Attitudes and perceptions regarding subspecialty training in female pelvic medicine and reconstructive surgery

The objective of the study was to evaluate perceptions regarding subspecialty training in female pelvic medicine and reconstructive surgery (FPMRS) in the United States. A 57-item questionnaire was anonymously mailed to fellows and applicants to FPMRS fellowship. Seventy-four American fellowship interviewees and current fellows completed the entire questionnaire (56% response rate). Key factors associated with higher interest in FPMRS compared to general obstetrics and gynecology (OBG) included competitiveness to get into fellowship and new developments. Key factors associated with higher interest in FPMRS compared to other subspecialties in obstetrics and gynecology (SUB) were lower risk of malpractice and higher sense of career satisfaction. Commonly cited attributes of FPMRS that attract to the field relate to the complexity of cases and the quantity of time spent in the operating room. Majority of responders preferred academics over private practice or a mixture (55.4%, 17.6%, and 27%, respectively). The most important reason for interest in FPMRS compared to OBG and SUB is quality time in the operating room and lower risk of malpractice, respectively. Results of this study may help attract medical students to OBG and help mentors with career counseling.     

Cardiovascular risk,obesity, and myocardial blood flow in postmenopausal women

Background. This study was designed to determine whether overweight or obese status is independently associated with myocardial flow reserve (MFR), an established predictor of cardiovascular mortality, in a group of postmenopausal women with no previous cardiovascular disease. Postmenopausal women are the largest group of overweight and physically inactive individuals in the United States. Increased body mass index (BMI) is consistently associated with increased cardiovascular mortality in this population. Whether this is because of obesity itself or the accompanying increase in cardiovascular risk factors (CRFs) remains controversial. Methods. We examined the relationship of myocardial blood flow (MBF), coronary vascular resistance, and MFR to BMI in 60 postmenopausal women with no coronary heart disease. Subjects underwent dynamic N-13 ammonia positron emission tomography for the measurement of MBF and MFR. Baseline demographics, CRF, and hemodynamic parameters were recorded for each subject. Datasets were divided into 3 groups according to BMI: normal (18 to 24), overweight (25 to 29), and obese (≥30). Results. The overweight and obese groups showed significantly higher resting MBF and lower MFR than the normal-weight group (both P<.001), even after adjusting for CRF. A further analysis of subjects without any CRF (n=35) showed that the MFR remained significantly lower in the obese compared with normal-weight subjects (P=.05). Levels of known markers of vascular inflammation (high-sensitivity C-reactive protein and homocysteine) and high-density lipoprotein cholesterol levels correlated with declining MFR. Conclusions. These findings provide a mechanistic link between obesity and coronary heart disease in this population. This study was funded by a Veterans Health Administration MERIT Review Award. C.S.D. is on the Speaker’s Bureau at Pfizer, Inc., and has received grant support from Pfizer, Inc., Eli Lilly & Co., and the Veterans Health Administration.     

Spontaneous intramural left atrial haematoma masquerading as left atrial thrombus

Spontaneous left atrial intramural haematoma is rare. We got one such case which gave rise to cardiac tamponade. This presentation is to increase awareness about its evaluation and management.     

Use of Tunneled-Cuffed Central Catheters in Patients with Cancer: A Single-Center Experience

Background

Effective and reliable venous access is among the cornerstones of modern medical therapy in oncology.

Transfusion Associated Graft Versus Host Disease Following Whole Blood Transfusion from an Unrelated Donor in an Immunocompetent Patient

Graft-versus-host disease (GVHD) is a well-known complication of allogeneic bone marrow transplantation. Transfusion associated graft-versus-host disease (TA-GVHD) is much less common and nearly uniformly fatal complication of blood transfusion. The risk factors underlying the development of TA- GVHD are incompletely defined, but it is commonly seen in individuals with congenital or acquired immunodeficiency, transfusions from blood relatives, intrauterine transfusions and HLA-matched platelet transfusions. Diagnosis of TA-GVHD may be difficult at a time due to rarity in occurrence and overlapping clinical features with various infections and drug reactions. We describe a case of transfusion-associated GVHD that occurred after transfusion of whole blood from unrelated donor in an immunocompetent patient.     

Adeno-associated virus type 2 infection activates caspase dependent and independent apoptosis in multiple breast cancer lines but not in normal mammary epithelial cells

Background

In normal cells proliferation and apoptosis are tightly regulated, whereas in tumor cells the balance is shifted in favor of increased proliferation and reduced apoptosis. Anticancer agents mediate tumor cell death via targeting multiple pathways of programmed cell death. We have reported that the non-pathogenic, tumor suppressive Adeno-Associated Virus Type 2 (AAV2) induces apoptosis in Human Papillomavirus (HPV) positive cervical cancer cells, but not in normal keratinocytes. In the current study, we examined the potential of AAV2 to inhibit proliferation of MCF-7 and MDA-MB-468 (both weakly invasive), as well as MDA-MB-231 (highly invasive) human breast cancer derived cell lines. As controls, we used normal human mammary epithelial cells (nHMECs) isolated from tissue biopsies of patients undergoing breast reduction surgery.

Results

AAV2 infected MCF-7 line underwent caspase-independent, and MDA-MB-468 and MDA-MB-231 cell lines underwent caspase-dependent apoptosis. Death of MDA-MB-468 cells was marked by caspase-9 activation, whereas death of MDA-MB-231 cells was marked by activation of both caspase-8 and caspase-9, and resembled a mixture of apoptotic and necrotic cell death. Cellular demise was correlated with the ability of AAV2 to productively infect and differentially express AAV2 non-structural proteins: Rep78, Rep68 and Rep40, dependent on the cell line. Cell death in the MCF-7 and MDA-MB-231 lines coincided with increased S phase entry, whereas the MDA-MB-468 cells increasingly entered into G2. AAV2 infection led to decreased cell viability which correlated with increased expression of proliferation markers c-Myc and Ki-67. In contrast, nHMECs that were infected with AAV2 failed to establish productive infection or undergo apoptosis.

Conclusion

AAV2 regulated enrichment of cell cycle check-point functions in G1/S, S and G2 phases could create a favorable environment for Rep protein expression. Inherent Rep associated endonuclease activity and AAV2 genomic hair-pin ends have the potential to induce a cellular DNA damage response, which could act in tandem with c-Myc regulated/sensitized apoptosis induction. In contrast, failure of AAV2 to productively infect nHMECs could be clinically advantageous. Identifying the molecular mechanisms of AAV2 targeted cell cycle regulation of death inducing signals could be harnessed for developing novel therapeutics for weakly invasive as well as aggressive breast cancer types.     

Simple options for improving signal detection in antidepressant clinical trials

Objective: Previous experience with antidepressant studies highlight the difficulties in discriminating an effective drug from placebo. In hopes of improving signal detection, three easy-to-implement methodologies were employed during the development of a recently approved antidepressant. Experimental Design: Results from alternative and traditional methods could be compared directly because most studies employed both methods. This database included 11 double-blind, placebo-controlled trials (some with multiple dose arms and/or active comparators) yielding 22 treatment arms of antidepressants at or above the minimally effective dose noted in their U.S. labels. Principal Observations: Results agreed with the previous evidence showing that the performance of a likelihood-based, mixed-effects model repeated measures (MMRM) analysis was superior to that of analysis of covariance with missing values imputed using the last observation carried forward (LOCF) approach; MMRM correctly identified drug as superior to placebo in 14/22 (63.6%) comparisons versus 11/22 (50.0%) for LOCF. In agreement with previous studies, use of subscales of the Hamilton Depression Rating scale (HAMD) improved signal detection compared to the HAMD total score. Using MMRM with HAMD subscales correctly identified drug as superior to placebo in up to 17/22 (77.3%) comparisons. Excluding double-blind, placebo lead-in responders did not increase the frequency of correctly identifying drug-versus-placebo differences. Conclusions: The 22 drug-versus-placebo comparisons in this report offer a small amount of evidence and therefore may not be convincing on their own, although results do agree with previous research. Researchers may be able to take advantage of these easy-to-implement methods while we wait for further improvements in other areas.     

Human papilloma virus circulating tumor DNA assay predicts treatment response in recurrent/metastatic head and neck squamous cell carcinoma

Despite the rising incidence of human papillomavirus related (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), treatment of metastatic disease remains palliative. Even with new treatments such as immunotherapy, response rates are low and can be delayed, while even mild tumor progression in the face of an ineffective therapy can lead to rapid death. Real-time biomarkers of response to therapy could improve outcomes by guiding early change of therapy in the metastatic setting. Herein, we developed and analytically validated a new droplet digital PCR (ddPCR)-based assay for HPV16 circulating tumor DNA (ctDNA) and evaluated plasma HPV16 ctDNA for predicting treatment response in metastatic HPV+ OPSCC. We found that longitudinal changes HPV16 ctDNA correlate with treatment response and that ctDNA responses are observed earlier than conventional imaging (average 70 days, range: 35–166). With additional validation in multi-site studies, this assay may enable early identification of treatment failure, allowing patients to be directed promptly toward clinical trials or alternative therapies.