BRCA1 and BRCA2 are the most important breast and ovarian cancer susceptibility genes. Biallelic mutations in BRCA2 can lead to Fanconi anemia and predisposition to cancers, whereas biallelic BRCA1 ...mutations have not been confirmed, presumably because one wild-type BRCA1 allele is required during embryogenesis. This study describes an individual who was diagnosed with ovarian carcinoma at age 28 and found to have one allele with a deleterious mutation in BRCA1, c.2457delC (p.Asp821Ilefs*25), and a second allele with a variant of unknown significance in BRCA1, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay, and significant toxicity from chemotherapy. BRCA1 p.Val1736Ala cosegregated with cancer in multiple families, associated tumors showed loss of wild-type BRCA1, and BRCA1 p.Val1736Ala showed reduced DNA damage localization. These findings represent the first validated example of biallelic deleterious human BRCA1 mutations and have implications for the interpretation of genetic test results.
Accurate assessment of genetic testing data for BRCA1 mutations is essential for clinical monitoring and treatment strategies. Here, we report the fi rst validated example of an individual with biallelic BRCA1 mutations, early-onset ovarian cancer, and clinically significant hypersensitivity to chemotherapy.
Davidson discusses the controversy over whether hormone replacement therapy is a risk for women's health. The debate about hormone replacement is largely fueled by fear of breast cancer.
Up to 15% of women with breast cancer have locally advanced disease at diagnosis. The poor response of these patients to local therapy alone and the frequent development of disseminated disease ...suggest that early intensive systemic therapy may benefit these women. Twenty-four patients with non-metastatic, locally advanced, primarily inflammatory, inoperable breast cancer were treated with a 16-week dose-intense chemotherapy regimen as induction therapy. Treatment consisted of 8 repetitive 2-week cycles consisting of 100 mg/m2 cyclophosphamide orally D1-7, 40 mg/m2 doxorubicin intravenously (IV) D1, 1 mg vincristine IV D1, 100 mg/m2 methotrexate IV D1, 10 mg/m2 leucovorin every 6 hours for six oral doses D2-3, and 600 mg/m2 5-FU IV over 2 hours D2. A continuous infusion of 300 mg/m2 5-FU per day was given IV D8-9 of each 2-week cycle. After induction all patients had at least a partial clinical response and were operable; 9/24 (37%) achieved a clinical complete response. All patients underwent at least a simple mastectomy. Pathologic examination revealed no evidence of gross macroscopic tumor in 11/24 patients (46%) and no evidence of microscopic disease in 4/24 patients (17%). Seven of 24 patients (29%) had no microscopic disease in the breast. At a median follow-up of 45 months, there have been 10 relapses in the 24 patients treated with this induction regimen. The actuarial relapse-free survival at 5 years is 58%. Actuarial overall survival at 5 years is 75%. We conclude that this regimen is safe and well-tolerated and that the results of this therapy are sufficiently promising to warrant further study of this regimen in patients with locally advanced breast cancer.
The need for improved systemic therapy for breast cancer is great. Cancer growth represents an imbalance between cell proliferation and cell death: thus, effective anti-cancer therapies may act to ...decrease cell proliferation or increase cell death, or both. This chapter delineates the role of the programmed cell death process in maintaining homeostasis in normal mammary tissues. The preservation of such death pathways in malignant mammary cells and the ability of chemotherapeutic agents to initiate the programmed cell death process in these cells is reviewed. Finally, ongoing research exploring new ways to take advantage of these death pathways in the clinical setting is examined.
IMPORTANCE Controversy remains about whether depression can be successfully managed after acute coronary syndrome (ACS) and the costs and benefits of doing so. OBJECTIVE To determine the effects of ...providing post-ACS depression care on depressive symptoms and health care costs. DESIGN Multicenter randomized controlled trial. SETTING Patients were recruited from 2 private and 5 academic ambulatory centers across the United States. PARTICIPANTS A total of 150 patients with elevated depressive symptoms (Beck Depression Inventory BDI score ≥10) 2 to 6 months after an ACS, recruited between March 18, 2010, and January 9, 2012. INTERVENTIONS Patients were randomized to 6 months of centralized depression care (patient preference for problem-solving treatment given via telephone or the Internet, pharmacotherapy, both, or neither), stepped every 6 to 8 weeks (active treatment group; n = 73), or to locally determined depression care after physician notification about the patient's depressive symptoms (usual care group; n = 77). MAIN OUTCOME MEASURES Change in depressive symptoms during 6 months and total health care costs. RESULTS Depressive symptoms decreased significantly more in the active treatment group than in the usual care group (differential change between groups, −3.5 BDI points; 95% CI, −6.1 to −0.7; P = .01). Although mental health care estimated costs were higher for active treatment than for usual care, overall health care estimated costs were not significantly different (difference adjusting for confounding, −$325; 95% CI, −$2639 to $1989; P = .78). CONCLUSIONS For patients with post-ACS depression, active treatment had a substantial beneficial effect on depressive symptoms. This kind of depression care is feasible, effective, and may be cost-neutral within 6 months; therefore, it should be tested in a large phase 3 pragmatic trial. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01032018
Over 120,000 U.S. children are hospitalized annually for traumatic injury, with approximately 20% developing acute stress disorder (ASD), posttraumatic stress disorder (PTSD), or depression. The ACS ...COT recommends that trauma centers address emotional recovery after injury; however, few pediatric trauma centers (PTCs) assess behavioral health symptoms. This study describes results from a survey with PTC providers assessing the landscape of behavioral health screening, education, and treatment.
Trauma program leaders from 83 US Level I and II trauma centers across 36 states completed a survey assessing center characteristics and decision-making, availability, and perceptions of behavioral health resources.
Nearly half (46%) of centers provide behavioral health screens for pediatric patients, and 18% screen family members, with screens mostly conducted by nurses or social workers for ASD or PTSD. Two-thirds provide child behavioral health education and 47% provide education to caregivers/family. Two-thirds provide treatment connections, typically via referrals or outpatient clinics. Behavioral health screening, education, and treatment connections were rated as very important (M > 8.5/10), with higher ratings for the importance of screening children versus caregivers. Child maltreatment (59%), observed patient distress (53%), child substance use (52%), injury mechanism (42%) and severity (42%) were prioritized in screening decision-making.
Service provision varies by method, resource, and provider, highlighting the lack of a roadmap for centers to provide behavioral health services. Adoption of universal education and screening procedures in PTCs is crucial to increase access to services for injured children and caregivers. PTCs are well-positioned to offer these services.
Level II
Abstract
Objective
Over 120,000 U.S. children are hospitalized for traumatic injury annually, a major risk factor for behavioral health problems such as acute/posttraumatic stress disorder (PTSD) and ...depression. Pediatric trauma centers (PTCs) are well positioned to address the recent mandate by the American College of Surgeons Committee on Trauma to screen and refer for behavioral health symptoms. However, most PTCs do not provide screening or intervention, or use varying approaches. The objective of this mixed-methods study was to assess PTCs’ availability of behavioral health resources and identify barriers and facilitators to service implementation following pediatric traumatic injury (PTI).
Methods
Survey data were collected from 83 Level I (75%) and Level II (25%) PTC program managers and coordinators across 36 states. Semistructured, qualitative interviews with participants (N = 24) assessed the feasibility of implementing behavioral health education, screening, and treatment for PTI patients and caregivers.
Results
Roughly half of centers provide behavioral health screening, predominantly administered by nurses for acute stress/PTSD. Themes from qualitative interviews suggest that (1) service provision varies by behavioral health condition, resource, delivery method, and provider; (2) centers are enthusiastic about service implementation including screening, inpatient brief interventions, and follow-up assessment; but (3) require training and lack staff, time, and funding to implement services.
Conclusions
Sustainable, scalable, evidence-based service models are needed to assess behavioral health symptoms after PTI. Leadership investment is needed for successful implementation. Technology-enhanced, stepped-care approaches seem feasible and acceptable to PTCs to ensure the availability of personalized care while addressing barriers to sustainability.
We report nine travellers with confirmed chikungunya virus infection, returning from tourist areas of Thailand to Sweden, Switzerland, the United Kingdom, Romania, Israel and France, diagnosed in ...January and February 2019. These sentinel tourists support the intensification of chikungunya virus circulation in Thailand and highlight the potential for importation to areas at risk of local transmission.
In this phase 1 study involving 76 healthy volunteers in England, a single dose of a monovalent chimpanzee adenovirus vaccine elicited immune responses to Ebola virus. The immune response was ...superior after a booster dose of a modified vaccinia Ankara strain.
The recent outbreak of Ebola virus disease (EVD) in West Africa has led to more than 11,000 deaths, with a peak in mortality from August through December of 2014 and a subsequent decline in the number of new cases. The development of a durable and effective Ebola vaccine is a priority both to eliminate the remnants of the outbreak and to prevent and control future epidemics. Several candidate vaccines have shown promising results in phase 1 trials,
1
–
6
and a recombinant vesicular stomatitis virus–based vaccine expressing the surface glycoprotein of
Zaire ebolavirus
(rVSV-ZEBOV) showed efficacy in an interim analysis of . . .
Breast Cancer Huang, Yi; Davidson, Nancy E
Principles of Molecular Medicine
Book Chapter
Breast cancer is the most common malignancy among Western women. Like other human cancers, breast cancer results from the accumulation of a series of genetic and/or epigenetic changes to genes with ...diverse functions, ultimately evolving to a malignant state. Recent scientific advances have offered many new approaches to identify and target a growing number of these genetic and epigenetic alterations in breast cancer. It is expected that this improved understanding of breast cancer biology will enhance risk assessment, prevention, diagnosis, and treatment of this disease.
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