Citations

Abstract Background: Pharmacogenomic studies on antidepressant treatment outcomes could be conducted using previously collected data from electronic health record (EHR)-linked biobanks. However, absence of EHR based outcome measures is an unmet need in designing such studies We aimed to define EHR-derived antidepressant outcome measures and explore their utility in showing associations between treatment outcomes and Cytochrome P450 (CYP) metabolizer phenotypes in a proof-of-concept study. Methods: Using data from the EHR-linked cohort, Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment (RIGHT 10K) Study, we collected prescription data and patient health questionnaire 9 (PHQ-9) scores to compute 3 proxy measures for antidepressant response, efficacy, and acceptability: change in PHQ-9 scores, longest treatment interval with a single antidepressant, and antidepressant non-refill. Subsequently, we tested the association of both prescription-based outcomes with DNA-predicted CYP metabolizer phenotypes in European-ancestry participants. Results: We identified 3920 RIGHT 10K participants with at least 1 antidepressant prescription and European-ancestry. Participants had a mean age of 61 years and 72% were women. Implementation of the PHQ-9 outcome was not feasible because of missingness. Of both prescription-based outcomes, antidepressant non-refill reproduced several known antidepressant-CYP interactions. However, the pilot was limited by small subgroups of participants with non-normal metabolizer phenotypes. Conclusions: Derived from structured data, antidepressant non-refill is a promising outcome measure for EHR-linked biobanks that partially reproduced antidepressant-CYP interactions. However, testing on larger datasets is necessary to understand whether it would be a useful for pharmacogenomic research.

ABSTRACTBackground and ObjectiveThe diagnosis of interstitial lung diseases (ILDs) often relies on the integration of various clinical, radiological, and histopathological data. Achieving high diagnostic accuracy in ILDs, particularly for distinguishing usual interstitial pneumonia (UIP), is challenging and requires a multidisciplinary approach. Therefore, this study aimed to develop a multimodal artificial intelligence (AI) algorithm that combines computed tomography (CT) and histopathological images to improve the accuracy and consistency of UIP diagnosis.MethodsA dataset of CT and pathological images from 324 patients with ILD between 2009 and 2021 was collected. The CT component of the model was trained to identify 28 different radiological features. The pathological counterpart was developed in our previous study. A total of 114 samples were selected and used for testing the multimodal AI model. The performance of the multimodal AI was assessed through comparisons with expert pathologists and general pathologists.ResultsThe developed multimodal AI demonstrated a substantial improvement in distinguishing UIP from non‐UIP, achieving an AUC of 0.92. When applied by general pathologists, the diagnostic agreement rate improved significantly, with a post‐model κ score of 0.737 compared to 0.273 pre‐model integration. Additionally, the diagnostic consensus rate with expert pulmonary pathologists increased from κ scores of 0.278–0.53 to 0.474–0.602 post‐model integration. The model also increased diagnostic confidence among general pathologists.ConclusionCombining CT and histopathological images, the multimodal AI algorithm enhances pathologists' diagnostic accuracy, consistency, and confidence in identifying UIP, even in cases where specialised expertise is limited. image

PURPOSE Predictive biomarkers to better tailor therapy for patients with early-stage human epidermal growth factor 2 (HER2)-positive breast cancer are a priority. We hypothesized that HER2 and immune-based biomarkers would be predictive of pathologic complete response (pCR) to preoperative trastuzumab/pertuzumab (HP). MATERIALS AND METHODS Patients with stage II/III, estrogen receptor (ER)-negative, HER2-positive breast cancer received neoadjuvant HP in the TBCRC026 clinical trial. The pCR after receiving HP alone was 22% (18/83). Tumor biopsies were performed at baseline. Secondary correlative objectives were to determine the relationship between HER2-based biomarkers and immune processes with pCR. NanoString code sets BC360 and IO360 were used to compare differential gene expression in baseline tumors that underwent pCR versus no pCR. NanoString GeoMx digital spatial profiling was used to assess immune protein abundance in intraepithelial and stromal segments. Stromal tumor-infiltrating lymphocytes and Ki67 were evaluated by hematoxylin and eosin and immunohistochemistry, respectively. RESULTS Intraepithelial HER2 protein abundance was significantly associated with pCR ( P = .001). Low HER2 abundance tumors were primarily basal-like, and essentially all (19/20) failed to achieve pCR. High HER2 abundance tumors that achieved pCR (14/51) exhibited a high degree of immune cell activity, whereas high HER2 abundance tumors that failed to achieve pCR tumors (37/51) were enriched for M-phase processes and epidermal growth factor receptor signaling. Baseline Ki67 was significantly higher in nonresponders ( P = .04). CONCLUSION ER-negative, HER2-positive breast cancer has unique molecular and immunologic features that may predict pCR after neoadjuvant HP. Validation of these potential biomarkers and composite biomarker analyses may guide design of future clinical trials.

Abstract Heart transplantation (HT) is one of the prodigious achievements in modern medicine and remains the cornerstone in the treatment of patients with advanced heart failure. Advances in surgical techniques, immunosuppression, organ preservation, infection control, and allograft surveillance have improved short‐ and long‐term outcomes thereby contributing to greater clinical success of HT. However, prolonged allograft and patient survival following HT are still largely restricted by the development of late complications, including allograft rejection, infection, cardiac allograft vasculopathy (CAV), and malignancy. The introduction of mTOR inhibitors early after HT has demonstrated multiple protective effects against CAV progression, renal dysfunction, and tumorigenesis. Therefore, several HT programs increasingly use mTOR inhibitors with partial or complete withdrawal of calcineurin inhibitor (CNI) in stable HT patients to reduce complications risk and improve long‐term outcomes. Furthermore, despite a substantial improvement in exercise capacity and health‐related quality of life after HT as compared to advanced heart failure patients, most HT recipients remain with a 30% to 50% lower peak oxygen consumption (Vo 2 ) than that of age‐matched healthy subjects. Several factors, including alterations in central hemodynamics, HT‐related complications and alterations in the musculoskeletal system, and peripheral physiological abnormalities, presumably contribute to the reduced exercise capacity following HT. Cardiac denervation and subsequent loss of sympathetic and parasympathetic regulation are responsible for various physiological alterations in the cardiovascular system, which contributes to restricted exercise tolerance. Restoration of cardiac innervation may improve exercise capacity and quality of life, but the reinnervation process is only partial even several years after HT. Multiple studies have shown that aerobic and strengthening exercise interventions improve exercise capacity by increasing maximal heart rate, chronotropic response, and peak Vo 2 after HT. Novel exercise modalities, such as high‐intensity interval training (HIT), have been proven as safe and effective for further improvement in exercise capacity, including among de novo HT recipients. Further developments have recently emerged, including donor heart preservation techniques, noninvasive CAV and rejection surveillance methods, and improvements in immunosuppressive therapies, all aiming at increasing donor availability and improving late survival after HT. © 2023 American Physiological Society. Compr Physiol 13:4719‐4765, 2023.

Purpose: This study aimed to compare long-term patient-reported outcomes in bowel and urinary domains between intensity-modulated radiotherapy (IMRT) and intensity-modulated proton therapy (IMPT) for localized prostate cancer. Methods and Materials: Patients with clinical T1–T2 prostate cancer receiving IMRT or IMPT at a tertiary cancer center from 2015–2018 were analyzed to determine the changes in the prospectively collected bowel function (BF), urinary irritative/obstructive symptoms (UO), and urinary incontinence (UI) domains of EPIC-26. The mean changes in EPIC-26 scores were evaluated from pretreatment to 24 months post-radiotherapy for each modality. A score change >50% of the baseline standard deviation was considered a clinically meaningful change. Results: A total of 82 patients treated with IMRT (52.2%) and 56 patients treated with IMPT (53.3%) completed the questionnaire at baseline and 24 months post-RT. There were no baseline differences in domain scores between treatment modalities. At 24 months post-radiotherapy, there was a significant and clinically meaningful decline in the BF mean score in the IMRT cohort (−4.52 (range −50, 29.17), p = 0.003), whereas the decline in BF score did not reach clinical relevance or significance (−1.88 (range −37.5, 50), p = 0.046) when accounting for the Bonferroni adjustment in the IMPT cohort. A higher proportion of patients treated with IMRT had a clinically relevant reduction in BF when compared with IMPT (47.37% vs. 25.93%, p = 0.017). The mean changes in the UI and UO scores of the IMRT and IMPT cohorts were neither statically significant nor clinically relevant. Conclusions: IMPT leads to a smaller decrease in BF than IMRT at 24 months post-RT, while there was no differential effect on UO and UI.

Purpose The time to complete oncology pharmacist tasks is needed to determine workload and productivity. The Hematology/Oncology Pharmacy Association (HOPA) and the Hematology/Oncology Practice and Research Network (PRN) of the American College of Clinical Pharmacy (ACCP) partnered with the aim of establishing consensus on the time required to complete oncology pharmacy tasks. Methods Fifteen patient care tasks and 9 non-patient care tasks, commonly completed by oncology pharmacists were each assigned an average amount of time to be completed. This list was then converted into 24 statements and the Delphi survey method was utilized with an expert panel to arrive at consensus between December 2023 and February 2024. Consensus was defined as at least 75% agreement. The complete manuscript was endorsed by HOPA and ACCP Hematology/Oncology PRN. Results Thirty-three pharmacist-experts agreed to participate in this survey with all participating in round 1, and 29 (87.9%) participating in round 2. In round 1, 9 tasks achieved consensus, with 7 of these being classified as patient care associated. Seven statements reaching 65% but less than 75% agreement were deemed to reach borderline consensus. Eight statements failed to achieve at least 65% agreement and were modified based on respondent feedback. In round 2, 15 statements were included with all achieving consensus. At the completion of round 2, all 24 statements reached consensus, and the survey was deemed complete. Conclusion This project produced the first comprehensive consensus statements for the average time for a US-based oncology pharmacist to complete common patient and non-patient care-related tasks.

Spatial heterogeneity of liver viscoelasticity, measured at three-dimensional vector MR elastography, positively correlated with metabolic dysfunction–associated steatotic liver disease progression.