OncoMed (United States)

Abstract Background: In the KEYNOTE-522 study (NCT03036488), neoadjuvant pembrolizumab (pembro) plus chemotherapy (chemo) followed by adjuvant pembro plus chemo significantly improved pathological complete response (pCR), event-free survival, and OS compared with placebo (pbo) plus chemo in participants (pts) with early-stage TNBC. Following neoadjuvant therapy, the estimated treatment difference in pCR for pembro plus chemo vs pbo plus chemo was 13.6% (95% CI, 5.4%‒21.8%; P < 0.001) at the first interim analysis (N=602). Although pCR provides a definitive indicator of neoadjuvant treatment success, other measures, such as RECIST v1.1 and functional tumor volume (FTV), may offer an earlier signal of therapeutic activity. This prespecified exploratory analysis evaluated associations of pCR with ORR at different time points per MRI by RECIST v1.1 and FTV by blinded independent central review. Methods: Pts with previously untreated TNBC (stage T1c N1-N2 or T2-T4 N0-N2) were randomized 2:1 to neoadjuvant pembro 200 mg Q3W or pbo, each with 4 cycles of paclitaxel plus carboplatin (treatment 1) then with 4 cycles of doxorubicin or epirubicin plus cyclophosphamide (treatment 2). After definitive surgery, pts received adjuvant pembro or pbo for 9 cycles or until recurrence/unacceptable toxicity. Breast MRI was performed for consenting pts at screening and after neoadjuvant treatments 1 and 2. Responders were defined as pts who achieved CR or PR per RECIST v1.1 by blinded independent central radiology review. The subgroup analyses population included the randomized pts who signed MRI consent and had baseline values by central radiology review. Results: At data cutoff (March 23, 2021), MRI subgroup analyses included 162 pts (pembro plus chemo, n = 97; pbo plus chemo, n = 65). After treatment 1, ORR per RECIST v1.1 was 91.8% for pembro plus chemo vs 84.6% for pbo plus chemo, while ORR per MRI FTV was 96.9% vs 93.8%. After treatment 2, ORR per RECIST v1.1 was 82.5% vs 90.8%, and ORR per MRI FTV was 84.5% vs 92.3% for pembro plus chemo and pbo plus chemo, respectively. In the post hoc exploratory analyses for pCR in the MRI subgroup, pCR rate (ypT0/Tis ypN0; 95% CI) was 62.9% (52.5%-72.5%) with pembro plus chemo vs 52.3% (39.5%-64.9%) with pbo plus chemo. Odds ratios (OR) for achieving pCR among pts with ORR per RECIST v1.1 or FTV across all patients (pembro plus chemo and pbo plus chemo combined) are shown in the Table. Conclusions: Across all pts (ie, for pembro plus chemo and pbo plus chemo combined), the odds of achieving pCR were higher among pts who had an objective response per either RECIST v1.1 or FTV. Citation Format: J. Cortés, R. Dent, H. McArthur, L. Pusztai, S. Kümmel, C. Denkert, J. O’Shaughnessy, P. A. Fasching, M. Untch, R. Tarnawaski, M. Mouret-Reynier, S. M. Stemmer, T. Foukakis, J. Boileau, C. Chung, M. Fernandez, J. A. Mejia, F. Beca, S. Hou, P. Schmid. Phase 3 study of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab for early-stage TNBC: KEYNOTE-522 magnetic resonance imaging (MRI) subgroup analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-07-24.

This study investigated the prevalence of implicit racial associations among academic physiatrists and trainees. We administered the Harvard Implicit Association Test on race (Black/White) to 71 participants from a national academic physiatry association. The survey gathered demographic data (age, gender, ethnicity, race, professional role, and years of experience) and Harvard Implicit Association Test results, where participants reported a preference for Black race, White race, or no race preference. The majority of respondents (54.5%) displayed a preference for White race, with regression analysis revealing that participant race was the only significant predictor of this bias ( P = 0.03), No associations were found between age, gender, ethnicity, or trainee status and the Harvard Implicit Association Test results. The results indicated a significant pattern of implicit bias favoring White race among academic physiatrists and trainees, consistent with findings in other medical fields. The study emphases the need for ongoing efforts to be aware of and manage implicit biases in the field of physician medicine and rehabilitation, aiming to enhance patient outcomes and reduce healthcare disparities.

Neurodegenerative diseases of both the central and peripheral nervous system are characterized by selective neuronal vulnerability, i.e., pathology that affects particular types of neurons. While much of this cell type selectivity may be driven by intrinsic differences among the neuron subpopulations, neuron-extrinsic mechanisms such as the selective malfunction of glial support cells may also play a role. Recently, we identified a population of Schwann cells (SCs) expressing Adamtsl1, Cldn14, and Pmp2 (a.k.a. PMP2+ SCs) that preferentially myelinate large-caliber motor axons. PMP2+ SCs are decreased in both amyotrophic lateral sclerosis (ALS) model mice and ALS patient nerves. Thus, PMP2+ SC dysfunction could contribute to motor-selective neuropathies. We engineered a tamoxifen-inducible Pmp2-CreERT2 mouse and expressed diphtheria toxin in PMP2+ SCs to assess the consequences of ablating this SC subtype in male and female mice. Loss of PMP2+ SCs led to significant loss of large-caliber motor axons with concomitant behavioral, electrophysiological, and ultrastructural defects. Subsequent withdrawal of tamoxifen restored both PMP2+ SCs and large-caliber motor axons and improved behavioral and electrophysiological readouts. Together, our findings highlight that the survival of large-caliber motor axons relies on PMP2+ SCs, demonstrating that malfunction of a specific SC subtype can lead to selective neuronal vulnerability.

Abstract Background Approximately 5–10% of breast cancer (BC) is caused by germline mutations in BC susceptibility genes. Genetic testing is mainly performed through multigene panels, which identify variants characterized as benign, pathogenic (PVs) or of uncertain significance (VUSs). In Greece, genetic testing is reimbursed in specific patient groups. Methods This observational, retrospective, cohort study included patients diagnosed with early BC and aimed to assess the distribution and prevalence of germline mutations in patients with early BC in North Greece, the differences in characteristics between tested and not-tested individuals and the impact of PVs on the disease-free survival (DFS). Results Out of 2245 participating patients, 797 (35.5%) underwent genetic testing, of which 565 (70.9%) were entitled to reimbursement. Mean age at diagnosis of the tested patients was 45.9 ± 10.2 years versus 57.4 ± 12.2 years of those not-tested (p < 0.001). A total of 166 patients (20.8% of tested individuals, 7.4% of the total cohort) harbored PVs and 302 (37.9%) harbored VUSs. The 44.6% of the identified mutations were located in BRCA1/2 genes, followed by mutations in CHEK2 (13.9%) and ATM (7.8%). PV-carriers had a statistically significant lower DFS (HR, 1.66; 95% CI, 1.17 to 2.36; p = 0.005). Conclusions In this real-world study, 1/3 of patients with early BC in North Greece were genetically tested, of which roughly 70% had at least one indication for reimbursement. PVs were detected in 7.4% of the participants with more frequent findings in BRCA1/2 genes. PV-carriers presented a statistically significant worse DFS.

O presente estudo tem como objetivo analisar a epidemiologia das internações por insuficiência cardíaca (IC), no Brasil, nos últimos cinco anos. O estudo foi realizado através de um levantamento epidemiológico descritivo, quantitativo e retrospectivo das internações por IC no Brasil no período de 2019 a 2023. No Brasil foram registradas 941.576 internações por insuficiência cardíaca ocorridos entre 2019 e 2023. Dentre as Regiões, a Região do Sudeste apresentou os maiores índices de incidência, a maior taxa de mortalidade e maior letalidade. Dessa forma, notou-se que homens entre 70 e 79 anos e da etnia parda constituem o perfil mais acometido pela insuficiência cardíaca.

Abstract Introduction: Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease characterized by a highly diverse genomic landscape. Despite recent advances in therapies, treatment outcome remains variable and largely defined by genomic abnormalities such as gene fusions, copy number alterations and point mutations. Mutations in epigenic modifiers, nucleophosmin (NPM1c), signaling and kinase pathway such as KMT2A-re-arrangements (KMT2A-r), internal tandem duplication (ITD) insertions in FLT3, and NRAS mutations are amongst the highest alterations in AML patients with a propensity towards poor response to treatment and overall disease outcome. Such limitations impact the ability to achieve long-lasting response to treatment and result in therapy-induced resistance eventually leading to relapse. Combinatorial strategies are required to combat resistance and maximize duration of antitumor activity. BCL2 and MEK blockade in combination with menin and/or FLT3 inhibitors potentiates an improved therapeutic strategy to achieve increased antitumor activity and overcome AML resistance. Here we explored the use of our clinical-stage covalent menin inhibitor, BMF-219, and BMF-500, a covalent FLT3 inhibitor, in combination with each other and in combination with BCL2 and MEK inhibitors in MV-4-11 and MOLM-13 cell lines for 4-days, then viability was measured using CellTiter Glo. Results: BMF-219 and BMF-500 as single agents induce effective antitumor activity on MOLM-13 and MV-4-11 cells lines. When dosed in combination, BMF-219 and BMF-500 show beneficial effects affording higher cell killing at lower concentrations. Repeated experiments revealed patterns of increased cell killing is achieved when trametinib, MEK inhibitor, and venetoclax, BCL2 inhibitor, are combined with BMF-219 treatment. Conclusions: Collectively, our studies demonstrate the utility of combination strategies to achieve higher antileukemic cell killing with reduced concentrations of menin and FLT3 covalent inhibitors. Additionally, we show benefit of combinatorial approaches of menin and FLT3 covalent inhibitors with MEK and BCL2 blockade. These data provide initial pre-clinical evidence for combining pathway specific inhibitors as a promising therapeutic strategy for further investigation in acute leukemia. Citation Format: Brian Law. Combinatorial approach using covalent menin inhibitor, BMF-219, and/or covalent FLT3 inhibitor, BMF-500, with MEK or BCL2 blockade potentiates therapeutic use in AML. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4939.