Street Journal that was critical of — what turns out to be — an increasingly common type of medical investigation: the observational study.

The WSJ story uses as its jumping-off point the (shocking? surprising?) discrepancy between two studies that both asked the same question and used the same data: does taking bisphosphonates (think Fosamax) increase your risk of stomach or throat cancer?

One study concluded that no, it does not significantly increase your cancer risk. The other said that yes, it does significantly increase said risk. ["Significantly" here means "probably", in the statistician's sense.] In neither case, though, did it find that your cancer risk would be particularly high: 0.1% vs 0.2% in 60/69-year-olds. So why the dustup?.....

DcR3 binds to ovarian cancer via heparan sulfate proteoglycans and modulates tumor cells response to platinum with corresponding alteration in the expression of BRCA1

DcR3 binds to ovarian cancer via heparan sulfateproteoglycans and modulates tumor cells response toplatinum with corresponding alteration in theexpression of BRCA1

Background
Overcoming platinum resistance is a major obstacle in the treatment of Epithelial Ovarian Cancer (EOC). In our previous work Decoy Receptor 3 (DcR3) was found to be related to platinum resistance. The major objective of this work was to define the cellular interaction of DcR3 with EOC and to explore its effects on platinum responsiveness.

Conclusions
Non-malignant cells contribute to the high levels of DcR3 in ovarian cancer. DcR3 binds readily to EOC cells via HSPGs and alter their responsiveness to platinum chemotherapy.The paradoxical responses seen were related to the expression pattern of HSPGs available on the cells surface to interact with. Although the mechanism behind this is not completely known alterations in DNA repair pathways including the expression of BRCA1 appear to be involved.