Evaluation of an Internal Medicine Transition to Residency Course.

OBJECTIVES: We sought to evaluate the effectiveness of a novel Internal Medicine (IM) transition to residency (TTR) curriculum. METHODS: We performed a paired pre-/postsurvey evaluation of graduating fourth-year medical students' perceived preparedness and medical knowledge after participating in a recently developed IM TTR course. RESULTS: The response rate was 51% (24 of 47). There was a significant improvement in 15 of 17 perceived preparedness items and significant improvement in the medical students' performance on the 8-question medical knowledge test. CONCLUSIONS: The IM TTR curriculum improved medical students' medical knowledge and perceived preparedness for internship on a variety of high-yield clinical topics. The curriculum may be appealing to other institutions that are developing or revamping TTR courses.

Medicare and Medicaid insurance status is associated with increased allogeneic red blood cell transfusion in cardiac surgery patients: 2007-2018.

BACKGROUND AND AIM: Allogeneic red blood cell (RBC) transfusion and health insurance status are independently associated with perioperative morbidity. The aim of this study was to evaluate the effect of insurance status on allogeneic and autologous transfusion risk in cardiac surgery patients. METHODS: We conducted a retrospective observational study of data spanning 2007-2018 from six states from the State Inpatient Databases. Patients were cohorted by medical insurance type. Rates and risk-adjusted odds ratios (aOR) were calculated for allogenic and autologous RBC transfusions. Interactions between insurance and race/ethnicity were assessed. RESULTS: A total of 710,296 cardiac surgery patients were included. Allogeneic infusions occurred in 34.7% of Medicare patients, 31.9% of Medicaid patients, 24.7% of privately insured patients, and 26.1% of uninsured patients. Autologous rates were 2.3%, 2.5%, 3.4%, and 2.6% for Medicare, Medicaid, privately insured, and uninsured patients, respectively. Medicare and Medicaid patients were more likely to receive allogeneic RBC than privately insured patients (Medicare: aOR: 1.42, 99% confidence interval [CI]: 1.40-1.44, p < .001, Medicaid: aOR: 1.18, 99% CI: 1.14-1.21, p < .001). Nonwhite Medicare patients showed higher odds of allogeneic transfusion compared with White patients with private insurance (Black Medicare: aOR 1.74, 99% CI: 1.65-1.83, p < .001, Hispanic Medicare: aOR 1.92, 99% CI: 1.84-2.00, p < .001). CONCLUSION: Cardiac surgery patients with Medicare and Medicaid insurance demonstrate increased risk of allogeneic RBC transfusion; nonwhite patient groups are particularly vulnerable. Further research is needed to understand the causes and implications of these disparities, and to help ensure equitable care across patient groups.

Racial Differences in Postpartum Blood Pressure Trajectories Among Women After a Hypertensive Disorder of Pregnancy.

Importance: Maternal morbidity and mortality are increasing in the United States, most of which occur post partum, with significant racial disparities, particularly associated with hypertensive disorders of pregnancy. Blood pressure trajectory after a hypertensive disorder of pregnancy has not been previously described. Objectives: To describe the blood pressure trajectory in the first 6 weeks post partum after a hypertensive disorder of pregnancy and to evaluate whether blood pressure trajectories differ by self-reported race. Design, Setting, and Participants: This prospective cohort study included deliveries between January 1, 2018, and December 31, 2019. Women with a clinical diagnosis of a hypertensive disorder of pregnancy were enrolled in a postpartum remote blood pressure monitoring program at the time of delivery and were followed up for 6 weeks. Statistical analysis was performed from April 6 to 17, 2020. Main Outcomes and Measures: Mixed-effects regression models were used to display blood pressure trajectories in the first 6 weeks post partum. Results: A total of 1077 women were included (mean [SD] age, 30.2 [5.6] years; 804 of 1017 White [79.1%] and 213 of 1017 Black [20.9%]). Systolic and diastolic blood pressures were found to decrease rapidly in the first 3 weeks post partum, with subsequent stabilization (at 6 days post partum: mean [SD] peak systolic blood pressure, 146 [13] mm Hg; mean [SD] peak diastolic blood pressure, 95 [10] mm Hg; and at 3 weeks post partum: mean [SD] peak systolic blood pressure, 130 [12] mm Hg; mean [SD] peak diastolic blood pressure, 85 [9] mm Hg). A significant difference was seen in blood pressure trajectory by race, with both systolic and diastolic blood pressure decreasing more slowly among Black women compared with White women (mean [SD] peak systolic blood pressure at 1 week post partum: White women, 143 [14] mm Hg vs Black women, 146 [13] mm Hg; P = .01; mean [SD] peak diastolic blood pressure at 1 week post partum: White women, 92 [9] mm Hg vs Black women, 94 [9] mm Hg; P = .02; and mean [SD] peak systolic blood pressure at 3 weeks post partum: White women, 129 [11] mm Hg vs Black women, 136 [15] mm Hg; P < .001; mean [SD] peak diastolic blood pressure at 3 weeks post partum: White women, 84 [8] mm Hg vs Black women, 91 [13] mm Hg; P < .001). At the conclusion of the program, 126 of 185 Black women (68.1%) compared with 393 of 764 White women (51.4%) met the criteria for stage 1 or stage 2 hypertension (P < .001). Conclusions and Relevance: This study found that, in the postpartum period, blood pressure decreased rapidly in the first 3 weeks and subsequently stabilized. The study also found that, compared with White women, Black women had a less rapid decrease in blood pressure, resulting in higher blood pressure by the end of a 6-week program. Given the number of women with persistent hypertension at the conclusion of the program, these findings also appear to support the importance of ongoing postpartum care beyond the first 6 weeks after delivery.

Pre-existing antitherapeutic antibodies against the Fc region of the hu14.18K322A mAb are associated with outcome in patients with relapsed neuroblastoma.

PURPOSE: Patients with cancer receiving tumor-reactive humanized monoclonal antibody (mAb) therapy can develop a human antihuman antibody (HAHA) response against the therapeutic mAb. We evaluated for HAHA in patients with neuroblastoma treated in a phase I study of humanized anti-GD2 mAb (immunoglobulin (Ig)G1 isotype), hu14.18K322A (NCT00743496). The pretreatment sera (collected prior to mAb treatment) from 9 of 38 patients contained antitherapeutic antibodies, even though they had no prior mAb exposure. We sought to characterize these pre-existing antitherapeutic antibodies (PATA). EXPERIMENTAL DESIGN: The PATA+ pretreatment samples were characterized via ELISA; clinical associations with PATA status were evaluated. RESULTS: Pretreatment sera from eight of nine PATA+ patients also bound rituximab and demonstrated preferential ELISA reactivity against the Fc portions of hu14.18K322A and rituximab as compared with the Fab portions of these mAbs. These PATA+ sera also recognized dinutuximab (human IgG1 isotype) and mouse IgG2a isotype mAbs, but not a mouse IgG1 isotype or the fully human panitumumab (IgG2 isotype) mAb. Of the 38 treated patients, only 4 patients (all in the PATA+ cohort) demonstrated no disease progression for >2.5 years without receiving further therapy (p=0.002). CONCLUSIONS: This study demonstrates an association between clinical outcome and the presence of PATA against determinant(s) on the Fc component of the therapeutic mAb, suggesting that the PATA may be playing a role in augmenting mAb-based antitumor effects. Further analyses for the presence of PATA in a larger cohort of patients with relapsed neuroblastoma, analyses of their clinical correlates, identification of their immunological targets, and potential antitumor mechanisms are warranted.

Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC.

Head and neck squamous cell carcinomas (HNSCC) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials, and identification of predictive biomarkers remains challenging. To investigate mTORC-specific inhibition, we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors ± cetuximab in a panel of HNSCC cell lines and patient-derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single-agent mTORC inhibition inhibited growth of one PIK3CA-mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA-mutant model. In all models, the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. Although single-agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence, suggesting that approaches that attempt to match biomarkers to the optimal therapy in HNSCC remain complex and challenging. Mol Cancer Ther; 16(7); 1257-68. ©2017 AACR.

Radiosensitization of Adenoid Cystic Carcinoma with MDM2 Inhibition.

Purpose: Adenoid cystic carcinoma (ACC) is a rare cancer arising from the major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents or known radiosensitizers for ACC. Unlike the more common head and neck squamous cell carcinomas that frequently harbor TP53 mutations, ACCs contain TP53 mutations at a rate of <5%, rendering them an attractive target for MDM2 inhibition.Experimental Design: We report the successful establishment and detailed characterization of a TP53-WT ACC patient-derived xenograft (PDX), which retained the histologic features of the original patient tumor. We evaluated this model for response to the MDM2 inhibitor AMG 232 as monotherapy and in combination with radiotherapy.Results: AMG 232 monotherapy induced modest tumor growth inhibition, and radiation monotherapy induced a transient tumor growth delay in a dose-dependent fashion. Strikingly, combination treatment of AMG 232 with radiotherapy (including low-dose radiotherapy of 2 Gy/fraction) induced dramatic tumor response and high local tumor control rates 3 months following treatment. Posttreatment analysis revealed that although both AMG 232 and radiotherapy alone induced TP53 tumor-suppressive activities, combination therapy amplified this response with potent induction of apoptosis after combination treatment.Conclusions: These data identify that MDM2 inhibition can provide potent radiosensitization in TP53-WT ACC. In light of the absence of effective systemic agents for ACC, the powerful response profile observed here suggests that clinical trial evaluation of this drug/radiotherapy combination may be warranted to improve local control in this challenging malignancy. Clin Cancer Res; 23(20); 6044-53. ©2017 AACR.