Vulvar cancer in Botswana in women with and without HIV infection: patterns of treatment and survival outcomes.

OBJECTIVES: Vulvar cancer is a rare gynecological malignancy. However, the incidence of human papillomavirus (HPV)-associated vulvar disease is increasing, particularly in low- and middle-income countries. HIV infection is associated with an increased risk of HPV-associated vulvar cancer. We evaluated treatment patterns and survival outcomes in a cohort of vulvar cancer patients in Botswana. The primary objective of this study was to determine overall survival and the impact of treatment modality, stage, and HIV status on overall survival. METHODS: Women with vulvar cancer who presented to oncology care in Botswana from January 2015 through August 2019 were prospectively enrolled in this observational cohort study. Demographics, clinical characteristics, treatment, and survival data were collected. Factors associated with survival including age, HIV status, stage, and treatment were evaluated. RESULTS: Our cohort included 120 women with vulvar cancer. Median age was 42 (IQR 38-47) years. The majority of patients were living with HIV (89%, n=107) that was well-controlled on antiretroviral treatment. Among women with HIV, 54.2% (n=58) were early stage (FIGO stage I/II). In those without HIV, 46.2% (n=6) were early stage (stage I/II). Of the 95 (79%) patients who received treatment, 20.8% (n=25) received surgery, 67.5% (n=81) received radiation therapy, and 24.2% (n=29) received chemotherapy, either alone or in combination. Median follow-up time of all patients was 24.7 (IQR 14.2-39.1) months and 2- year overall survival for all patients was 74%. Multivariate analysis demonstrated improved survival for those who received surgery (HR 0.26; 95% CI 0.08 to 0.86) and poor survival was associated with advanced stage (HR 2.56; 95% CI 1.30 to 5.02). Survival was not associated with HIV status. CONCLUSIONS: The majority of women with vulvar cancer in Botswana are young and living with HIV infection. Just under half of patients present with advanced stage, which was associated with worse survival. Improved survival was seen for those who received surgery.

A Residency Interview Training Program to Improve Medical Student Confidence in the Residency Interview.

Introduction: The Residency Match is becoming more competitive each year, and more than ever, medical students must prove themselves in the residency interview. Data from the 2018 National Residency Matching Program's Program Director Survey highlight the importance of the interview on Match performance. We developed a residency interview training program with the goal of preparing medical students for residency interviews, and we assessed the impact of the training on medical student confidence. Methods: Our residency interview training program includes (1) a short didactic session on the residency interview process, (2) an informational packet with commonly asked questions, (3) two 20-minute practice (mock) interviews, (4) 10 minutes of face-to-face feedback from interviewers, (5) a facilitated group debriefing, and (6) access to a participant's two videotaped interviews and a guided self-assessment. To evaluate the effectiveness of our program, we assessed student confidence with a pre- and postsurvey. Results: We have been running our residency interview training program since 2014. Over the last 5 years, 73 fourth-year medical students have participated. When polled after completing their first authentic residency interview, students felt they had more knowledge of the interview process, better preparation, and more confidence in their skills to interview successfully; they also believed that the program improved their interview performance. Discussion: Performance during the residency interview is the most important factor used by residency programs to rank applicants. Using our residency interview training program, medical students can improve their confidence prior to interviews.

Radical hysterectomy is not associated with a survival benefit for patients with stage II endometrial carcinoma.

OBJECTIVE: To evaluate the role of radical hysterectomy in the management of patients with stage II endometrial carcinoma. MATERIALS: Patients diagnosed between 2004 and 2015, with stage II (based on the revised FIGO staging) endometrial carcinoma who had hysterectomy and regional lymph node surgery were identified in the National Cancer Database. Those who had radical or modified radical (RH), or total hysterectomy (TH) were selected. Overall survival (OS) was assessed with Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to evaluate survival after controlling for confounders. RESULTS: A total of 7552 patients who met the inclusion criteria were identified. Rate of RH was 10.5%. Those who underwent RH had longer hospital stay (median 3 vs 2 days, p < 0.001) and a higher 90-day (1.6% vs 0.8%, p = 0.05) mortality. There was no difference in OS between patients who had RH (n = 712) and SH (n = 5955) (p = 0.62); 5-year survival rates were 77.4% and 76.9%, respectively. After controlling for patient age (<65, ≥65 years), race (white, black, other/unknown), insurance status, presence of comorbidities, tumor size (<5, ≥5 cm, unknown), histology (endometrioid, non-endometrioid), performance of adequate lymphadenectomy, and receipt of adjuvant chemotherapy and radiation therapy, performance of radical hysterectomy was not associated with better survival (HR: 1.01, 95% CI: 0.85, 1.21). CONCLUSIONS: Radical hysterectomy was not associated with a survival benefit in a cohort of patients with stage II endometrial carcinoma.

A NOVEL SEARCH BUILDER TO EXPEDITE SEARCH STRATEGIES FOR SYSTEMATIC REVIEWS.

OBJECTIVES: Developing a search strategy for use in a systematic review is a time-consuming process requiring construction of detailed search strings using complicated syntax, followed by iterative fine-tuning and trial-and-error testing of these strings in online biomedical search engines. METHODS: Building upon limitations of existing online-only search builders, a user-friendly computer-based tool was created to expedite search strategy development as part of production of a systematic review. RESULTS: Search Builder 1.0 is a Microsoft Excel®-based tool that automatically assembles search strategy text strings for PubMed (www.pubmed.com) and Embase (www.embase.com), based on a list of user-defined search terms and preferences. With the click of a button, Search Builder 1.0 automatically populates the syntax needed for functional search strings, and copies the string to the clipboard for pasting into Pubmed or Embase. The offline file-based interface of Search Builder 1.0 also allows for searches to be easily shared and saved for future reference. CONCLUSIONS: This novel, user-friendly tool can save considerable time and streamline a cumbersome step in the systematic review process.

Preemptive ultrasound-guided paravertebral block and immediate postoperative lung function.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the effects of preemptive ultrasound-guided thoracic paravertebral block versus intercostal block on postoperative respiratory function and pain control in patients undergoing video-assisted thoracoscopic surgery. SUBJECTS: 50 consecutive patients undergoing video-assisted thoracoscopic surgery. METHOD: A prospective cohort of patients who received either ultrasound-guided thoracic paravertebral block immediately before the procedure or intercostal block placed by the surgeon at the end of the procedure were studied. Pulmonary function was assessed before surgery and 4 h postoperatively. Pain was assessed with the visual analog scale at 2 and 4 h after surgery both at rest and on coughing. RESULTS: 30 patients on the paravertebral block group and 20 on the intercostal block group were studied. Forced vital capacity (p < 0.001), forced expiratory volume at 1 s (p < 0.001) and forced expiratory flow 25-75% (p = 0.001) were significantly higher at 4 h with paravertebral block compared to the intercostal block group. The visual analog score for pain was significantly improved with paravertebral block at rest (p < 0.05) and with cough (p = 0.00). Perioperative narcotic use was significantly reduced with paravertebral block in comparison to intercostal block (p = 0.04). CONCLUSIONS: When compared to intercostal blocks, ultrasound-guided thoracic paravertebral block appears to preserve lung function and provide better pain control in the immediate postoperative period after video-assisted thoracoscopic surgery.

A breast cancer cell microarray (CMA) as a rapid method to characterize candidate biomarkers.

Tissue microarrays (TMAs) have become an invaluable tool in cancer research to evaluate expression and subcellular localization of proteins in cells and tissues. As the catalogs of candidate biomarkers and therapeutic targets become more extensive, there is a need to characterize and validate these targets and biomarkers in cell lines as a primary biological system in research laboratories. Thus, cell microarrays (CMAs) are useful as a high-throughput screening tool. Here, we constructed a CMA containing 32 publicly available immortalized breast cell lines with the goal of creating a method to rapidly screen for antigens of interest in breast cancer research in a relatively easy, rapid and cost-effective manner. As proof of concept, we performed immunocytochemical staining of the HER2 receptor, as the status of this protein is relevant to breast cancer and has previously been reported for these cell lines. We observed a complete concordance of our staining with the published status of HER2 in these cell lines. In addition, we examined the expression of CD44, epithelial markers EpCAM and E-cadherin and tyrosine phosphoproteins. The labeling of these proteins correlates with the known biology of the cell lines. Our results demonstrate the utility of our method to screen for potential biomarkers and therapeutic targets in breast cancer and we suggest that CMAs be used as a general approach in breast cancer research.

Oxidative stress and nerve function after cardiopulmonary bypass in patients with diabetes.

BACKGROUND: Chronic hyperglycemia has been associated with increased oxidative stress in skeletal muscle and sympathetic nerve dysfunction. We investigated the effect of chronic hyperglycemia on the myocardium of patients with uncontrolled diabetes (UD) compared with patients with well-controlled diabetes (CD) and patients without diabetes (ND) after cardioplegic cardiopulmonary bypass (CP/CPB) with acute intraoperative glycemic control. METHODS: Atrial tissue and serum were collected from 47 patients (ND=18 with glycated hemoglobin [HbA1c] of 5.8±0.2; CD=8 with HbA1c of 6.1±0.1; with UD=21 with HbA1c=9.6±0.5) before and after CP/CPB for immunoblotting, protein oxidation assays, immunohistochemical evaluation, and microarray analysis. RESULTS: The uncontrolled group had increased total protein oxidation (p<0.05) and decreased levels of antioxidative enzyme manganese superoxide dismutase (MnSOD) (p<0.05) after CP/CPB compared with the controlled group. Collagen staining revealed increased fibrosis in patients with UD (p<0.05) compared with patients with CD and patients without diabetes. The uncontrolled group also showed a decrease in the neurogenic and angiogenic markers nerve growth factor (NGF) (p<0.05), neurotrophin (NT)-3 (p<0.05), and platelet-derived growth factor (PDGF)-ß (p<0.05) compared with the other groups after CP/CPB. Atrial and serum microarray analysis showed increased oxidative stress and sympathetic nerve damage, increased fibrosis, and a decrease in angiogenesis in patients with UD (p<0.03) compared with patients without diabetes. CONCLUSIONS: CP/CPB led to higher oxidative stress in patients with UD before surgical intervention, even after normal glucose levels were maintained intraoperatively. Thus, controlled HbA1C in addition to acute intraoperative glucose control may be a more suitable end point for patients with diabetes undergoing cardiac operations.

Pancreatic Cancer Database: an integrative resource for pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer-related death in the world. The etiology of pancreatic cancer is heterogeneous with a wide range of alterations that have already been reported at the level of the genome, transcriptome, and proteome. The past decade has witnessed a large number of experimental studies using high-throughput technology platforms to identify genes whose expression at the transcript or protein levels is altered in pancreatic cancer. Based on expression studies, a number of molecules have also been proposed as potential biomarkers for diagnosis and prognosis of this deadly cancer. Currently, there are no repositories which provide an integrative view of multiple Omics data sets from published research on pancreatic cancer. Here, we describe the development of a web-based resource, Pancreatic Cancer Database (http://www.pancreaticcancerdatabase.org), as a unified platform for pancreatic cancer research. PCD contains manually curated information pertaining to quantitative alterations in miRNA, mRNA, and proteins obtained from small-scale as well as high-throughput studies of pancreatic cancer tissues and cell lines. We believe that PCD will serve as an integrative platform for scientific community involved in pancreatic cancer research.

Local infiltration of neuropeptide Y as a potential therapeutic agent against apoptosis and fibrosis in a swine model of hypercholesterolemia and chronic myocardial ischemia.

While the angiogenic effects of Neuropeptide Y (NPY) in myocardial ischemia and hypercholesterolemia have been studied, its effects on altering oxidative stress, fibrosis and cell death are not known. We hypothesized that local infiltration of NPY in a swine model of chronic myocardial ischemia and hypercholesterolemia will induce nerve growth and cell survival, while reducing oxidative stress and fibrosis. Yorkshire mini-swine (n=15) were fed a high cholesterol diet for 5 weeks. Three weeks after surgical induction of focal myocardial ischemia, an osmotic pump was implanted, which delivered NPY (n=8, high cholesterol treated, HCT) or the vehicle (n=7, high cholesterol control, HCC) for 5 weeks. Then myocardium was harvested for analysis. Assessment of myocardial function and perfusion was made the last intervention. Immunoblotting demonstrated significantly decreased levels of MMP-9 (p=0.001) and TGF-ß (p=0.05) and significantly increased levels of Ang-1 (p=0.002), MnSOD (p=0.006) and NGF (p=0.01) in HCT. Immunohistochemistry results revealed significantly decreased TUNEL staining (p=0.005) and GLUT4 translocation (p=0.004) in HCT. The functional data showed significantly improved blood flow reserve (p=0.02) and improved diastolic function -dP/dt (p=0.009) in the treated animals. Local infiltration of NPY results in positive remodeling in ischemic myocardium in the setting of hypercholesterolemia. By initiating angio and neurogenesis, NPY infiltration improves blood flow reserve and restoration of fatty acid metabolism. The associated increased cell survival and decreased fibrosis result in improved myocardial diastolic function. NPY may have a potential therapeutic role in patients with hypercholesterolemia associated coronary artery disease.

The effect of a quality improvement intervention on perceived sleep quality and cognition in a medical ICU.

OBJECTIVES: To determine if a quality improvement intervention improves sleep and delirium/cognition. DESIGN: Observational, pre-post design. SETTING: A tertiary academic hospital in the United States. PATIENTS: 300 medical ICU patients. INTERVENTIONS: This medical ICU-wide project involved a "usual care" baseline stage, followed by a quality improvement stage incorporating multifaceted sleep-promoting interventions implemented with the aid of daily reminder checklists for ICU staff. MEASUREMENTS AND MAIN RESULTS: Primary ICU outcomes were perceived sleep quality and noise ratings (measured on a 0-100 scale using the valid and reliable Richards-Campbell Sleep Questionnaire) and delirium/coma-free days. Secondary outcomes included ICU and hospital length of stay and mortality. Post-ICU measures of cognition and perceived sleep quality were evaluated in an ICU patient subset. During the baseline and sleep quality improvement stages, there were 122 and 178 patients, respectively, with more than one night in the ICU, accounting for 634 and 826 patient-days. Within the groups, 78 (63.9%) and 83 (46.6%) patients received mechanical ventilation. Over the 826 patient-day quality improvement period, checklist item completion rates ranged from 86% to 94%. In multivariable regression analysis of the quality improvement vs. baseline stages, improvements in overall Richards-Campbell Sleep Questionnaire sleep quality ratings did not reach statistical significance, but there were significant improvements in daily noise ratings (mean ± SD: 65.9±26.6 vs. 60.5±26.3, p = 0.001), incidence of delirium/coma (odds ratio: 0.46; 95% confidence interval, 0.23-0.89; p = 0.02), and daily delirium/coma-free status (odds ratio: 1.64; 95% confidence interval, 1.04-2.58; p = 0.03). Improvements in secondary ICU outcomes and post-ICU outcomes did not reach statistical significance. CONCLUSIONS: An ICU-wide quality improvement intervention to improve sleep and delirium is feasible and associated with significant improvements in perceived nighttime noise, incidence of delirium/coma, and daily delirium/coma-free status. Improvement in perceived sleep quality did not reach statistical significance.

Rapid characterization of candidate biomarkers for pancreatic cancer using cell microarrays (CMAs).

Tissue microarrays have become a valuable tool for high-throughput analysis using immunohistochemical labeling. However, the large majority of biochemical studies are carried out in cell lines to further characterize candidate biomarkers or therapeutic targets with subsequent studies in animals or using primary tissues. Thus, cell line-based microarrays could be a useful screening tool in some situations. Here, we constructed a cell microarray (CMA) containing a panel of 40 pancreatic cancer cell lines available from American Type Culture Collection in addition to those locally available at Johns Hopkins. As proof of principle, we performed immunocytochemical labeling of an epithelial cell adhesion molecule (Ep-CAM), a molecule generally expressed in the epithelium, on this pancreatic cancer CMA. In addition, selected molecules that have been previously shown to be differentially expressed in pancreatic cancer in the literature were validated. For example, we observed strong labeling of CA19-9 antigen, a prognostic and predictive marker for pancreatic cancer. We also carried out a bioinformatics analysis of a literature curated catalog of pancreatic cancer biomarkers developed previously by our group and identified two candidate biomarkers, HLA class I and transmembrane protease, serine 4 (TMPRSS4), and examined their expression in the cell lines represented on the pancreatic cancer CMAs. Our results demonstrate the utility of CMAs as a useful resource for rapid screening of molecules of interest and suggest that CMAs can become a universal standard platform in cancer research.