Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies are desperately needed. We observe antiproliferative potency of genetic depletion of PTPN11 or pharmacological inhibition using the SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its antiproliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.

This mixed-methods study quantified and characterized incidents of microaggressions experienced by Asian American medical students. The authors report on their impact and suggest improvements to create a more equitable and supportive learning environment. Quantitative and qualitative data were collected from 305 participants who self-identified as Asian American or Pacific Islander. An online, anonymous survey was sent to US medical students through the Asian Pacific American Medical Student Association (APAMSA). Questions explored incidence, characteristics of, and response to microaggressions. We conducted four focus groups to further characterize students' experiences. Data were organized and coded, and thematic analysis was used to identify core themes. Racial microaggressions were prevalent among Asian American medical students. Nearly 70% (n = 213) of survey respondents reported experiencing at least one incident during their medical training to date. The most common perpetrators were patients (n = 151, 70.9%) and fellow medical students (n = 126, 59.2%), followed by professors (n = 90, 42.3%). The most prevalent themes included being perceived as a perpetual foreigner, the assumption of timidness, and ascription of the model minority myth. Students rarely reported the incident and usually did not respond immediately due to fear of retaliation, uncertainties about the experience or how to respond appropriately, and perception that they would bear the burden of advocacy alone. Experiences with microaggressions led to feelings of frustration and burnout and had a negative impact on mental health. Recommendations were made to improve the anonymous reporting systems in medical schools, and to increase diversity and inclusion in medical education and leadership. Asian American medical students face high exposure to racial microaggressions during their medical education that adversely impact their mental health. Changes are needed in medical training to create a more equitable and inclusive learning environment.

Purpose: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft-tissue sarcomas and the leading cause of mortality in individuals with neurofibromatosis type 1 (NF1). Despite many clinical trials, outcomes for patients with MPNST have remained stagnant, and most succumb to their disease; thus, novel therapeutic approaches are needed. A better understanding of the MPNST immune ecosystem will aid in the development of strategies to activate the immune system against the tumor. In this study, we profile the tumor immune microenvironment (TIME) in NF1-associated peripheral nerve sheath tumors (PNST) to discover insights on the role played by tumor-infiltrating immune cells in malignant transformation. Experimental Design: Using fresh and formalin-fixed paraffin-embedded tissue from patients diagnosed with NF1-PNST, we dissected the TIME through IHC, multiparameter flow cytometry, and comparative transcriptomic studies. Results: Immunophenotyping confirmed increased immune cell infiltration during malignant progression, with a predominance of infiltrating myeloid cells, particularly CD163+ tumor-associated macrophages (TAM). The T cells within MPNST exhibited signs of tumor activation, characterized by high programmed cell death 1 expression. Additionally, MPNST specimens demonstrated elevated levels of immunosuppressive TAM, with heightened PD-L1 expression. The proportion of CD163+ myeloid cells within the TIME correlated with poorer progression-free survival. Notably, loss of H3K27 trimethylation correlated with low immune cell infiltration in MPNST. Conclusions: Malignant transformation of NF1-PNST is characterized by an immunosuppressive microenvironment comprising TAM with high expression of PD-L1, which is associated with inferior outcomes. These findings suggest the clinical potential of immune-modulating therapeutics that can unleash an antitumor immune response.

Discrimination faced by Asian American trainees in medical school include those reported by female trainees. This study aims to characterize the microaggressions faced by Asian American woman medical students. We use a mixed methods approach to characterize the experiences of Asian Americans in United States (US) medical schools through an anonymous online survey and participation in focus groups. Among our 305 participants, 65.9 ​% were women. More women experienced microaggressions than men (p ​< ​0.001). Compared to men, women reported significantly higher rates of supervisors having higher expectations of them, implying they were submissive, and describing them as too quiet. Women felt that their experiences with microaggressions were entangled with being Asian and a woman, but could not distinguish which identity was being targeted. The intersectionality of being Asian American and a woman in medical training has not been explored. We found that this duality intensified experiences of microaggressions.

The Asian race represents one of the fastest growing racial groups in the United States that have unique health-care issues and barriers to services. Despite being the second largest racial group among medical students, Asians represent a markedly smaller proportion of leadership. Greater inclusion may facilitate Asian-related curriculum content development, community-engaged research, and increased services for Asian communities. This article explores Southeast and East Asian American (AA) medical students’ perceptions of and challenges toward pursuing academic medicine careers. We collected quantitative and qualitative data among 138 participants. Factors that increased trainees’ interests include collaboration with others, teaching and research opportunities, and influential role models/mentors. Interventions identified to overcome perceived challenges include exposure to senior-level race-concordant role models and mentors, enhancement of communication skills, and informed career discussions between parents and trainees. Such interventions may engage more AA trainees into academia and facilitate their growth as leaders.