Commentary: Accountable Care Organizations and Community Empowerment - — JAMA

Less apparent to the public during this period of historic change are the struggles occurring in US board rooms among hospital groups, specialty physicians, and primary care clinicians—debating quietly but intensely over how to form these ACOs, how to be accountable for care delivery, and how to divide anticipated savings derived from ACOs. However, in most of these settings, important constituencies—middle class and other working patients whose health and welfare are at stake—are not included in the discussions.......................The high and accelerating increases in the cost of health care and the limited roles of patients in decision making central to health and health care delivery are too real to ignore. Decision making by distal proxies such as elected legislators may no longer be enough to address the United States' mounting problems with health care, outcomes, and costs.

abstract: Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy — JAMA

Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy

A Randomized Controlled Trial

Abstract

Context 

The Women's Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported. 

Objective 

To examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009. 

Design, Setting, and Participants 

The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10 739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent. 

Main Outcome Measures 

The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death. 

Results 

The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction). 

Conclusions 

Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. 

A decreased risk of breast cancer persisted. 

abstract: Familial Cancer - Mutation deep within an intron of MSH2 causes Lynch syndrome

"...thus highlighting the need for more extensive sequencing approaches in families where routine procedures fail to find a mutation."

abstract: Familial Cancer, A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance—functional analysis reveals the pathological one

Abstract

Inherited pathogenic mutations in the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2 predispose to Lynch syndrome (LS). However, the finding of a variant or variants of uncertain significance (VUS) in affected family members complicates the risk assessment. Here, we describe a putative LS family carrying VUS in both MSH2 (c.2768T>A, p.Val923Glu) and MSH6 (c.3563G>A, p.Ser1188Asn). Two colorectal cancer (CRC) patients were studied for mutations and identified as carriers of both variants. In spite of a relatively high mean age of cancer onset (59.5 years) in the family, many CRC patients and the tumor pathological data suggested that the missense variation in MSH2, the more common susceptibility gene in LS, would be the predisposing alteration. However, MSH2 VUS was surprisingly found to be MMR proficient in an in vitro MMR assay and a tolerant alteration in silico. By supplying evidence that instead of MSH2 p.Val923Glu the MSH6 p.Ser1188Asn variant is completely MMR-deficient, the present study confirms the previous findings, and suggests that MSH6 (c.3563G>A, p.Ser1188Asn) is the pathogenic mutation in the family. Moreover, our results strongly support the strategy to functionally assess all identified VUS before predictive gene testing and genetic counseling are offered to a family.

LOVD - An Open Source DNA variation database system (eg. genetic testing/unknown clinicial variant/s)

LOVD stands for Leiden Open (source) Variation Database.
LOVD's purpose : To provide a flexible, freely available tool for Gene-centered collection and display of DNA variations.

Mutalyzer

LOVD features integration with the Mutalyzer sequence variant nomenclature checker, allowing for direct nomenclature checking of sequence variants during the submission process.

If you are looking for a specific gene database, please check the list of gene variant databases at the HGVS site, in our list of LSDBs, or in the list of registered LOVD installations.

abstract: Calculator for ovarian carcinoma subtype prediction : Modern Pathology

Abstract:

With the emerging evidence that the five major ovarian carcinoma subtypes (high-grade serous, clear cell, endometrioid, mucinous, and low-grade serous) are distinct disease entities, management of ovarian carcinoma will become subtype specific in the future.

In an effort to improve diagnostic accuracy, we set out to determine if an immunohistochemical panel of molecular markers could reproduce consensus subtype assignment.

Immunohistochemical expression of 22 biomarkers were examined on tissue microarrays constructed from 322 archival ovarian carcinoma samples from the British Columbia Cancer Agency archives, for the period between 1984 and 2000, and an independent set of 242 cases of ovarian carcinoma from the Gynaecologic Tissue Bank at Vancouver General Hospital from 2001 to 2008. Nominal logistic regression was used to produce a subtype prediction model for each of these sets of cases. These models were then cross-validated against the other cohort, and then both models were further validated in an independent cohort of 81 ovarian carcinoma samples from five different centers.

Starting with data for 22 markers, full model fit, backwards, nominal logistic regression identified the same nine markers (CDKN2A, DKK1, HNF1B, MDM2, PGR, TFF3, TP53, VIM, WT1) as being most predictive of ovarian carcinoma subtype in both the archival and tumor bank cohorts. These models were able to predict subtype in the respective cohort in which they were developed with a high degree of sensitivity and specificity (κ statistics of 0.88±0.02 and 0.86±0.04, respectively).

When the models were cross-validated (ie using the model developed in one case series to predict subtype in the other series), the prediction equation's performances were reduced (κ statistics of 0.70±0.04 and 0.61±0.04, respectively) due to differences in frequency of expression of some biomarkers in the two case series. Both models were then validated on the independent series of 81 cases, with very good to excellent ability to predict subtype (κ=0.85±0.06 and 0.78±0.07, respectively).

A nine-marker immunohistochemical maker panel can be used to objectively support classification into one of the five major subtypes of ovarian carcinoma.

Observations: Electronic health records face human hurdles more than technological ones

abstract: Early detection of ovarian cancer - Early detection of ovarian cancer† If only we had a “Pap smear” for this disease

Abstract:

Primary care physicians are recognizing the symptoms of ovarian cancer and ordering the appropriate diagnostic tests. On the basis of the diverse behavior of epithelial cancers, the goal of screening technology should shift from diagnosing early stage to diagnosing low-volume disease.

abstract: Symptom burden in cancer survivors 1 year after diagnosis Cancer

CONCLUSIONS:

More than 1 in 4 cancer survivors had high symptom burden 1 year postdiagnosis, even after treatment termination. These results indicate a need for continued symptom monitoring and management in early post-treatment survivorship, especially for the underserved.

abstract: Cancer-related chronic pain - Cancer

CONCLUSIONS:

The authors extend the literature by showing that 20% of diverse cancer survivors had cancer-related CP, and 43% had experienced pain since diagnosis, revealing racial and sex disparities in cancer-related CP's incidence and impact on QOL. Having pain was related to poorer QOL in several domains and was more frequently experienced by women. Although black race was not related to pain prevalence, it was related to greater severity. This study reveals an unaddressed cancer survivorship research, clinical, and policy issue

press release U.S. - FDA Grants Orphan Drug Designation for Nektar's Investigational Drug, NKTR-102, for Treatment of Women with Ovarian Cancer (NKTR-102)

Nektar Therapeutics (Nasdaq: NKTR) today announced that the company's oncology drug candidate, NKTR-102, has been granted orphan drug status for the treatment of women with ovarian cancer by the U.S. Food and Drug Administration (FDA).




Nektar has a Phase 2 study ongoing for NKTR-102 that is enrolling approximately 125 patients with platinum-resistant ovarian cancer whose disease has progressed following treatment with pegylated liposomal doxorubicin (PLD) therapy.  In addition, Phase 3 planning is also underway for NKTR-102 in ovarian cancer.  For more information about clinical trials for NKTR-102, please visit the Nektar Therapeutics website.


NKTR-102 is an investigational agent and is not approved by the FDA, the European Medicines Agency (EMA) or other Health Authorities.

abstract: Pharmacokinetics and antitumor activity of patupilone combined with midazolam or omeprazole in patients with advanced cancer (inhibitors)

PURPOSE:
Patupilone is a novel microtubule-targeting cytotoxic agent with potential interaction with CYP3A4/CYP2C19 enzymes. Midazolam and omeprazole are primarily metabolized by CYP3A4 and CYP2C19, respectively. We evaluated the inhibitory effects of patupilone on the CYP3A4/CYP2C19 pathways.

METHODS:
This study had 2 parts: in an initial core phase, patients were randomly assigned to receive midazolam 4 mg or omeprazole 40 mg PO (days 1 and 29) and patupilone 10 mg/m(2) IV (days 8 and 29). Patients without progression continued patupilone every 3 weeks until disease progression or unacceptable toxicity (extension phase).

full free access: Docetaxel Distribution Following Intraperitoneal Administration in Mice Journal of Pharmacy & Pharmaceutical Sciences (technical)

Note: in mice (research); technical

abstract: Role of Minimally Invasive Surgery in Staging of Ovarian Cancer

Abstract

OPINION STATEMENT:
Since the introduction of laparoscopy and robotic surgery in gynecologic practice in the last several decades, use of these minimally invasive surgical techniques has increased dramatically. The role of minimally invasive surgical techniques continues to expand because they offer reduced intraoperative and postoperative complications, less intraoperative blood loss, and a shorter postoperative recovery. Despite initial concerns about the use of minimally invasive surgery in gynecologic oncology, this approach has been shown to be safe and effective in the management of uterine and cervical cancer, and minimally invasive surgical management of these malignancies is now commonplace. Concerns remain regarding the use of minimally invasive surgery for the staging and management of ovarian cancer, including concerns regarding the adequacy of abdominal exploration and staging with minimally invasive approaches compared to traditional laparotomy and the risks and implications of intra-operative tumor cyst rupture and port-site metastases. However, several case series, retrospective reviews, and case-control studies have demonstrated that minimally invasive surgery is both safe and effective for the staging of borderline ovarian tumors and early-stage epithelial ovarian cancer when performed by a trained gynecologic oncologist. Data to support the role of minimally invasive surgery for advanced epithelial ovarian cancer are scant and use of minimally invasive surgery in this setting is not recommended.

abstract: Case studies in the diagnosis and management of Peutz-Jeghers Syndrome (PJS) (ovarian sex cord tumors)

Abstract

Peutz-Jeghers syndrome (PJS) is a rare genetic disorder characterized by melanotic macules, gastrointestinal polyps and increased cancer risks. We discuss several common scenarios encountered in the diagnosis and management of PJS patients. If the diagnosis is unclear, all pathological material should be re-evaluated by an expert gastrointestinal pathologist. The PJS discussion email list-serve (patient managed) and the peutz-jeghers.com, geneclinics.org, stk11.com websites are useful resources for patients.

abstract: Breast and Ovarian Cancer: The Forgotten Paternal Contribution

Individuals with a paternal family history were found to have a different, and higher, pattern of risk estimates. No significant difference was seen between the type of referrals sent by general practitioners, oncologists, and gynecologists.

full free access: Phase ii/iii study of intraperitoneal chemotherapy after neoadjuvant chemotherapy for ovarian cancer: Canada

Note:

1) see Section 2.3 for study criteria (patient enrollment requirements);
2) .... acquisition of tumour specimens both before study therapy is started and after neoadjuvant chemotherapy has been received provides a unique opportunity for a correlative study of differing drug responses within the same patients.

Although the study is led by the ncic ctg, the protocol, the accompanying IP therapy guidelines, and a companion document intended to summarize and promote best practice in the administration of IP therapy are the result of a collaboration between the ncic ctg and the Society of Gynecologic Oncologists of Canada, with international partners in the United Kingdom (National Cancer Research Institute), Spain (Spanish Ovarian Cancer Research Group), and the United States (Southwest Oncology Group).

Abstract: (including full free text access):

abstract: Early Detection of Recurrent Ovarian Cancer in Patients with Low-Level Increases in Serum CA-125 Levels by PET/CT

Abstract

Purpose: Serum CA-125 has been shown to be a sensitive tumor marker of recurrent ovarian cancer. The goal of this study was to evaluate the use of 2-[F-18]fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in the early detection of recurrent ovarian cancer in patients with low-level increases in serum CA-125 levels.

abstract: A longitudinal investigation of (PTSD) posttraumatic stress disorder in patients with ovarian cancer

Abstract
INTRODUCTION:
Exposure to the aggressive and life-threatening nature of ovarian cancer and its treatment is potentially traumatic. However, little is known about the occurrence of posttraumatic stress disorder (PTSD) in these patients.

abstract: Ovarian cancer in the elderly: Impact of surgery on morbidity and survival (France)

Note: in this study 'elderly' =  70+ yrs

CONCLUSION:

Elderly ovarian cancer patients undergo less extensive surgery and have lower OS (overall survival) despite similar postoperative morbidity, optimal resection and DFS. OS decrease could be explained by difference in the management of recurrences.

Apr 2011: free full access - Recognition and initial management of ovarian cancer: summary of NICE guidance -- bmj.com

Note: guidelines include Carboplatin alone in high-risk early stage; IP for advanced stage ovarian cancer via clinical trial/s (which brings up the question as to the availability of trials??) Future research What is the relationship between the duration and frequency of symptoms in women with ovarian cancer before diagnosis, and the stage of disease at diagnosis and subsequent survival? What is the optimum threshold on the risk of malignancy index I (RMI I) that should be applied in secondary care to guide the management of women with suspected ovarian cancer? How does computed tomography compare with magnetic resonance imaging in accuracy of staging and prediction of optimal cytoreduction? Answering this will require large, multicentre case-control studies. What are the cost effectiveness and risks of systematic retroperitoneal lymphadenectomy in women whose ovarian cancer seems to be confined to the ovaries? Answering this will require a prospective randomised trial. What is the effectiveness of primary surgery in women with advanced ovarian cancer that cannot be fully excised?

free full access: Calcium supplements with/without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative - bmj.com (including responses)

Abstract/Conclusions:
Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted.

excerpt (from full text):

"...An important question that arises is whether co-administered calcium and vitamin D affects cardiovascular risk. The Women’s Health Initiative reported no adverse effect of calcium and vitamin D (1 g calcium/400 IU vitamin D daily) on any cardiovascular end point in their large (n=36 282), seven year, randomised, placebo controlled trial.3 4 However, 54% of the participants were taking personal (non-protocol) calcium supplements at randomisation and 47% were taking personal vitamin D supplements, effectively rendering this trial a comparison of higher dose and lower dose calcium and vitamin D for most of the participants.

Allowing clinical trial participants free access to the intervention being studied is unusual and has the potential to obscure both adverse and beneficial effects..."