Bone marrow fibrosis is associated with non-response to CD19 CAR T-cell therapy in B-acute lymphoblastic leukemia.

CD19 directed CAR T-cell therapy is used to treat relapsed/refractory B-cell acute lymphoblastic leukemia. The role of the pre-CAR bone marrow (BM) stromal microenvironment in determining response to CAR T-cell therapy has been understudied. We performed whole transcriptome analysis, reticulin fibrosis assessment and CD3 T-cell infiltration on BM core biopsies from pre- and post-CAR timepoints for 61 patients, as well as on a cohort of 54 primary B-ALL samples. Pathways of fibrosis, extracellular matrix development, and associated transcription factors AP1 and TGF-ß3, were enriched and upregulated in nonresponders (NR) even prior to CAR T cell therapy. NR showed significantly higher levels of BM fibrosis compared to complete responders by both clinical reticulin assessment and AI-assisted digital image scoring. CD3+ T cells showed a trend toward lower infiltration in NR. NR had significantly higher levels of pre-CAR fibrosis compared to primary B-ALL. High levels of fibrosis were associated with lower overall survival after CAR T-cell therapy. In conclusion, BM fibrosis is a novel mechanism mediating nonresponse to CD19-directed CAR T-cell therapy in B-ALL. A widely used clinically assay for quantitating myelofibrosis can be repurposed to determine patients at high risk of non-response. Genes and pathways associated with BM fibrosis are a potential target to improve response.

The medical humanities at United States medical schools: a mixed method analysis of publicly assessable information on 31 schools.

INTRODUCTION: There have been increasing efforts to integrate the arts and humanities into medical education, particularly during undergraduate medical education (UME). Previous studies, however, have focused on courses and curricular programming without rigorous characterization of the associated paracurricular environment or infrastructure enabling or facilitating these offerings. METHODS: To assess opportunities for students to engage the arts and humanities during their medical education as well as the institutional resources to support those opportunities, we developed the Humanities and Arts Programming Scale (HARPS): an 18-point scale involving eight sub-domains (Infrastructure, Curricular Opportunities, Extracurricular Engagement, Opportunities for Immersion, Faculty Engagement, Staff Support, Student Groups, and Scholarship). This scale was used to evaluate the top-31 ranked United States medical schools as determined by US News and World Report's (USWNR) Medical School Research Rankings using information derived from public-facing, online information. RESULTS: Mean cumulative HARPS score was 11.26, with a median score of 12, a standard deviation of 4.32 and a score range of 3-17. Neither USWNR ranking nor private/public institution status were associated with the cumulative score (p = 0.121, p = 0.739). 52% of institutions surveyed had a humanities-focused center/division with more than 70% of the schools having significant (> 5) faculty engaged in the medical humanities. 65% of schools offered 10 or more paracurricular medical humanities events annually, while 68% of the institutions had more than 5 medical humanities student organizations. While elective, non-credit courses are available, only 3 schools required instruction in the arts and humanities, and comprehensive immersive experiences in the medical humanities were present in only 29% of the schools. CONCLUSIONS: Although there is a significant presence of the medical humanities in UME, there is a need for integration of the arts and humanities into required UME curricula and into immersive pathways for engaging the medical humanities.

Transoral Robotic Surgery-Assisted Removal of Upper Aerodigestive Tract Foreign Bodies with Intraoperative Localization.

OBJECTIVE: To describe the use of transoral robotic surgery (TORS) in conjunction with intraoperative localization techniques for removal of challenging upper aerodigestive tract (UADT) foreign bodies. METHODS: Three cases were taken to the operating room for removal of UADT foreign bodies. Two of these cases had previously undergone failed surgery(s). TORS was performed in all 3 cases and intraoperative localization was used in 2 cases. RESULTS: All foreign bodies were successfully removed. CONCLUSION: This case series is the largest-to-date on UADT foreign body removals using TORS. Additionally, the novel use of intraoperative localization techniques in conjunction with TORS is described. Such an approach can facilitate the identification of difficult-to-identify foreign bodies, as well as potentially decreasing operative time, number of operations, and associated morbidity.

When is laparotomy for mesenteric ischemia after aortic dissection futile?

BACKGROUND: Tissue necrosis from persistent mesenteric ischemia after aortic dissection may progress to sepsis and death without emergent laparotomy. However, the signs of mesenteric necrosis are common in patients experiencing non-survivable multisystem failure after aortic catastrophe. No study has yet examined when and whether laparotomy offers a chance for meaningful survival in these patients. METHODS: A total of 145 patients treated for acute Type A or Type B aortic dissection with mesenteric ischemia were identified from a single institution from 2006 to 2022. Of those, 29 underwent laparotomy all for compelling clinical indication. Detailed clinical characteristics were studied with respect to short and long-term outcomes in these patients. RESULTS: Among laparotomy patients, 45% (13/29) survived to discharge compared to 71% (103/145) of all mesenteric malperfusion patients. Serum lactate and arterial pH were both very strongly associated with survival after laparotomy. Among survivors and non-survivors, mean lactate prior to laparotomy was 6.3 mmol/L vs 13.4 mmol/L (p=0.024) and pH was 7.39 vs 7.20 (p<0.001). In particular, lactate over 8 mmol/L (OR [95%CI] = 16.5 [2.0-192], p=0.003) and pH under 7.30 (OR [95%CI] = 14.4 [1.87-128], p=0.003) were highly predictive of mortality. Survival to discharge after laparotomy for patients with both severe lactatemia and severe acidosis (defined above) was 9% (1/11) compared to 90% (9/10) for patients with neither severe lactatemia nor acidosis. CONCLUSIONS: The degree of lactic acidosis can very effectively identify patients for whom laparotomy is futile and those for whom it is not after aortic dissection with mesenteric ischemia.

Human epidermal growth factor receptor 2 expression in head and neck squamous cell carcinoma: Variation within and across primary tumor sites, and implications for antigen-specific immunotherapy.

BACKGROUND: The purpose of this study is to describe human epidermal growth factor 2 (HER2) overexpression in head and neck squamous cell carcinoma (HNSCC) and re-evaluate its potential as a target for HER2-directed immunotherapies. METHODS: A retrospective cohort of patients with HNSCC receiving curative treatment was identified, and HER2 expression evaluated in archival tissue by immunohistochemistry and correlated with clinicopathological characteristics. HER2 expression data were also determined for HNSCC patients in The Cancer Genome Atlas. RESULTS: Nineteen percent of HNSCC and 39% of oropharyngeal HNSCC (OPSCC) were HER2 positive. HER2 expression positively correlated with nodal metastasis (p = 0.035). Patients with HER2-positive tumors had decreased overall survival (p = 0.012), including within the human papilloma virus-positive OPSCC subgroup (p = 0.007). CONCLUSIONS: A substantial fraction of HNSCC overexpresses HER2 protein, suggesting it may be a suitable target for antigen-directed immunotherapy. HER2 expression and its correlation with survival vary across HNSCC subsites, making it unsuitable as a prognostic marker.