Citations

Abstract Molecular characterization of high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), is hindered by its rarity, evolving definition, and poor diagnostic reproducibility. To address this challenge, we analyzed 92 HGBCL-NOS tumors collected across Lymphoma/Leukemia Molecular Profiling Project sites. Leveraging comparison cohorts of diffuse large B-cell lymphoma, NOS (DLBCL-NOS) and Burkitt lymphoma (BL), and molecular frameworks described in these entities, our analysis revealed a heterogenous molecular landscape, reminiscent of DLBCL-NOS but with an enrichment of BL features. By cell-of-origin classification, 59% were germinal center B-cell–like (GCB), and 25% were activated B-cell–like (ABC). LymphGen, a genetic classifier for DLBCL-NOS, assigned a genetic subtype to 34% of HGBCL-NOS. Although classification rate was lower than in DLBCL-NOS (66%), assigned subtypes spanned the spectrum of LymphGen classes, including 31% of ABCs classified as MCD. Features differentiating HGBCL-NOS from DLBCL-NOS included MYC rearrangement (47% vs 6%); dark zone signature (DZsig) expression (45% vs 7%); and more frequent mutation of ID3, MYC, CCND3, and TP53, all common to BL. A genetic classifier that differentiates DLBCL-NOS from BL classified 53% of DZsig+ tumors as BL-like, and those classified as DLBCL-like were frequently BCL2-rearranged. Among DZsig− GCB tumors, 95% were DLBCL-like. Centralized pathology review reclassified almost half of tumors as DLBCL-NOS but did not identify a more homogenous HGBCL-NOS population, with no difference in features between confirmed and reclassified tumors. In conclusion, molecular testing enables a subset of HGBCL-NOS to be assigned to established categories. Based on rarity and diagnostic challenges, broader inclusion of HGBCL-NOS should be considered in biomarker-driven DLBCL trials.

Space exploration exposes astronauts to unique conditions such as microgravity and space radiation, potentially influencing gene expression and triggering carcinogenesis. Paradoxically, these extreme environments could uncover other pro-treatment aspects of cancer biology. Despite numerous reviews addressing these aspects in isolation, a comprehensive synthesis of the effects of space stressors on cancer development is incomplete. This scoping review aims to provide a holistic perspective on the influence of spaceflight and associated stressors—including gravitation (hyper- and microgravity), radiation, and vibration—on the potential for cancer development and altered cellular mechanisms. We adhered to the PRISMA-ScR checklist for our review. A multitiered search strategy was employed in English, starting with a preliminary keyword identification in Google Scholar and PubMed. Subsequently, the main search was conducted across five databases—Cochrane, Embase, PubMed, Scopus, and Web of Science—until 22 February 2024. All included studies were thoroughly assessed by two independent reviewers. Of the 15,553 identified articles, 158 were deemed eligible. The majority (92%) were experimental studies, predominantly cell-based (74.17%). Breast (15.19%), thyroid (13.92%), and hematopoietic (11.40%) cancers were the most frequently examined. Spaceflight stressors could affect different biological systems variably, with microgravity impacting spatial growth and metastasis, and cosmic radiation exerting both tumor-suppressive and mutagenic effects. Our findings highlight the need for large-scale, prolonged analog studies mimicking space conditions to enhance mission safety and shed light on the nuanced effects of space stressors on cancer. Additionally, further extensive studies need to be performed in the true weightlessness of spaceflight, both animal-based and on human tissue (cell cultures and potentially whole perfusion organ models), in addition to crew pre/intra/post-flight long-duration evaluations. Furthermore, this unique research avenue may reveal cancer cell sensitivities to these stressors, opening new pathways for innovative therapeutic strategies in cancer treatment.

Abstract This retrospective analysis examined 15 years of autologous stem cell transplantation (ASCT) for light chain (AL) amyloidosis at the Mayo Clinic (2010-2024). We aimed to assess ASCT utilization trends, factors influencing practice changes, and current indications amid newer therapies. Four hundred and forty-one ASCTs were divided into cohort 1 (2010-2019) and cohort 2 (2020-2024), revealing a significant ASCT reduction in cohort 2 (385 vs 56, average 71% annual decrease). Cohort 2 patients were older, more likely to have relapsed/refractory disease, and had higher baseline bone marrow plasma cell burden compared to cohort 1. Pre-ASCT induction was more frequent in cohort 2 (89.3% vs 56.4%), with daratumumab (Dara)–cyclophosphamide-bortezomib-dexamethasone (CyBorD) replacing CyBorD as the predominant induction regimen. Lymphoma-based regimens were also more common in cohort 2 (15.1% vs 5.3%, P = .02). Day-100 satisfactory hematological response improved in cohort 2 (91.1% vs 72.7%, P = .001), although hematological complete response rates did not significantly differ (50.9% vs 38.8%, P = .09). In summary, there is a decrease in the utilization of ASCT in AL amyloidosis. This procedure is primarily reserved for patients with suboptimal responses, relapsed/refractory disease, lymphoplasmacytic clones (predominantly immunoglobulin M amyloidosis), or high bone marrow plasma cell burden (myeloma phenotype). This study underscores a significant shift in ASCT practice, driven by novel therapies, emphasizing more personalized management in AL amyloidosis.

Somali Americans, originating from East Africa, are a fast-growing minority in the United States. Emerging data suggest Somali individuals exhibit increased cardiovascular (CV) risk compared to non-Hispanic White adults. Previous data from our laboratory demonstrated elevated ambulatory arterial stiffness in Somali Americans, as derived from 24-hour blood pressure monitoring. We sought to confirm these vascular stiffness findings via gold-standard applanation tonometry and examine potential sex differences, given that females of African ancestry are at elevated risk of CV disease (CVD). We therefore examined aortic hemodynamics and carotid-femoral pulse wave velocity in male and female Somali Americans. We hypothesized that female Somali Americans would present with greater aortic wave reflection and arterial stiffness compared to males. We further examined the accuracy of prediction of aortic wave reflection from a predominantly White population, when applied to the Somali American population. We utilized applanation tonometry to quantify arterial stiffness in 24 female (age: 27±10 years, BMI: 27±6 kg/m 2 ) and 19 male (age: 22±6 years, BMI: 27±5 kg/m 2 ) Somali Americans without CVD. Each participant arrived in the laboratory at Mayo Clinic, fasted for at least three hours, and did not consume caffeine or exercise for at least 12 hours prior to testing. After 15 minutes of supine rest, duplicate recordings of aortic blood pressure and augmentation index (AIx) were obtained via pulse wave analysis. Similarly, aortic stiffness was quantified via duplicate carotid-femoral pulse wave velocity recordings. Statistical analysis included independent samples t-tests to test for sex differences in aortic hemodynamics, and paired samples t-tests to determine differences between estimated and obtained AIx (α≤0.05). Aortic systolic arterial pressure (111±11 vs. 108±7 mmHg, p=0.295) was similar between female and male Somali Americans. Aortic diastolic arterial pressure (75±7 vs. 67±7 mmHg, p<0.001) and heart rate (67±9 vs. 57±7 beats/min, p<0.001) were higher in female Somali adults. Similarly, AIx (28±14 vs. 19±12%, p=0.045) and AIx normalized to 75 heart beats/minute (24±13 vs. 10±13%, p=0.001) were higher in female Somali Americans. Carotid-femoral pulse wave velocity (5.4±0.9 vs. 5.5±0.8 m/s, p=0.661) was similar between sexes. Estimated AIx (corrected for sex, age, height, and resting heart rate) was markedly lower than observed AIx in both female (13±7 vs. 28±14%, p<0.001) and male (6±5 vs. 19±12%, p<0.001) Somali Americans. These findings, obtained in young, healthy Somali adults are suggestive of elevated CVD risk, evident at an early age. These data are particularly concerning regarding vascular dysfunction in Somali females and suggest that prediction models for arterial stiffness should factor in race to optimize performance. Future work into mechanisms underlying vascular dysfunction in Somali Americans is warranted. Sleep Number Grant to Mayo Clinic and by NIH R01-HL160619, R01-HL169320, T32-DK007013, K12 AR084222, and AHA 24POST1241616. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Context Endothelial dysfunction and altered psychological measures have been identified in women with functional hypothalamic amenorrhea (FHA). Estradiol (E2) replacement, a known vasodilator, may potentially reverse vascular dysfunction and improve psychological health. Objective To evaluate 12 weeks of physiologic E2 replacement on vascular, hormonal, and psychological outcomes in women with FHA. Methods A randomized, double-blind, placebo-controlled trial was conducted in 29 women with FHA with 0.1 mg/day transdermal E2 (n = 14) or placebo patch (n = 15) twice weekly for 12 weeks. FHA was defined as amenorrhea ≥3 consecutive months, E2 &lt; 50 pg/mL, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) &lt;10 mIU/L, LH:FSH &lt;1, excluding other etiologies. Endothelial dysfunction (reactive hyperemic index ≤ 1.67) was assessed, as were hormonal and psychological measures. Results Women with FHA had a mean age of 26.2 ± 6.3 years, body mass index of 21.5 ± 3.3 kg/m2, with 63% being non-Hispanic White. Baseline characteristics did not differ between groups. After 12 weeks, E2 levels were significantly higher in the E2 group (112.0 vs 36.5 pg/mL, P = .0002). However, there were no significant differences in vascular, hormonal, or psychological outcomes between E2 and placebo groups at week 12. Cortisol levels showed a near-significant decrease in the E2 group compared to an increase with placebo (−.4 vs 3.1 µg/dL, P = .05). Conclusion In women with FHA, 12 weeks of transdermal E2 increased serum E2 levels but did not improve vascular or psychological health measures. Further studies with larger sample sizes and longer follow-up are needed to explore the long-term effects of E2 therapy on cardiovascular and mental health outcomes in this population.

Abstract Objective This study was undertaken to evaluate the response to second treatments for infantile epileptic spasms syndrome (IESS). Methods Infants aged 2–24 months with IESS were prospectively enrolled in the National Infantile Spasms Cohort study at 21 pediatric epilepsy centers in the United States from 2012 to 2018. We analyzed data from infants who initially received standard treatment (hormonal therapy [adrenocorticotropic hormone, high‐dose prednisolone] or vigabatrin), had continued or recurring epileptic spasms, and received a second treatment. We excluded those with tuberous sclerosis. Treatment groups included hormonal therapy followed by vigabatrin (reference), hormonal‐to‐hormonal, hormonal‐to‐nonstandard, vigabatrin‐to‐hormonal, and vigabatrin‐to‐nonstandard. Nonstandard treatments included other antiseizure medications and dietary therapy. Treatment groups were tested for differences in 3‐month clinical remission using a binary logistic regression to estimate odds ratios (ORs). Results There were 153 infants with IESS who received second treatments. The highest rates of 3‐month remission were among infants in the hormonal‐to‐vigabatrin (22/65, 34%) and vigabatrin‐to‐hormonal (9/26, 35%) groups, followed by vigabatrin‐to‐nonstandard (3/10, 30%), hormonal‐to‐hormonal (4/22, 18%), and hormonal‐to‐nonstandard (1/30, 3.3%). Compared to the hormonal‐to‐vigabatrin group (reference), fewer infants had remission in the hormonal‐to‐nonstandard group (OR = .07, 95% confidence interval [CI] = .01–.53), and there was a trend toward fewer infants in the hormonal‐to‐hormonal group (OR = .43, 95% CI = .13–1.4, p = .17). Following initial hormonal treatment, the number needed to treat was three infants for one additional infant to have remission when treated with vigabatrin compared to nonstandard therapy as the second treatment. Significance This updated analysis with an expanded sample size provided power for additional subgroup analysis. Overall response rates were low, and at best only one third had remission after second treatment. Results support a clinical strategy of switching mechanism of action when selecting a second medication for epileptic spasms (i.e., use vigabatrin after hormonal therapy, or hormonal therapy after vigabatrin). Our findings also support the use of standard over nonstandard therapies.

Background/Objectives: Acute Lymphoblastic Leukemia (ALL) is a cancer that predominantly affects white blood cells within the blood and bone marrow of adults and children. Currently, ALL is one of the most prevalent malignancies in pediatric patients and is most seen among Caucasian and Hispanic descent, with lower incidence in African American children. The goal of the study was to investigate the expression of immune cell receptors in racial/ethnic populations and risk factors for relapse that could potentially influence the pediatric ALL outcomes. Methods: Twenty healthy subjects and forty-two pediatric ALL subjects were enrolled in the study and whole-blood was collected at diagnosis and post-chemotherapy, and the cell surface expression of various immune receptors, including 2B4, CS1, LLT1, Nkp30, and NKp46, was determined by flow cytometry. Results: Very high-risk and high-risk of relapse ALL subjects showed increased expression of LLT1 on NK cells, T cells, and monocytes at diagnosis compared to healthy subjects. CS1 was also significantly overexpressed on monocytes of very-high risk ALL subjects both at diagnosis and after the end of chemotherapy as compared to healthy subjects. Also, there was a significantly increased expression of NKp30 on T cells of Caucasians as compared to Hispanics and African Americans at diagnosis, and downregulation of CS1 and LLT1 on T cells of Caucasians post-induction chemotherapy. Conclusions: The altered expression of immune receptors in racial/ethnic and risk stratified groups may provide insights into the immune surveillance mediated by T cells and NK cells against pediatric ALL.