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Alnuctamab, a bivalent B-cell maturation antigen-targeting T cell engager for patients with relapsed or refractory multiple myeloma: results from a phase 1, first-in-human study.
No full textB-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers
Executive Summary of the American Radium Society (ARS) Appropriate Use Criteria (AUC) for Management of Locally Advanced Endometrial Cancer.
No full textPURPOSE: Locally advanced endometrial cancers are heterogeneous and challenging to treat. Immunotherapy has transformed the treatment landscape. Given the complexity of tailoring adjuvant treatment recommendations, the multidisciplinary American Radium Society Gynecologic Cancer Panel created evidence-based guidelines for the management of locally advanced endometrial adenocarcinoma.
METHODS AND MATERIALS: Search terms, key questions, and associated clinical case variants were formed by panel consensus. A review of the literature was conducted from January 1, 1996, to March 5, 2024, using the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines to systematically search the PubMed, Embase, and Web of Science databases to retrieve a comprehensive set of relevant articles. A well-established methodology (modified Delphi) was used by the expert panel to rate the appropriate use of procedures.
RESULTS: Evidence for key questions in advanced-stage endometrial cancer was examined. Two rounds of voting were completed pertaining to the appropriateness of key management decisions for 4 clinical variants. Optimal adjuvant treatment is based on pathologic and molecular risk factors, and typically consists of combined modality therapy, with both chemotherapy and radiation, to minimize the risk of local and distant recurrence; there are no prospective data on optimal sequencing. Molecular data from PORTEC-3 highlights that adding chemotherapy to radiation is especially crucial for p53 abnormal tumors. Inclusion criteria for the NRG-GY018/RUBY trials can guide appropriateness of incorporating immunotherapy, which should be considered especially in mismatch repair-deficient (dMMR) patients. Radiation fields should be extended to include para-aortic lymph nodes in IIIC2 disease. Within pelvic radiation, intensity modulated radiation therapy is the preferred technique to mitigate toxicity as supported by prospective data.
CONCLUSION: Selecting appropriate adjuvant therapies for advanced-stage endometrial cancer is nuanced. Further prospective studies harnessing molecular markers as therapeutic targets will help advance and optimize therapies for more personalized treatment of this complex disease
Ethics Roundtable: Prescribing Controlled Substances in a Terminally Ill Patient With Suspected Substance Abuse Disorder and Opioid Agreement Violations.
No full text
Hypertensive Disorders of Pregnancy: Clinical Features and Characteristics Associated with Postpartum Readmissions
No full textA pilot trial of long-distance shipped, extended- and cold-stored platelets in 100% plasma for cardiothoracic surgical bleeding.
No full textBACKGROUND: In this pilot trial, we tested the feasibility of conducting a randomized controlled trial in cardiac surgery patients using extended-, 100% plasma-, cold-stored, and long-distance-shipped platelets (CSPs).
STUDY DESIGN AND METHODS: We conducted a single center, controlled, double-blind pilot study in adult patients undergoing elective redo or complex cardiothoracic surgery. Patients were allocated in a week-based block randomization scheme to receive either room temperature-stored platelets (RTPs) or CSPs shipped from a Texas-based blood center and stored between 10 and 14 days. The primary outcome was defined as the feasibility of recruitment and accrual. Several other secondary endpoints were assessed. All platelet units were screened for aggregates using RTP release criteria.
RESULTS: In a post-hoc as treated analysis, 15 patients received RTPs, and 9 received CSPs (including 3 who received both). We found that most CSPs (58%) were not usable for transfusion due to the presence of aggregates. This resulted in an excess of subjects receiving RTPs; consequently, the final nine transfused participants were allocated to receive CSPs without randomization. We accrued 0.7 evaluable subjects/month of active enrollment, which was below our desired primary outcome feasibility target of ≥1.2. One death within 28 days occurred in the RTP transfusion group, while none occurred in the CSPs group. In vitro testing yielded contradictory results.
CONCLUSION: Due to slow recruitment and the abundance of aggregates in CSPs, this pilot trial does not support the feasibility of the study protocol
Pregnancy and breastfeeding are associated with less later-life cognitive decline in a longitudinal, prospective cohort.
No full textIntroduction: The brains of female mammals evolved to undergo structural and functional changes during pregnancy and lactation, equipping them for motherhood. However, long-term cognitive health implications of these adaptations in women are poorly understood.
Methods: In the Women\u27s Health Initiative (WHI) Memory Study (WHIMS; n = 7427) and WHI Study of Cognitive Aging (WHISCA; n = 2304), postmenopausal women completed reproductive history interviews, annual global cognitive assessment from mean age 70 for up to 13 years, and multi-domain cognitive testing for up to 8 years.
Results: Each additional month pregnant was associated with higher scores of global cognition. Each additional month of breastfeeding corresponded to higher scores of global cognition, verbal memory, and visual memory. We observed equivalent results for binary formulations of gravidity and breastfeeding.
Discussion: Low rates of fertility and breastfeeding may have implications for postmenopausal cognitive health at the population level. Next steps include examining mechanisms linking women\u27s reproductive history with postmenopausal cognitive health.
Highlights: Motherhood may leave an enduring mark on women\u27s brains, shaping cognitive health. Over 7000 women were assessed annually from approximately age 70 for up to 13 years. Ever being pregnant and cumulative time pregnant were linked with better cognition. Ever having breastfed and more time breastfeeding were linked with better cognition. These results imply that declining fertility may affect cognitive aging in future generations