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DEK::AFF2 fusion nonkeratinizing squamous cell carcinoma (NKSCC) is an emerging entity in the sinonasal tract, temporal bone, and skull base. However, the clinical behavior of these tumors has not been well studied. Here, we report the largest cohort of DEK::AFF2 carcinomas to determine if morphology, mitotic rate, and/or Ki-67 IHC are associated with patient outcomes, including a comparison with high-risk human papillomavirus (HPV)-associated and independent patients. We solicited cases of molecularly or AFF2 immunohistochemistry (IHC) proven DEK::AFF2 SCC from surgical pathologists to collect patient demographic, clinical, and outcome data. Using representative H&E slides, we characterized the morphology and counted mitoses. Ki-67 immunohistochemistry was performed. We also compared the DEK::AFF2 survival rates to those in a cohort of AFF2 IHC-negative HPV-associated and HPV-independent SCC. DEK::AFF2 carcinomas most commonly arose in the nasal cavity (13/30, 43%), and the average number of recurrences was 1.8 (range: 0 to 10). At the last follow-up, most patients were disease free (19/30, 63%) or were alive with disease (9/30, 30%). There was an average mitotic rate of 2 per 2 mm2 (range: 0 to 9) and Ki-67 proliferation rate of 26% (range: 3% to 60%). Local recurrence was common, but morphology, mitotic activity, and Ki-67 index were not associated with recurrence or survival. On Kaplan-Meier survival analysis, DEK::AFF2 patients had lower disease-free survival but otherwise had similar outcomes to conventional SCC patients. Our multi-institutional study shows that local recurrence is common in DEK::AFF2 fusion nonkeratinizing SCC patients, but patients have survival rates similar to conventional SCC. Despite showing a range of different features and proliferation rates, traditional grading by morphology, mitotic rate, and/or Ki-67 activity does not seem to be predictive of outcome.

Everyone has the right to the highest attainable standard of health, and modern preventive, preventive and rehabilitative manipulations promote health and well-being. Thanks to a number of fundamental projects on the study of human health at various levels (genomic, proteomic, and metabolomic), and molecular mechanisms of the development of pathological conditions, there has been a great leap in the field of applied sectors of industrial biotechnology, including segments of the pharmaceutical and food industries, significantly replenished health-saving resources and improved the quality of life of the population. This article will review the advanced achievements of fundamental and applied research, as well as promising areas of the bioindustry.

OBJECTIVE This study aimed to evaluate local control (LC) of tumors, patient overall survival (OS), and the safety of stereotactic radiosurgery (SRS) for esophageal cancer brain metastases (EBMs). METHODS This retrospective cohort study used data from 15 International Radiosurgery Research Foundation facilities encompassing 67 patients with 185 EBMs managed using SRS between January 2000 and May 2022. The median patient age was 63 years, with a male predominance (92.5%). Most patients (64.2%) had a single brain metastasis, while 7.5% had more than 5 metastases. The median tumor volume was 0.9 cm 3 , and the median margin dose delivered to the tumor was 20 Gy. RESULTS The median OS post-SRS was 15.2 months, with 1- and 2-year OS rates of 65.7% and 32.3%, respectively. A significant inverse correlation was found between the number of EBMs and OS in the univariable analysis. LC rates at 1 and 2 years were 89% and 76%, respectively. Adverse radiation effects (AREs) were observed in 17.9% of patients, with 13.4% being mild and transient and 4.5% severely symptomatic (Common Terminology Criteria for Adverse Events grade 3). New intracranial disease developed in 58.2% of patients, with 1- and 2-year rates of 58% and 73%, respectively. CONCLUSIONS SRS for EBMs demonstrated high survival rates and effective tumor control, with a low incidence of severe AREs. These findings highlight the potential role of SRS in the multidisciplinary multimodality management paradigm of EBM.

Background: The ethical discourse regarding the delivery of global surgical care has increased in the 21st century. The aims of this manuscript are to explore the differences in ethical domains in the global cleft surgical literature discussed by authors from high-income countries versus lower-middle-income countries and to elucidate changes in ethical discussions over the last decade. Methods: A thematic coding analysis was completed using NVivo 12 qualitative data analysis software. Articles were analyzed and coded for discussion of 24 distinct subdomains in the global cleft surgical literature from 1992 to 2022. Findings: The domains with the most significant discourse in the global cleft surgery literature found were (1) clinical care and delivery and (2) engagement in collaborations and partnerships. Furthermore, when manuscripts are first authored by low- and middle-income country (LMIC) authors, the subdomains of (1) level of visiting trainee supervision, (2) relevance of educational activities, and (3) patient/procedure/location selection increase in relative discourse. The impact of visiting trainees on local educational programs is the ethical subdomain that has the largest increase in the last decade. There are barriers to publication as evidenced by the exclusion of abstracts which included LMIC authors but did not result in publications in peer-reviewed journals. Conclusions: A critical finding of this study is that the distribution of discussed ethical domains differs when LMIC authors are included as authors, in particular when primary authorship is from an LMIC author. To the authors' knowledge, there is no other study to date which has attempted this form of analysis.

Introduction Patients (pts) with progressive disease after ≥2 prior lines of systemic therapy are unlikely to derive additional benefit from current salvage immunochemotherapies, and survival declines significantly with each subsequent treatment. Pts with refractory disease following second-line therapy have worse outcomes, with reported overall response rates (ORRs) of 1% to 14% and overall survival (OS) of 5 months (Blood. 2017;130[16]:1800-1808). While chimeric antigen receptor (CAR) T-cell therapy has become a preferred strategy in the second- and third-line settings, pts with R/R disease following CAR-T experience dismal survival, with progression-free survival (PFS) and OS as low as 3 and 5 months, respectively, and no agreed standard of care post CAR-T (Blood. 2022;140[24]:2527-2529). The randomized, global, phase 3 ECHELON-3 study (NCT04404283) was conducted in pts with R/R DLBCL after ≥2 prior therapies who were ineligible for hematopoietic stem cell transplant and/or CAR-T. Here, we present subgroup analyses in pts with 2 prior lines of therapy, refractory disease, or prior CAR-T. Methods In these subgroup analyses of ECHELON-3, eligible pts had 2 prior lines of systemic therapy, disease refractory to the last prior therapy, or prior exposure to CAR-T. Pts could qualify for ≥1 subgroup and were analyzed separately. Refractory disease was defined as stable or progressive disease as best overall response to last line of treatment or relapse ≤6 months from the end of treatment. Pts were randomized 1:1 to receive brentuximab vedotin (BV; 1.2 mg/kg) or placebo every 3 weeks (q3w), in combination with rituximab (R; 375 mg/m2) q3w and lenalidomide (Len; 20 mg) once daily. Efficacy was assessed by investigators per Lugano 2014 classification. The primary endpoint was OS, with key secondary endpoints of PFS and ORR. P values are descriptive. Results In total, 230 pts were enrolled in ECHELON-3 from April 2021 to November 2023, with a median follow-up of 16.4 months (range, 0.1-31.5 months). Overall, 94 pts with 2 prior lines of systemic therapy were enrolled and randomized to BV+Len+R (n=48) or placebo+Len+R (n=46). Median OS was 16.3 months (95% CI, 12.6 months-not estimable) with BV+Len+R vs 8.5 months (95% CI, 4.1-15.8 months) with placebo+Len+R (hazard ratio [HR], 0.557; 95% CI, 0.317-0.977; P=.0388). Median PFS was 7.1 months (95% CI, 3.6-12.6 months) with BV+Len+R vs 2.7 months (95% CI, 1.4-4.0 months) with placebo+Len+R (HR, 0.462; 95% CI, 0.279-0.764; P=.0020). ORR was 68.8% (95% CI, 53.7%-81.3%) with BV+Len+R vs 43.5% with placebo+Len+R (95% CI, 28.9%-58.9%; P=.0216); complete response (CR) rate was 52.1% vs 13.0%, respectively. Additional data for pts by lines of therapy received will be presented. In total, 194 pts with disease refractory to the most recent systemic therapy were enrolled and randomized to BV+Len+R (n=98) and placebo+Len+R (n=96). Median OS was 11.7 months (95% CI, 8.8-16.3 months) with BV+Len+R vs 5.5 months (95% CI, 3.7-8.5 months) with placebo+Len+R (HR, 0.566; 95% CI, 0.396-0.808; P=.0015). Median PFS was 4.1 months (95% CI, 2.8-5.4 months) with BV+Len+R vs 1.5 months (95% CI, 1.4-2.6 months) with placebo+Len+R (HR, 0.508; 95% CI, 0.363-0.712; P<.0001). ORR was 59.2% (95% CI, 48.8%-69.0%) with BV+Len+R vs 29.2% (95% CI, 20.3%-39.3%) with placebo+Len+R (P<.0001); CR rate was 34.7% vs 11.5%, respectively. Overall, 67 pts who received prior CAR-T were enrolled and randomized to BV+Len+R (n=32) and placebo+Len+R (n=35). Median OS was 15.6 months with BV+Len+R vs 4.4 months with placebo+Len+R (HR, 0.38; 95% CI, 0.2-0.75). Median PFS was 3.0 months with BV+Len+R vs 1.4 months with placebo+Len+R (HR, 0.41; 95% CI, 0.22-0.76). ORR was 65.6% (95% CI, 46.8%-81.4%) with BV+Len+R vs 25.7% (95% CI, 12.5%-43.3%) with placebo+Len+R (P=.0014); CR rate was 37.5% vs 11.4%, respectively. Conclusions BV+Len+R demonstrated a clinically meaningful improvement in all key efficacy outcomes, including CR and OS, in pts with 2 prior lines of therapy, disease refractory to prior treatment, or prior CAR-T. This treatment benefit was generally consistent with that observed in the overall ECHELON-3 study population. Therefore, BV+Len+R has the potential to address an unmet need for effective and tolerable therapy in heavily pretreated pts, as described above.

Introduction: Systems-based hematology (SBH) is an emerging field focused on improving hematology care delivery through quality improvement (QI) and health systems science (HSS). However, a universal definition and standardized training curriculum are lacking. This study aimed to explore experts' perspectives on defining SBH, identify core knowledge and skills, and discuss challenges and opportunities in developing a curriculum. Methods: Semi-structured interviews were conducted with eight hematologists who have expertise in SBH through practical experience, scientific publications, and serve on related committees for the American Society of Hematology. These interviews were automatically transcribed through Microsoft Teams. Thematic analysis, using both inductive and deductive coding, was employed to identify themes and subthemes from the verbatim interview transcripts. This was accomplished with a large language model (LLM; Google Gemini Advanced, June 2024). Results: In combination, these semi-structured interviews lasted approximately 400 minutes and generated 231 pages of transcript text with 63117 words for analysis. Five main themes and associated subthemes were identified. (1) Defining SBH: experts highlighted the lack of a universal definition for SBH, emphasizing the reason it is often defined by its functions, such as improving healthcare delivery, ensuring appropriate use of resources, and addressing disparities in care. They often compared SBH to other fields like antimicrobial stewardship or implementation science to illustrate its expansive role and scope. (2) The Role and Scope of SBH: experts described SBH as encompassing a broad range of activities, including improving healthcare delivery, implementing QI initiatives, conducting pragmatic research, and advocating for policy changes at various levels. They emphasized the importance of data-driven approaches and collaboration with other healthcare professionals. (3) Training and Education in SBH: the lack of formal training programs and curricula for SBH was a recurring theme. Experts suggested that a comprehensive curriculum should include QI methodologies, implementation science, clinical informatics, health economics, leadership skills, and hematology-specific examples and case studies. They proposed various delivery methods, including asynchronous online modules, virtual workshops, and in-person sessions, targeting hematology fellows, junior faculty, and other healthcare professionals involved in hematology care. They unanimously agreed that a SBH curriculum could borrow heavily from an established HSS curriculum but should incorporate hematology-specific examples. (4) Challenges and Barriers to Implementing SBH: experts identified several challenges, including the lack of awareness and recognition of SBH among healthcare professionals and administrators, resource constraints, and the need for institutional buy-in. They also highlighted the technical difficulty of measuring and demonstrating the value of SBH interventions, particularly in terms of cost savings and improved patient outcomes. (5) The Future of SBH: despite the challenges, experts expressed optimism about the future of SBH, predicting its growing importance and expanding scope, including malignant hematology, community practice, and pediatrics. They envisioned SBH playing a crucial role in addressing rising healthcare costs, quality concerns, and disparities in care. They also anticipated the integration of new technologies like artificial intelligence, “virtual” care delivery, and molecular genetics into SBH practice. Conclusions: This study provides valuable insights into the current state of SBH and the need for a standardized curriculum. The findings can inform the development of educational resources and training programs to equip future practitioners with the necessary knowledge and skills to effectively practice SBH and improve hematology care delivery. This study also sheds light on the utility of qualitative research within SBH and the emerging analytical tools that will require further exploration and standardization (e.g., LLM prompt engineering).

Abstract Immune thrombotic thrombocytopenic purpura (iTTP) is a chronically relapsing disorder caused by autoantibody-mediated deficiency of ADAMTS13. Rituximab is frequently administered to prevent relapses, but whether the durability of rituximab effect is maintained with subsequent treatment courses has not been studied. Using the United States Thrombotic Microangiopathy Consortium (USTMA) retrospective iTTP registry, we evaluated clinical relapse-free survival (RFS) with subsequent courses of rituximab treatment in multiply relapsing patients. Separately, we evaluated overall RFS (composite of time to clinical relapse, ADAMTS13 relapse, or preemptive rituximab) in a prospective iTTP cohort from the Johns Hopkins University and the University of Minnesota. In the USTMA registry, median clinical RFS was shorter after the second or subsequent rituximab-treated episode than the first (2.1 vs 6.0 years; P = .04). White patients’ clinical relapse risk after the second and subsequent rituximab courses was not significantly different compared with the first (hazard ratio [HR], 1.86; 95% confidence interval [CI], 0.22-15.80; P = .57), whereas for Black patients, clinical relapse risk was significantly higher after the second or subsequent courses (HR, 2.82; 95% CI, 1.52-5.24; P = .001). In the prospective cohort, overall RFS progressively shortened after each episode of rituximab treatment with the first episode having the longest RFS (2.8 years; interquartile range, 2.0-6.0) and this loss of response durability was most pronounced in Black patients. The durability of rituximab’s effect declines with subsequent treatments, which is more pronounced in Black patients, who may benefit from closer monitoring and alternative immunomodulatory approaches such as maintenance rituximab and consideration of other agents.

Importance Typical cysteine-altering NOTCH3 ( NOTCH3 cys ) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3 -SVD severity spectrum is needed and currently lacking. Objective To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3 -SVD severity spectrum. Design, Setting, and Participants A cohort study was performed in which the NOTCH3 -SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3 cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3 cys -positive cases from families with CADASIL; the validation set included 1713 NOTCH3 cys -positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3 cys -positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024. Main Outcomes and Measures Percentage of cases following the sequence of events of the NOTCH3 -SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level. Results The NOTCH3 -SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3 -SVD staging system. The NOTCH3 -SVD stages were associated with neuroimaging outcomes in the NOTCH3 cys -positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3 -SVD staging system captured disease progression and was associated with 18-year survival. Conclusions and Relevance The NOTCH3 -SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3 cys variant to patients with end-stage disease. The NOTCH3 -SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.