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Purpose: Hippocampus-avoidance whole brain radiotherapy with simultaneous integrated boost (HA-WBRT+SIB) is a complex treatment option for patients with multiple brain metastases, aiming to prevent neurocognitive decline and simultaneously increase tumor control. Achieving efficient hippocampal dose reduction in this context can be challenging. The aim of the current study is to present and analyze the efficacy of complete directional hippocampal blocking in reducing the hippocampal dose during HA-WBRT+SIB. Methods: A total of 30 patients with multiple metastases having undergone HA-WBRT+SIB were identified. The prescribed dose was 30 Gy in 12 fractions to the whole brain, with 98% of the hippocampus receiving ≤ 9 Gy and 2% ≤ 17 Gy and with SIB to metastases/resection cavities of 36–51 Gy in 12 fractions. Alternative treatment plans were calculated using complete directional hippocampal blocking and compared to conventional plans regarding target coverage, homogeneity, conformity, dose to hippocampi and organs at risk. Results: All alternative plans reached prescription doses. Hippocampal blocking enabled more successful sparing of the hippocampus, with a mean dose of 8.79 ± 0.99 Gy compared to 10.07 ± 0.96 Gy in 12 fractions with the conventional method (p < 0.0001). The mean dose to the whole brain (excluding metastases and hippocampal avoidance region) was 30.52 ± 0.80 Gy with conventional planning and 30.28 ± 0.11 Gy with hippocampal blocking (p = 0.11). Target coverage, conformity and homogeneity indices for whole brain and metastases, as well as doses to organs at risk were similar between planning methods (p > 0.003). Conclusion: Complete directional hippocampal blocking is an efficient method for achieving improved hippocampal sparing during HA-WBRT+SIB. [ABSTRACT FROM AUTHOR]

Background: All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis. Objective: While dose-dependent anemia and thrombocytopenia limit the use of JAK2 inhibition, selectively targeting JAK1 has been explored as a means to suppress inflammation and STAT-associated pathologies related to neoplastogenesis. The objective of this study is to employ JAK1 inhibition (JAK1i) in the presence of ATRA as a potential therapy in non-M3 acute myeloid leukemia (AML). Methods: Efficacy of JAK1i using INCB52793 was assessed by changes in cell cycle and apoptosis in treated AML cell lines. Transcriptomic and proteomic analysis evaluated effects of JAK1i. Synergy between JAK1i+ ATRA was assessed in cell lines in vitro while efficacy in vivo was assessed by tumor reduction in MV-4-11 cell line-derived xenografts. Results: Here we describe novel synergistic activity between JAK1i inhibition and ATRA in non-M3 leukemia. Transcriptomic and proteomic analysis confirmed structural and functional changes related to maturation while in vivo combinatory studies revealed significant decreases in leukemic expansion. Conclusions: JAK1i+ ATRA lead to decreases in cell cycle followed by myeloid differentiation and cell death in human leukemias. These findings highlight potential uses of ATRA-based differentiation therapy of non-M3 human leukemia. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: We compared the operative and immediate postoperative experience of the trocar-based Prolift® and non-trocar-based Elevate® techniques used to repair vaginal prolapse. Methods: A retrospective review of Prolift and Elevate repairs was performed. Baseline characteristics and operative and postoperative variables evaluated included compartment(s) repaired, adjacent organ injury, operative time (OT), change in hemoglobin (ΔH), pain score, narcotic use, length of stay (LOS), and short-term complications. Categorical variables were assessed as counts and percent frequency. Data were compared using chi-squared analysis and paired t test. Results: Prolift ( n = 143) and Elevate ( n = 77) patients were similar in age ( p = 0.19). Concurrent hysterectomy was done in 22 (15.4 %) and 24 (31.2 %), respectively, and concurrent midurethral sling placed in 100 (70 %) and 50 (65 %), respectively. LOS (median, 25th,75th) after anterior/apical compartment repairs was shorter with Elevate, whether with (1.0; 1.0,1.5 vs. 2.0 days;1.0, 2.0; p = 0.003) or without (2.0; 1.0, 2.0 vs. 2.0 days; 2.0, 3.0; p = 0.024) hysterectomy, but no differences in OT, ΔH, pain score, or narcotic use occurred. Posterior compartment mean pain scores were lower with Prolift (3.6 ± 2.2 vs. 1.7 ± 1.5, p = 0.035), and three-compartment-repair pain scores were lower with Elevate (0.6 ± 1.3 vs 2.5 ± 1.9; p = 0.013). Three bladder injuries occurred with Prolift but none with Elevate. Conclusions: Operative and postoperative experiences were similar between groups; however, Elevate anterior/apical repairs had shorter LOS, which might reflect more aggressive discharge planning. There were no bowel or major vascular injuries, and the Prolift trocar bladder injuries did not alter the surgical procedure. [ABSTRACT FROM AUTHOR]

Context: Research suggests that pharmaceutical marketing influences prescribing and may cause cognitive dissonance for prescribers. This work has primarily been with physicians and physician-trainees. Questions remain regarding why prescribers continue to meet with pharmaceutical representatives (PRs).Objective: To describe the reasons that prescribers from various health professions continue to interact with PRs despite growing evidence of the influence of these interactions.Design, Setting, and Participants: Multi-disciplinary focus groups with 61 participants held in practice settings and at society meetings.Results: Most prescribers participating in our focus groups believe that overall PR interactions are beneficial to patient care and practice health. They either trust the information from PRs or feel that they are equipped to evaluate it independently. Despite acknowledgement of study findings to the contrary, prescribers state that they are able to effectively manage PR interactions such that their own prescribing is not adversely impacted. Prescribers describe few specific strategies or policies for these interactions, and report that policies are not consistently implemented with all members of a clinic or institution. Some prescribers perceive an inherent contradiction between academic centers and national societies receiving money from pharmaceutical companies, and then recommending restriction at the level of the individual prescriber. Prescribers with different training backgrounds present a few novel reasons for these meetings.Conclusions: Despite evidence that PR detailing influences prescribing, providers from several health professions continue to believe that PR interactions improve patient care, and that they can adequately evaluate and filter information presented to them by PRs. Focus group comments suggest that cultural change is necessary to break the norms that exist in many settings. Applying policies consistently, considering non-physician members of the healthcare team, working with trainees, restructuring the current primary care model and offering convenient, individualized, non-biased educational options may aid success. [ABSTRACT FROM AUTHOR]

Background: Recent changes in healthcare system and training mandates have altered the clinical learning environment. We incorporated reflective writing into Internal Medicine clerkships (IMcs) in multiple institutions so students could consider the impact of clerkship experiences on their personal and professional development. We analyzed student reflections to inform curricula and support learning.Methods: We qualitatively analyzed the reflections of students at 3 US medical schools during IMcs (N = 292) to identify themes, tone, and reflective quality using an iterative approach. Chi-square tests assessed differences between these factors and across institutions.Findings: Students openly described powerful experiences. Major themes focused on 4 categories: personal issues (PI), professional development (PD), relational issues (RI), and medical care (MC). Each major theme was represented at each institution, although with significant variability between institutions in many of the subcategories including student role (PI), development-as-a-physician (PD), professionalism (PD) (p < 0.001). Students used positive tones to describe student role, development-as-a-physician and physician-patient relationship (PD) (p < 0.01-0.001), and negative tones for quality and safety (MC) (p < 0.05). Only 4% of writings coded as professionalism had a positive tone. Students employed a "reporting" voice in writing about clinical problem-solving, healthcare systems, and quality/safety (MC).Discussion: Reflection is considered important to professional development. Our analysis suggests that students at 3 institutions reflect on similar experiences. Theme variability across institutions implies curricula should be tailored to local culture. Reflective quality analysis suggests students are better equipped to reflect on certain experiences over others, which may impact learning. Student reflections can function as a mirror for our organizations, offer institutional feedback for support and improvement, and inform curricula for learners and faculty. [ABSTRACT FROM AUTHOR]

BACKGROUND: Disclosure of medical errors is encouraged, but research on how patients respond to specific practices is limited. OBJECTIVE: This study sought to determine whether full disclosure, an existing positive physician-patient relationship, an offer to waive associated costs, and the severity of the clinical outcome influenced patients' responses to medical errors. PARTICIPANTS: Four hundred and seven health plan members participated in a randomized experiment in which they viewed video depictions of medical error and disclosure. DESIGN: Subjects were randomly assigned to experimental condition. Conditions varied in type of medication error, level of disclosure, reference to a prior positive physician-patient relationship, an offer to waive costs, and clinical outcome. MEASURES: Self-reported likelihood of changing physicians and of seeking legal advice: satisfaction, trust, and emotional response. RESULTS: Nondisclosure increased the likelihood of changing physicians, and reduced satisfaction and trust in both error conditions. Nondisclosure increased the likelihood of seeking legal advice and was associated with a more negative emotional response In the missed allergy error condition, but did not have a statistically significant impact on seeking legal advice or emotional response in the monitoring error condition. Neither the existence of a positive relationship nor an offer to waive costs had a statistically significant impact. CONCLUSIONS: This study provides evidence that full disclosure is likely to have a positive effect or no effect on how patients respond to medical errors. The clinical outcome also influences patients' responses. The impact of an existing positive physician-patient relationship, or of waiving costs associated with the error remains uncertain. [ABSTRACT FROM AUTHOR]

CONTEXT: Trainees are exposed to medical errors throughout medical school and residency. Little is known about what facilitates and limits learning from these experiences. OBJ'ECT/VE: To identify major factors and areas of tension in trainees' learning from medical errors. DESIGN, SETTING, AND PARTICIPANTS: Structured telephone interviews with 59 trainees (medical students and residents) from 1 academic medical center. Five authors reviewed transcripts of audiotaped interviews using content analysis. RESULTS: Trainees were aware that medical errors occur from early in medical school. Many had an intense emotional response to the idea of committing errors in patient care. Students and residents noted variation and conflict in institutional recommendations and individual actions. Many expressed role confusion regarding whether and how to initiate discussion after errors occurred. Some noted the conflict between reporting errors to seniors who were responsible for their evaluation. Learners requested more open discussion of actual errors and faculty disclosure. No students or residents felt that they learned better from near misses than from actual errors, and many believed that they learned the most when harm was caused. CONCLUSIONS: Trainees are aware of medical errors, but remaining tensions may limit learning, institutions can immediately address variability in faculty response and local culture by disseminating clear, accessible algorithms to guide behavior when errors occur. Educators should develop longitudinal curricula that integrate actual cases and faculty disclosure. Future multi-institutional work should focus on identified themes such as teaching and learning in emotionally charged situations, learning from errors and near misses and balance between individual and systems responsibility. [ABSTRACT FROM AUTHOR]

Human telomerase reverse transcriptase (hTERT) is the catalytic component of a functional telomerase complex, which is important in maintaining cell immortality. In most normal human adult cells, the expression of telomerase is very low and/or transient. In contrast, almost 90% of human tumors express a relatively high level of telomerase implying the possibility of using hTERT as a universal candidate tumor antigen. In this study, we show that human monocyte-derived dendritic cells (DCs) lack telomerase activity. Similar to other normal somatic cells, DCs express the RNA (hTR) component but not the catalytic component, hTERT. We also show that telomerase activity could be reconstituted using either lipid-mediated transfection of the hTERT plasmid DNA or transduction with an E1-, E3-deleted adenoviral vector containing the hTERT gene. However, relative to plasmid transfection, adenoviral gene transfer produced higher levels of hTERT expression. Nine of 10 Adh TERT-transduced DCs were able to generate CTL responses, while only three of nine plasmid-transfected DCs did. CTLs primed against hTERT exhibited killing of telomerase positive but not telomerase negative tumor lines of diverse tissue origins. Antigenic specificity of these T cells to telomerase was further determined by introducing hTERT gene into a telomerase negative cell line, U2OS, by adenoviral transduction. Although some antigenic specificity was directed against adenoviral epitopes, the majority of CTLs were targeted against telomerase-derived antigen(s). Thus, the hTERT gene, particularly as delivered via the recombinant adenovirus, may be useful as vaccine to induce specific T-cell-mediated tumor immunity in cancer patients. In addition, our results suggest that telomerase activity and/or telomerase expression after hTERT gene transfer have a predictive value in the success of hTERT/DC-based cancer vaccination. [ABSTRACT FROM AUTHOR]