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Introduction: High dose chemotherapy and autologous stem cell transplantation (ASCT) is one of the most effective therapies in light chain (AL) amyloidosis. It is associated with a high hematologic response rate and leads to durable remissions. High dose melphalan is the most frequently used conditioning chemotherapy, as has been used in multiple myeloma (MM). Melphalan dose is based on renal function, age, degree of cardiac involvement and patients' frailty and is predictive of outcomes. While studies that assessed the conditioning schedule have been conducted in MM, with variable results, no such studies were done in AL amyloidosis. Methods: In this retrospective study, we explored the impact of the conditioning schedule on post-transplant outcomes in a large multicenter study. Patients with AL amyloidosis who underwent ASCT for the primary diagnosis of AL amyloidosis between January 1, 2003, and December 31, 2020, were included in this study. Results: One thousand seven hundred and eighteen (n=1718) patients from 9 centers are included. The median age was 58 years, and 61% were male. Most patients had one (43%) or two (33%) involved organs, with the most involved organs were the kidneys (69%) followed by the heart (52%). Induction therapy was given to 52% of patients. The conditioning regimen was almost exclusively melphalan (99.2%), with 65% receiving full dose melphalan (≥170 mg/m 2). Melphalan was given over two days in most patients (80%). A rest day between conditioning and stem cell infusion was provided in 53% of patients, mostly in those who received melphalan on a single day rather than over 2 days (87% vs 44%, P<0.001). Post-transplant hematologic response was available for 1569 patients (91% of patients) and were assessed from baseline. Complete response (CR) and very good partial responses (VGPR) were achieved post-ASCT in 33.7% of patients each. Low dFLC-partial response (PR) was achieved in 2.7% and PR in 18% of patients. Altogether, satisfactory post-ASCT response (CR, VGPR, or low-dFLC PR combined) was achieved in 70% of patients. Compared to no induction, less than a PR to induction was associated with a lower probability of achieving satisfactory post-ASCT response, while PR or better to induction had higher chances of satisfactory post-ASCT response (65% vs 46% vs 84%, P<0.001). A single day of melphalan conditioning was associated with a higher probability of satisfactory post-ASCT response compared to two days of conditioning (82% vs 67%, P<0.001). Omitting a day of rest between conditioning and stem cell infusion was also associated with higher satisfactory post-ASCT response compared to having a rest day (76% vs 65%, P<0.001). The Table lists other predictors for a post-ASCT satisfactory hematologic response. In a nominal multivariate logistic regression analysis, independent predictors for higher post-ASCT satisfactory hematological response rate included: PR or better to induction therapy, female gender, kappa light chain isotype, lower dFLC at baseline, and kidney and liver involvement. In addition, full dose melphalan, conditioning given over a single day and having no rest day between conditioning and stem cell infusion were also associated with a higher likelihood of satisfactory post-ASCT response. Post-ASCT hematologic CR rate was higher in those receiving full dose conditioning (36% vs 28%, P<0.001), in those having no rest day (40% vs 28%, P<0.001) but not in those who received one day of conditioning versus two days (35% vs 33%, P=0.5). The rate of ICU admission was higher in those receiving no day rest (17.7% vs 12.6%), P=0.003) and among those who received reduced dose melphalan (18.1% vs 13.3%, P=0.008) but not based on number of conditioning days (P=0.56). Day 100 mortality was significantly higher in the no rest day group (5.6% vs 3.2%, P=0.01) and among those receiving reduced dose melphalan (6.8% vs 3.1%, P=0.004) compared to their counterparts, but not based on the number of days of conditioning (P=0.89). The median follow-up in the entire cohort was 104 months (95% CI 98-110). In a multivariate analysis for overall survival (OS), the conditioning dose but not the conditioning schedule was independently associated with OS. Conclusions: This study is the first to demonstrate the effect of melphalan conditioning schedule on post-transplant response. This study supports a single day melphalan conditioning in AL amyloidosis to improve post-ASCT response.

Introduction: Despite governmental and industry-sponsored efforts, clinical trial participation among rural residents and racial and ethnic minorities remains low. The NIH Revitalization Act of 1993 directed the NIH to establish guidelines for inclusion of women and minorities in clinical research. In 2015, the Food and Drug Administration launched an action plan to improve the quality of demographic subgroup data collection, identify barriers to enrollment, employ strategies to increase participation, and promote transparency of related data. However subsequent studies (Green et al. Health Aff. March 2022, Kanapuru et al. Blood Advances. March 2022.) showed no improvement in participation of racial minorities, including Blacks and Hispanics since this plan was enacted. Various complex system- and individual-based factors, including lack of clinical trial availability; lack of diversity in the investigator work force; scant patient and provider awareness of clinical trials; lack of trust in the health care system; and issues with access to care-often driven by financial, geographic, or social constraints (Allison et al. Cureus. Apr 2022.), and stringent eligibility criteria are deemed responsible. The Leukemia & Lymphoma Society (LLS) IMPACT (Influential Medicine Providing Access to Clinical Trials) research grant strives to bridge this unrelenting care gap. Methods: The LLS IMPACT program includes a 5-year research grant which was launched in 2021. The IMPACT grants support the establishment of clinical trial networks involving academic cancer centers (“Hubs”) linked to community clinics and oncology centers (“Spokes”). The program's overall goal is to provide patients access to trials through participation at the community sites. Initially, 3 institutional sites were selected to participate. These institutions had unique and tailored strategies to improve engagement of underrepresented patients, including black, indigenous, people of color, Hispanic, Latina/Latino, and people from rural communities in vastly different climates and local cultures. The IMPACT grant expanded to encompass 4 additional sites given the imminent needs and clamor of the hematology clinical trials community (Figure 1A). The catchment areas and strategies employed at each institution are summarized in the table (Figure 1B). Results: At the start of the grant period, focus was on building clinical research infrastructure and opening non-interventional clinical trials to teach personnel about clinical research and create relationships with patients. Other programs such as webinar series, tumor boards, technological advancements, and educational workshops were also established to enhance engagement among physicians, match patients to clinical trials, and to provide clinical trial education to potential patients. One trial that has seen early success is the CHIVE IMPACT trial, a non-interventional registry and biorepository which has enrolled 24 patients at a rural and underserved site as of July 2023. The purpose of CHIVE is to enroll patients who have clonal hematopoiesis (CH) or are at risk of CH and follow prospectively in efforts to understand risk of progression and potential for early intervention. The Universal Protocol is another biorepository trial which has more than tripled its enrollment number at a community site between 2021 and 2022. Of the 63 patients enrolled in 2022, 66% of them identified as a race other than White. As our core goal is to increase access to interventional trials, we hope to bring industry sponsored phase II and phase III studies to underrepresented areas that serve a broad patient population. Lack of financial resources, lack of transportation and distance to trial sites, and residual distrust of the medical community (e.g., legacy of Tuskegee experiments) are barriers the grantees are focused on overcoming to enroll the intended populations into clinical trials. Conclusion: The innovative strategies employed to expand access to clinical trials for underrepresented population at the various institutions through the LLS's IMPACT research grant can be utilized during clinical trials design and implementation phases to improve generalizability of clinical trials in hematologic malignancies. In the third year of this program, 7 participating sites are engaging impactful strategies (Figure 1B) which will be reported at the end of the grant period.

This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.

AbstractBackgroundOver the past decade, advances in sepsis identification and management have resulted in decreased sepsis mortality. This increase in survivorship has highlighted a new clinical obstacle: chronic critical illness (CCI), for which there are no effective treatment options. Up to half of sepsis survivors suffer from CCI, which can include multi‐organ dysfunction, chronic inflammation, muscle wasting, physical and mental disabilities, and enhanced frailty. These symptoms prevent survivors from returning to regular day‐to‐day activities and are directly associated with poor quality of life.MethodsMice were subjected to cecal ligation and puncture (CLP) with daily chronic stress (DCS) as an in vivo model to study sepsis late‐effects/sequelae on skeletal muscle components. Longitudinal monitoring was performed via magnetic resonance imaging, skeletal muscle and/or muscle stem cell (MuSCs) assays (e.g., post‐necropsy wet muscle weights, minimum Feret diameter measurements, in vitro MuSC proliferation and differentiation, number of regenerating myofibres and numbers of Pax7‐positive nuclei per myofibre), post‐sepsis whole muscle metabolomics and MuSC isolation and high‐content transcriptional profiling.ResultsWe report several findings supporting the hypothesis that MuSCs/muscle regeneration are critically involved in post‐sepsis muscle recovery. First, we show that genetic ablation of muscle stem cells (MuSCs) impairs post‐sepsis muscle recovery (maintenance of 5–8% average lean mass loss compared with controls). Second, we observe impaired MuSCs expansion capacity and morphological defects at 26 days post‐sepsis compared with control MuSCs (P < 0.001). Third, when subjected to an experimental muscle injury, sepsis‐recovered mice exhibited evidence of impaired muscle regeneration compared with non‐septic mice receiving the same muscle injury (CLP/DCS injured mean minimum Feret is 92.1% of control injured, P < 0.01). Fourth, we performed a longitudinal RNA sequencing study on MuSCs isolated from post‐sepsis mice and found clear transcriptional differences in all post‐sepsis samples compared with controls. At Day 28, CLP/DCS mice satellite cells have multiple altered metabolic pathways, such as oxidative phosphorylation, mitochondrial dysfunction, sirtuin signalling and oestrogen receptor signalling, compared with controls (P < 0.001).ConclusionsOur data show that MuSCs and muscle regeneration are required for effective post‐sepsis muscle recovery and that sepsis triggers morphological, functional, and transcriptional changes in MuSCs. Moving forward, we strive to leverage a more complete understanding of post‐sepsis MuSC/regenerative defects to identify and test novel therapies that promote muscle recovery and improve quality of life in sepsis survivors.

AbstractBackgroundTo determine the impact of personalized risk communication and opioid prescribing on nonprescribed opioid use, we conducted a secondary analysis of randomized controlled trial participants followed prospectively for 90 days after an emergency department (ED) visit for acute back or kidney stone pain.MethodsA total of 1301 individuals were randomized during an encounter at four academic EDs into a probabilistic risk tool (PRT) arm, a narrative‐enhanced PRT arm, or a general risk information arm (control). In this secondary analysis, both risk tool arms were combined and compared with the control arm. We used logistic regressions to determine associations between receiving personalized risk information, receiving an opioid prescription in the ED, and nonprescribed opioid use in general and by race.ResultsComplete follow‐up data were available for 851 participants; 23.3% (n = 198) were prescribed opioids (34.2% of White vs. 11.6% of Black participants, p < 0.001). Fifty‐six (6.6%) participants used nonprescribed opioids. Participants in the personalized risk communication arms had lower nonprescribed opioid use odds (adjusted odds ratio [aOR] 0.58, 95% confidence interval [CI] 0.4–0.83). Black versus White participants had greater nonprescribed opioid use odds (aOR 3.47, 95% CI 2.05–5.87, p < 0.001). Black participants who were prescribed opioids had a lower marginal probability of using nonprescribed opioids versus those who were not (0.06, 95% CI 0.04–0.08, p < 0.001 vs. 0.10, 95% CI 0.08–0.11, p < 0.001). The absolute risk difference in nonprescribed opioid use for Black and White participants, respectively, in the risk communication versus the control arm, was 9.7% and 0.1% (relative risk ratio 0.43 vs. 0.95).ConclusionsAmong Black but not White participants, personalized opioid risk communication and opioid prescribing were associated with lower odds of nonprescribed opioid use. Our findings suggest that racial disparities in opioid prescribing—which have been previously described within the context of this trial—may paradoxically increase nonprescribed opioid use. Personalized risk communication may effectively reduce nonprescribed opioid use, and future research should be designed specifically to explore this possibility in a larger cohort.

Abstract Matrix metalloproteinases (MMPs) regulate the degradation of extracellular matrix (ECM) components in biological processes. MMP activity is controlled by natural tissue inhibitors of metalloproteinases (TIMPs) that non-selectively inhibit the function of multiple MMPs via interaction with the MMPs' Zn2+-containing catalytic pocket. Recent studies suggest that TIMPs engineered to confer MMP specificity could be exploited for therapeutic purposes, but obtaining specific TIMP-2 inhibitors has proved to be challenging. Here, in an effort to improve MMP specificity, we incorporated the metal-binding non-canonical amino acids (NCAAs), 3,4-dihydroxyphenylalanine (L-DOPA) and (8-hydroxyquinolin-3-yl)alanine (HqAla), into the MMP-inhibitory N-terminal domain of TIMP2 (N-TIMP2) at selected positions that interact with the catalytic Zn2+ ion (S2, S69, A70, L100) or with a structural Ca2+ ion (Y36). Evaluation of the inhibitory potency of the NCAA-containing variants towards MMP-2, MMP-9 and MMP-14 in vitro revealed that most showed a significant loss of inhibitory activity towards MMP-14, but not towards MMP-2 and MMP-9, resulting in increased specificity towards the latter proteases. Substitutions at S69 conferred the best improvement in selectivity for both L-DOPA and HqAla variants. Molecular modeling revealed how MMP-2 and MMP-9 are better able to accommodate the bulky NCAA substituents at the intermolecular interface with N-TIMP2. The models also showed that, rather than coordinating to Zn2+, the NCAA side chains formed stabilizing polar interactions at the intermolecular interface with MMP-2 and MMP-9. The findings illustrate how incorporation of NCAAs can be used to probe and exploit differential tolerance for substitution within closely related protein-protein complexes to achieve improved specificity.

This selection from the NCCN Guidelines for Rectal Cancer focuses on management of malignant polyps and resectable nonmetastatic rectal cancer because important updates have been made to these guidelines. These recent updates include redrawing the algorithms for stage II and III disease to reflect new data supporting the increasingly prominent role of total neoadjuvant therapy, expanded recommendations for short-course radiation therapy techniques, and new recommendations for a “watch-and-wait” nonoperative management technique for patients with cancer that shows a complete response to neoadjuvant therapy. The complete version of the NCCN Guidelines for Rectal Cancer, available online at NCCN.org , covers additional topics including risk assessment, pathology and staging, management of metastatic disease, posttreatment surveillance, treatment of recurrent disease, and survivorship.

The evidence base supporting the management of patients with acute stroke is evolving at a rapid rate, as new methods that aim to reduce disability and death from stroke are explored. Intravenous tissue plasminogen activator remains the only treatment shown in numerous studies to reduce disability 3 months after stroke with no increase in the risk of death and a relatively minor rate of symptomatic intracerebral hemorrhage complications. Despite these findings, health care providers have been slow to adopt this evidence-based treatment, which results in many patients experiencing disability caused by stroke. Numerous controversies exist related to the management of patients with acute stroke, including the use of tissue plasminogen activator, positioning and early mobility, blood pressure lowering in acute intracerebral hemorrhage, and even the use of innovative advanced practice nurse–led stroke treatment teams, with varying amounts of evidence available to provide direction. This article explores controversies associated with both approved and evolving treatments for ischemic and hemorrhagic stroke and makes recommendations for practice on the basis of the body of existing evidence, with an aim to improve the delivery of acute stroke treatment.

Abstract Foxp3⁺ regulatory T cells (Tregs) maintain immune homeostasis, yet the process that preserves their stability during aging remain unclear. Mechanistic progress has been hindered by models that ablate Tregs or delete Foxp3 , which induce acute autoimmunity and prevent longitudinal study of physiological regulatory drift. Here, we establish a dose-dependent mitochondrial framework that preserves Treg lineage survival while permitting gradual metabolic attenuation. Using Treg-restricted TFAM modulation, a complementary haploinsufficient model, and whole-spleen single-cell profiling. We identify lineage-selective immune remodeling characterized by contraction of naïve CD8⁺ and follicular B-cell pools, alteration of CD4⁺ states, expansion of activated Tregs, and emergence of neuroimmune stress linked transcriptional modules that parallel physiological aging. Mechanistically, mitochondrial insufficiency is associated with functional loss of FOXP3- centered chromatin coordination and enrichment of NF-κB/NFAT/AP-1 inflammatory and senescence programs while lineage identity remains detectable. Partial mitochondrial attenuation within Tregs alone is sufficient to drive chronic low-grade systemic inflammation, neuromuscular decline, gut microbial restructuring, and elevated microglial responsiveness without Treg depletion. Pharmacologic and microbiota-directed interventions partially reduce inflammatory tone and improve functional metrics. Together, our findings identify TFAM as a key regulator of immune aging and reveal that healthy mitochondrial function in Tregs is essential for protecting against inflammaging and age-associated functional decline.