e19543 Background: Multiple myeloma (MM) is a plasma cell malignancy characterized by immune dysfunction and end-organ damage. Emerging preclinical evidence suggests vitamin D is implicated in MM biology through effects on plasma cell differentiation and immune regulation. Vitamin D deficiency is common among patients with MM, yet its prognostic significance remains unclear. Clarifying its role may inform risk stratification and supportive management in MM. Methods: We conducted a retrospective cohort study using the multicenter TriNetX research network. Adults aged ≥20 years diagnosed with MM between 2011 and 2024 were included. Vitamin D status was defined using serum 25-hydroxyvitamin D levels, with deficiency defined as ≤30 ng/mL and normal levels defined as 31–80 ng/mL. Patients were stratified into two groups based on vitamin D status at the time of MM diagnosis. Propensity score matching (1:1) was performed to balance age, sex, race, baseline laboratory values, and clinically relevant comorbidities between groups. Kaplan–Meier survival analyses and Cox proportional hazards models were performed for outcome analyses. Results: A total of 36,273 patients with MM were included, of whom 42% (n = 15,262) had vitamin D deficiency. After propensity score matching, 14,023 vitamin D–deficient patients were well balanced with 14,006 non-deficient patients across baseline characteristics. In the matched cohort, the mean age was 64 years, 49% were female, and 64% were White. At five years, vitamin D deficiency was associated with a significantly higher risk of mortality (hazard ratio [HR] 1.63, 95% CI 1.54–1.72), with lower five-year overall survival (OS) compared with non-deficient patients (71.1% vs 80.8%, p<0.05). Vitamin D deficiency was also associated with increased risks of pneumonia (risk ratio [RR] 1.11), bacteremia (RR 1.22), and critical care admission (RR 1.30) (all p<0.05). Additionally, deficient patients had higher risks of acute kidney injury (AKI) (RR 1.19) and venous thromboembolism (RR 1.18) (both p<0.05). Notably, the risk of MM relapse was modestly increased among vitamin D-deficient patients (RR 1.07, 95% CI 1.01–1.13). No significant associations were observed between vitamin D deficiency and amyloidosis or pathologic fractures. In multivariable Cox regression, vitamin D deficiency remained independently associated with worse five-year OS (adjusted HR 1.60, 95% CI 1.52–1.67). Conclusions: This study highlights the negative impact of vitamin D deficiency in patients with MM. It identifies a high-risk subgroup of patients characterized by worse five-year OS, higher rates of serious infections, AKI, critical care utilization, and an increased risk of MM relapse. These findings suggest vitamin D deficiency as a clinically relevant prognostic marker in MM. Prospective studies are warranted to determine whether vitamin D level optimization can improve MM outcomes.

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:Retrospective case series have identified having cancer and receiving treatment for cancer as risk factors for inferior COVID-19 outcomes. Objective:To determine risk factors for hospitalization and death in patients with cancer with COVID-19 infection. Design, Setting, and Participants:The National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS) is a prospective longitudinal natural history cohort study examining the impact of COVID-19 on patients with cancer. Adults were eligible within 14 days of an initial positive SARS-CoV-2 test result if they were receiving active treatment for cancer or had prior stem cell/bone marrow transplant or CAR T-cell treatment. The statistical analysis took place between September 2024 and April 2025. Main Outcomes and Measures:The primary objective of the study was to determine patient factors, therapy types, and cancer types associated with COVID-19 severity, defined as hospitalization for or death from COVID-19 within 30 and 90 days after the first positive SARS-CoV-2 test result. Multivariable regressions were performed for COVID-19-specific hospitalization and mortality (proportional hazard and cause-specific hazard models). Results:Of 1572 eligible adult patients (median [range] age, 60 [18-93] years; 840 female [53.4%]), 1066 (67.8%) had a solid tumor, with 683 (64.0%) having metastatic disease; breast (252 [23.6%]) and lung cancer (148 [13.9%]) were most common. At enrollment, 1013 patients (64.4%) were unvaccinated for SARS-CoV-2. COVID-19-related mortality at 90 days was 3.0% and did not increase at subsequent time points. The cumulative incidence of COVID-19-specific death in the first 90 days was highest in patients with lymphoma, intermediate in patients with acute leukemia and lung cancer, and lowest in patients with other solid tumors and other hematologic cancers. In multivariable analysis, receipt of chemotherapy (hazard ratio [HR], 1.97; 95% CI, 1.52-2.54) and baseline history of stroke, atrial fibrillation, or pulmonary embolism (HR, 1.78; 95% CI, 1.33-2.38) were associated with a higher risk of hospitalization. Vaccination prior to SARS-CoV-2 infection was associated with a lower risk of hospitalization (HR, 0.52; 95% CI, 0.38-0.70). Over 2 years of follow-up, there were 1739 cancer treatment disruptions, of which 881 (50.7%) were attributed to COVID-19, with most disruptions occurring within the first 30 days. Conclusions and Relevance:The results of this prospective cohort study showed that COVID-19 had a significant impact on patients with cancer, including hospitalization, treatment disruptions, and death.

Retrospective case series have identified having cancer and receiving treatment for cancer as risk factors for inferior COVID-19 outcomes. To determine risk factors for hospitalization and death in patients with cancer with COVID-19 infection. The National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS) is a prospective longitudinal natural history cohort study examining the impact of COVID-19 on patients with cancer. Adults were eligible within 14 days of an initial positive SARS-CoV-2 test result if they were receiving active treatment for cancer or had prior stem cell/bone marrow transplant or CAR T-cell treatment. The statistical analysis took place between September 2024 and April 2025. The primary objective of the study was to determine patient factors, therapy types, and cancer types associated with COVID-19 severity, defined as hospitalization for or death from COVID-19 within 30 and 90 days after the first positive SARS-CoV-2 test result. Multivariable regressions were performed for COVID-19–specific hospitalization and mortality (proportional hazard and cause-specific hazard models). Of 1572 eligible adult patients (median [range] age, 60 [18-93] years; 840 female [53.4%]), 1066 (67.8%) had a solid tumor, with 683 (64.0%) having metastatic disease; breast (252 [23.6%]) and lung cancer (148 [13.9%]) were most common. At enrollment, 1013 patients (64.4%) were unvaccinated for SARS-CoV-2. COVID-19–related mortality at 90 days was 3.0% and did not increase at subsequent time points. The cumulative incidence of COVID-19–specific death in the first 90 days was highest in patients with lymphoma, intermediate in patients with acute leukemia and lung cancer, and lowest in patients with other solid tumors and other hematologic cancers. In multivariable analysis, receipt of chemotherapy (hazard ratio [HR], 1.97; 95% CI, 1.52-2.54) and baseline history of stroke, atrial fibrillation, or pulmonary embolism (HR, 1.78; 95% CI, 1.33-2.38) were associated with a higher risk of hospitalization. Vaccination prior to SARS-CoV-2 infection was associated with a lower risk of hospitalization (HR, 0.52; 95% CI, 0.38-0.70). Over 2 years of follow-up, there were 1739 cancer treatment disruptions, of which 881 (50.7%) were attributed to COVID-19, with most disruptions occurring within the first 30 days. The results of this prospective cohort study showed that COVID-19 had a significant impact on patients with cancer, including hospitalization, treatment disruptions, and death.

Painimation, a novel digital pain assessment tool, allows patients to communicate their pain quality, intensity, and location using abstract animations (painimations) and a paintable body image. This study determined the construct validity of painimations and body image measures by testing correlations with validated pain outcomes in adults with sickle cell disease (SCD). Analyses used baseline data from a multisite randomized trial of 359 adults with SCD and chronic pain. Participants completed questionnaires on demographics, pain severity, frequency and interference, catastrophizing, opioid use, mood and quality of life, plus the Painimation app. Participants were categorized by selected painimations, and were split into groups based on the proportion of painted body image. Potential confounding was evaluated by age, gender, race, education, disability, site, depression, and anxiety. The 'shooting' painimation was strongly associated with daily pain intensity, pain interference, frequency, and severity. 'Electrifying' was associated with daily pain and opioid misuse, while greater body area in pain correlated with worse outcomes across all pain measures. Both painimations and body image measures correlated with validated pain outcomes, quality of life and mental health measures. This demonstrates animations and body image data can assess SCD pain severity, potentially with more accuracy than a 0-10 scale. Future research will explore whether Painimation can differentiate biological and psychosocial pain components. Perspective: This article presents the preliminary construct validity of Painimation in SCD by examining the associations of "painimations" and body area image data with daily e-diary and traditional self-report pain outcomes.

Depressive symptoms are prevalent in individuals living with sickle cell disease (SCD) and may exacerbate pain. This study examines whether higher depressive symptoms are associated with pain outcomes, pain catastrophizing, interference and potential opioid misuse in a large cohort of adults with SCD. The study utilized baseline data from the 'CaRISMA' trial, which involved 357 SCD adults with chronic pain. Baseline assessments included pain intensity, daily mood, the Patient Health Questionnaire (PHQ), the Generalized Anxiety Disorders scale, PROMIS Pain Interference, Pain Catastrophizing Scale, the Adult Sickle Cell Quality of Life Measurement Information System and the Current Opioid Misuse Measure. Participants were categorized into 'high' or 'low' depression groups based on PHQ scores. Higher depressive symptoms were significantly associated with increased daily pain intensity, negative daily mood, higher pain interference and catastrophizing, poorer quality of life and a higher likelihood of opioid misuse (all p < 0.01). SCD patients with more severe depressive symptoms experienced poorer pain outcomes, lower quality of life and increased risk of opioid misuse. Longitudinal data from this trial will determine whether addressing depressive symptoms may potentially reduce pain frequency and severity in SCD.

ABSTRACT Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of this, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well as the endogenous F 1 -ATPase inhibitor ATP5IF1 . In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F 1 -ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as a cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy.

Background Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events. Methods This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, S beta-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 10 mg three times a day up to 25 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 05 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment- emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed. Findings Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 227% (n=15) in the riociguat group and 313% (n=20) in the placebo group (difference -85% [90% CI -214 to 45]; p=019). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (167 [n=11] vs 219% [n=14]; difference -52% [-172 to 65]; p=042), mean pain severity (318 vs 332; adjusted mean difference -014 [-070 to 042]; p=069), and pain interference (315 vs 312; 004 [-062 to 069]; p=093) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -820 mm Hg (-1048 to -591) compared with -124 (-358 to 110) in those taking placebo (-696 mm Hg (90% CI -1022 to -369; p<0001). Interpretation Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials. Copyright (c) 2024 Elsevier Ltd. All rights reserved.

Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen-reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of -1.5% (95% confidence interval [CI], -2.7 to -0.2). In patients requiring >= 2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, -2.4%; 95% CI, -4.2 to -0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving >= 2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, demonstrated high probability of reduced severe pulmonary injury requiring assisted

This is a celebratory reprint of a historical paper published in STH in 1998. The original Abstract follows. The PFA-100 system is a platelet function analyzer designed to measure platelet-related primary hemostasis. The instrument uses two disposable cartridges: a collagen/epinephrine (CEPI) and a collagen/ADP (CADP) cartridge. Previous experience has shown that CEPI cartridges detect qualitative platelet defects, including acetylsalicylic acid (ASA)-induced abnormalities, while CADP cartridges detect only thrombocytopathies and not ASA use. In this seven-center trial, 206 healthy subjects and 176 persons with various platelet-related defects, including 127 ASA users, were studied. The platelet function status was determined by a platelet function test panel. Comparisons were made as to how well the defects were identified by the PFA-100 system and by platelet aggregometry. The reference intervals for both cartridges, testing the 206 healthy subjects, were similar to values described in smaller studies in the literature (mean closure time [CT] of 132 seconds for CEPI and 93 seconds for CADP). The use of different lot numbers of cartridges or duplicate versus singleton testing revealed no differences. Compared with the platelet function status, the PFA-100 system had a clinical sensitivity of 94.9% and a specificity of 88.8%. For aggregometry, a sensitivity of 94.3% and a specificity of 88.3% were obtained. These values are based on all 382 specimens. A separate analysis of sensitivity by type of platelet defect, ASA use versus congenital thrombocytopathies, revealed for the PFA-100 system a 94.5% sensitivity in identifying ASA users and a 95.9% sensitivity in identifying the other defects. For aggregometry, the values were 100% for ASA users and 79.6% for congenital defects. Analysis of concordance between the PFA-100 system and aggregometry revealed no difference in clinical sensitivity and specificity between the systems (p > 0.9999). The overall agreement was 87.5%, with a Kappa index of 0.751. The two tests are thus equivalent in their ability to identify normal and abnormal platelet defects. Testing 126 subjects who took 325 mg ASA revealed that the PFA-100 system (CEPI) was able to detect 71.7% of ASA-induced defects with a positive predictive value of 97.8%. The overall clinical accuracy of the system, calculated from the area under the receiver operating characteristic curve, was 0.977. The data suggest that the PFA-100 system is highly accurate in discriminating normal from abnormal platelet function. The ease of operation of the instrument makes it a useful tool to use in screening patients for platelet-related hemostasis defects.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation’s Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option. Longitudinal genomic and transcriptomic profiling of 1,143 patients with multiple myeloma by the Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study yields an improved copy number and gene expression subtype scheme, most notably a high-risk proliferative subtype associated with complete loss of RB1 or MAX.

Abstract Despite the burden of chronic pain in sickle cell disease (SCD), nonpharmacological approaches remain limited. This multisite, randomized trial compared digital cognitive behavioral therapy (CBT) with a digital pain/SCD education program (“Education”) for managing pain and related symptoms. Participants were recruited virtually from seven SCD centers and community organizations in the United States. Adults (aged ≥18 years) with SCD-related chronic pain and/or daily opioid use were assigned to receive either CBT or Education for 12 weeks. Both groups used an app with interactive chatbot lessons and received personalized health coach support. The primary outcome was the change in pain interference at six months, with secondary outcomes including pain intensity, depression, anxiety, quality of life, and self-efficacy. Of 453 screened participants, 359 (79%) were randomized to CBT (n = 181) or Education (n = 178); 92% were Black African American, and 66.3% were female. At six months, 250 participants (70%) completed follow-up assessments, with 16 (4%) withdrawals. Engagement with the chatbot varied, with 76% connecting and 48% completing at least one lesson, but 80% of participants completed at least one health coach session. Both groups showed significant within-group improvements in pain interference (CBT: −2.13; Education: −2.66), but no significant difference was observed between them (mean difference, 0.54; P = .57). There were no between-group differences in pain intensity, depression, anxiety, or quality of life. High engagement with health coaching and variable engagement with digital components may explain the similar outcomes between interventions in this diverse, hard-to-reach population.

Background:Mortality due to immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains significant. Predicting mortality risk may potentially help individualize treatment. The French Thrombotic Microangiopathy (TMA) Reference Score has not been externally validated in the United States. Recent advances in machine learning technology can help analyze large numbers of variables with complex interactions for the development of prediction models.Objectives:To validate the French TMA Reference Score in the United States Thrombotic Microangiopathy (USTMA) iTTP database and subsequently develop a novel mortality prediction tool, the USTMA TTP Mortality Index.Methods:We analyzed variables available at the time of initial presentation, including demographics, symptoms, and laboratory findings. We developed our model using gradient boosting machine, a machine learning ensemble method based on classification trees, implemented in the R package gbm.Results:In our cohort (n = 419), the French score predicted mortality with an area under the receiver operating characteristic curve of 0.63 (95% CI: 0.50-0.77), sensitivity of 0.35, and specificity of 0.84. Our gradient boosting machine model selected 8 variables to predict acute mortality with a cross-validated area under the receiver operating characteristic curve of 0.77 (95% CI: 0.71-0.82). The 2 cutoffs corresponded to sensitivities of 0.64 and 0.50 and specificities of 0.76 and 0.87, respectively.Conclusion:The USTMA Mortality Index was acceptable for predicting mortality due to acute iTTP in the USTMA registry, but not sensitive enough to rule out death. Identifying patients at high risk of iTTP-related mortality may help individualize care and ultimately improve iTTP survival outcomes. Further studies are needed to provide external validation. Our model is one of many recent examples where machine learning models may show promise in clinical prediction tools in healthcare.

Introduction: Sickle cell disorders are the most prevalent inherited hemoglobinopathies, affecting over 100,000 in the United States. Owing to accelerated chronic hemolysis, pigment gallstone formation is common and may be complicated by cystic or common bile obstruction. Gallstones and their acute complications also burden the general population, though favoring the cholesterol calculi subtype. In this study, we aimed to evaluate the healthcare utilization and outcomes of hospital admissions for acute biliary calculi disease in patients with sickle cell disorders compared to the general population. Methods: We conducted a retrospective cohort study of the 2016-2020 National Inpatient Sample dataset to compare admissions of patients age ≥ 18 years with acute gallstone disease using International Classification of Diseases-10 codes for acute cholecystitis and acute cholangitis with and without a secondary coded diagnosis of sickle cell disease (SCD). The primary outcome, length of stay, was assessed using a Poisson regression model. Secondary outcomes - total charges and admission mortality, were assessed using Poisson and logistic regression model respectively. Admission characteristics compared between patients with and without SCD included age, sex, race/ethnicity, hospital region, hospital bed size, expected primary payer, total charges, and Charlson Comorbidity score using Wald's test. Results: 74,085 hospitalizations were identified meeting inclusion criteria of adult admissions for gallstone disease. Among these, 125 (0.17%) had SCD. Poisson regression analysis revealed SCD admissions to have 27% longer hospital stay (p < 0.002, CI [1.09 - 1.47]. Total charges were also 25% higher in SCD admissions (p = 0.014, CI [1.04 - 1.50]). There was also an observed 38% higher mortality rate in the SCD group, however this difference did not reach statistical significance (p = 0.76). Unadjusted analysis showed SCD patients with gallstone disease more likely to be younger [18-35 years] (46.40% vs 11.72%, p < 0.001), Black (84.8% vs 10.2%, p<0.001), treated in Southern state facilities (52.0% vs 39.7%, p = 0.008), have Medicaid as primary payer (32.0% vs 14.35%, p<0.001), have higher total hospital charges ($71,641.80 vs $56,421.58, p<0.001) and to have fewer comorbidities with a significant proportion having Charlson Comorbidity score of 0 (48% vs 36.42%, p=0.010). Discussion: Despite being younger and having fewer comorbidities, the SCD cohort had higher admission charges, longer lengths of stay, and potential trend towards higher mortality when admitted for acute gallstone disease compared to patients without SCD. This may be due to the difficulty in diagnosing acute biliary calculi in SCD patients, where symptoms often mimic a vaso-occlusive crisis, leading to delayed diagnosis. Socioeconomic disparities common in SCD patients could also contribute to these outcomes. Further research should investigate the specific mechanisms behind these findings, improve diagnostic accuracy and timeliness, and develop tailored management strategies to enhance care and prognosis for SCD patients with acute gallstone disease.

4005 Background: If 5FU/Capecitabine sensitized radiotherapy (RT) is beneficial in the adjuvant (adj) management of PA after adj chemotherapy (chemo) is controversial. NRG/RTOG 0848 was designed to address this issue. Methods: This was a 2 step NCTN randomized (rndmzd) trial. Step 1 rndmzd patients (pts) to 5 cycles of gemcitabine +/- Erlotinib. Step 2 rndmzd pts to a 6th cycle of the same chemo +/- 5FU/Capecitabine with 50.4 Gy in 28 fractions RT (chemo+CRT). Step 1 eligibility included: R0/R1 resection, M0, ECOG PS 0-1, CA19-9≤180. Step 2 eligibility included > 4 cycles chemo (gem, gem combo, (m)FOLFIRINOX). RT included real time 3D/IMRT treatment (RX) plan review, scoring, and approval. At Step 2, pts stratified by nodal status (+ vs -), CA19-9 (≤90 vs > 90-180), surgical margins (R0 vs R1), and adjuvant chemo. Primary endpoint was OS. Secondary endpoints are DFS and AEs (CTCAEv4). Assuming 17 months median OS (chemo) and hypothesized 22.5 months (chemo+CRT), sample size was 354 pts (HR = 0.76, 80% power, 1-sided α = 0.05, 316 OS events). Due to lower than projected event rate, trial was amended to report at the earlier of (a) 316 observed OS events or (b) 5 years of follow-up time from Step 2 accrual closure (265 OS events, 72% power, same α). OS and DFS were estimated by Kaplan-Meier and arms compared using log-rank test. Multivariable analyses (MVA) used Cox proportional hazards models. Results: Accrual began 11/2009; closed 10/2018. 354 pts rndmzd (174 chemo, 180 chemo+CRT). Median follow-up for all & alive pts = 2 & 7 years, respectively, with 270 OS events. Median age 63, 45% female, 81% white, 13% AA. 83% R0, 26% node negative, 96% CA19-9 < 90. 13% of chemo+CRT pts did not receive RT. AEs were comparable (grade 4: 10% [chemo] vs 11% [chemo+CRT] and 1 grade 5 AE in each arm). Univariate OS/DFS results shown in Table. In initial MVA, RX, CA19-9, surgical margins were not statistically significantly associated with OS or DFS, but nodal status (OS, DFS) and race (OS) were. In further analyses, significant interactions were found between RX and nodal status for both OS and DFS. Node negative pts treated with chemo+CRT had better outcome than chemo pts; node positive pts did not (Table). Conclusions: Chemo+CRT did not improve OS overall, but did improve DFS. Both OS and DFS were improved with Chemo+CRT in node negative pts. Chemo+CRT did not increase Gr 4 or 5 AEs compared to chemo. Clinical trial information: NCT01013649 . [Table: see text]

Background: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy carrying a poor prognosis. Relative to non-leukemic myeloid progenitors, AML cells present with elevations in mitochondrial metabolism driven by higher mitochondrial content. Despite having more mitochondria per cell, AML cells are inefficient at coupling respiration to ATP synthesis, indicative of intrinsic deficiencies in oxidative phosphorylation (OXPHOS) flux. The present study aimed to determine the relationship between mitochondrial OXPHOS kinetics and chemotherapy response in a clinical cohort of AML patients by comparing mitochondrial bioenergetic profiles between responders to induction chemotherapy with those who have persistent disease, and between adverse risk and intermediate risk AML. Methods: In this prospective study from January 2020 to February 2023, we collected bone marrow aspirate samples from patients with new diagnosis of AML on day 1 to evaluate the bioenergetic phenotype of the AML cells. We collected data on primary induction therapy, response to induction therapy, relapse, and other clinical features. We compared the bioenergetic phenotypes between the responders to primary induction chemotherapy and non-responders who had persistent disease post induction chemotherapy. We did the same comparison between patients with adverse risk and intermediate risk AML per European LeukemiaNet (ELN) 2022 risk stratification. Mitochondrial bioenergetic profiles were generated via high resolution respirometry using freshly isolated mononuclear cells from each patient's bone marrow aspirate. The Fisher exact test was used for categorical variables and the Wilcoxon Rank Sum for continuous variables. Results: In 18 AML patients included in the study, median age was 64 years (range 30-85 years), 67% (N=12) were male, 33% female, 61%(n=11) were Caucasian and 39%(n=7) were African Americans. Day 1 median blast count was 57% (range 20-92%). Initial induction therapy with cytarabine/daunorubicin (standard 7+3) with or without midostaurin (in patients with FLT3 mutations) was done in 12 (67%) patients and hypomethylating agent/venetoclax was used in 5 (28%) patients. One patient was managed with azacitidine only. Seven (39%) patients had persistent disease after induction and others responded to the initial induction. Relapsed disease after achieving remission with initial induction was seen in 8 (44%) patients. No patients had favorable risk cytogenetics/molecular findings, 10 had adverse risk AML and 9 had intermediate risk AML. TP53 mutation was observed in 4 patients, FLT3 mutation in 5 patients, IDH1 mutation in 4, and IDH2 mutation in 3 patients. The fraction of the respiratory network capable of performing OXPHOS (i.e., Fractional OXPHOS) was 0.426 in responders and 0.629 in non-responders (p=0.93). In responders, basal respiration in intact cells was non-significantly (p=0.54) lower ( JO2 9.838 pmol/s/million cells) compared to non-responders ( JO2 11.52 pmol/s/million cells). Adverse risk patients had lower fractional OXPHOS, and higher basal and maximal respiration rates as compared to intermediate risk AML patients (Table 1). Conclusion: While Fractional OXPHOS and basal respiration were lower in the patients who had remission after induction therapy, this difference was not statistically significant. We did not find a clinically significant correlation in the bioenergetic profile of AML cells; however, our study is limited by small sample size. Further research is warranted to investigate the role of OXPHOS kinetics in patients of AML that can translate into clinically meaningful outcomes.

Key Clinical Message:Acquired factor VIII inhibitors can be a rare cause of extensive intramuscular bleeding requiring fasciotomy. The subsequent postoperative period requires close monitoring due to high risk of fatal blood loss. Abstract:Acquired factor VIII inhibitors are a rare cause of often extensive bleeding and subsequently large hematomas. This disorder's overall mortality can reach 38%, largely due to immunosuppression and subsequent infections or an underlying cause such as malignancy. The patient in this case study presented with a hematoma and extensive ecchymosis of the hand and forearm, which continued to progress, precipitating compartment syndrome of the hand and forearm and ultimately requiring fasciotomy. The combination of factors led to significant blood loss in the postoperative period requiring major fluid resuscitation and intensive care unit (ICU) level care. Due to this disorder's rarity and overall mortality, we present this case report with a literature review for management of acquired hemophilia in the setting of urgent fasciotomy.

Since 2002, when Dr. William Bobzien first provided insight into the challenges of providing oncology care in Eastern North Carolina, we have made significant improvements. But we still face challenges, many of which are related to the ongoing socioeconomic issues of the citizens of our region.

Background: Acute painful vaso-occlusive crises (VOCs), the hallmark of sickle cell disease (SCD), are associated with chronic and potentially life-threatening complications. The SOLACE-adults study (NCT03264989) interim analysis (cutoff date: August 1, 2020) demonstrated the long-term pharmacokinetic (PK) and pharmacodynamic (PD) properties, potential sustained efficacy (VOC reduction), and long-term safety of crizanlizumab 5 mg/kg and 7.5 mg/kg during ≥12 months' (mo) treatment in >80% of patients (pts) with SCD [Kanter J et al . Blood advances 2023]. Here we report the updated PK/PD, including ex vivo P-selectin inhibition, safety, and efficacy results from the final interim analysis of this study (cutoff date: June 1, 2022) for all pts who received crizanlizumab 5 mg/kg (~3.5 years [y]) and 7.5 mg/kg (~3 y). Methods: This is a phase 2, multicenter, open-label study in pts with SCD, aged 16 to 70 y, who had experienced ≥1 VOC (defined as pain crises and complicated SCD crises such as acute chest syndrome, priapism and hepatic or splenic sequestration) in the 12 mo prior to screening. Pts were enrolled into 5 mg/kg and then 7.5 mg/kg groups sequentially and received crizanlizumab by intravenous infusion over 30 minutes on day 1, day 15, and every 4 weeks (wk) thereafter. Pts receiving hydroxyurea/hydroxycarbamide (HU/HC) and/or erythropoietin-stimulating agents for at least 6 mo prior to screening were allowed to continue the same dose and schedule during the study. Results: Overall, 57 pts were enrolled: 45 received crizanlizumab 5 mg/kg (median age, 29 [IQR 22, 39] y) for a median of 191 (IQR 98, 210) wk, and 12 received 7.5 mg/kg (median age, 21 [IQR 18, 41] y) for a median of 167 (IQR 120,182) wk. At cutoff, 22 pts (49%) in 5 mg/kg group and 6 pts (50%) in 7.5 mg/kg group discontinued the treatment, primarily because of physicians' (5 mg/kg, n=6; 7.5 mg/kg, n=4) and pts' decisions (5 mg/kg, n=9). For both doses, serum crizanlizumab concentrations increased to nearly maximum levels (C max) at the end of the 30-minute infusion and remained steady for 6 hours after infusion. For each dose, C max at wk 1 and 15 was similar ( Table), indicating no significant accumulation. Crizanlizumab exposure increased almost dose proportionally from 5 mg/kg to 7.5 mg/kg. P-selectin inhibition was nearly complete throughout the dosing interval for both doses at steady state (5 mg/kg, 90% to 98%; 7.5 mg/kg, 86% to 96%), with consistent and stable pre-dose inhibition throughout the study ( Figure). All pts reported ≥1 adverse events (AEs) in both dose groups. The most common AEs were pyrexia (5 mg/kg, 14 [31%]; 7.5 mg/kg, 3 [25%]), headache and hypokalemia (5 mg/kg, 12 [27%]; 7.5 mg/kg, 2 [17%], each). Grade ≥3 AEs occurred in 27 pts (60%) in the 5 mg/kg group and in 6 pts (50%) in the 7.5 mg/kg group. At least one serious AE was reported in 22 pts (49%) in the 5 mg/kg group and 5 pts (42%) in the 7.5 mg/kg group; 1 was drug related in 5 mg/kg group (none in the 7.5mg/kg group). One pt in each of the 5 mg/kg (2%) and 7.5 mg/kg (8%) groups discontinued treatment because of drug-related AEs. One pt in each group died while on treatment, but the death was not considered related to crizanlizumab. Two pts in the 5 mg/kg group had severe crizanlizumab-related infusion-related reactions (IRR) (grade 2 pain [n=1], grade 3 IRR [n=1]), which resolved with treatment. No grade ≥3 treatment-related infections or bleeding events were reported. No pts developed antibodies against crizanlizumab. The median (IQR) annualized rate of VOCs leading to a healthcare visit in the 5 mg/kg group was 4 (1, 7) at baseline and 2.75 (1.03, 5.32) on treatment; absolute change from baseline, -0.76 (-2.94, 2.01). In the 7.5 mg/kg group, the corresponding rates were 2 (1, 4.5) and 1.09 (0.30, 3.36), -0.91 (-1.06, -0.50). Eight pts (18%) in the 5 mg/kg group and 2 pts (17%) in the 7.5 mg/kg group were VOC free during the entire treatment period. Conclusions: These long-term results for ~3.5 y in 5 mg/kg and ~3 y in 7.5 mg/kg groups demonstrate that serum crizanlizumab concentrations rose to a near maximum level shortly after infusion and remained steady 6 hours after infusion for both doses. Crizanlizumab with or without HU/HC was safe with no new/unexpected safety concerns and no apparent differences between the two doses in the frequency and severity of AEs. Consistent with previously reported results from SUSTAIN study, crizanlizumab reduced the annualized rate of VOCs leading to a healthcare visit from baseline.

Introduction: Sickle Cell Disease (SCD) is an inherited hemolytic disorder due to an autosomal recessive mutation affecting mainly African Americans. SCD can lead to various complications, including Sickle Cell Crisis (SCC), Acute Chest Syndrome (ACS), strokes, and different osseous complications. Notably, these complications can be provoked using steroids. Sarcoidosis is a multisystem inflammatory disorder that is characterized by the presence of bilateral hilar lymphadenopathy that is commonly treated with steroids. Unfortunately, it is also preferentially affecting African Americans. The complication rates in patients with both diseases have rarely been described. We aim to describe the effect of sarcoidosis on the mortality and complication rates of admitted patients with SCC. Methods: Using the National Inpatient Sample (NIS) 2016-2020, we analyzed adult SCC and ACS hospitalizations with and without sarcoidosis using International Classification of Diseases - 10 Clinical Modification (ICD-10-CM) codes. The primary outcome was inpatient mortality. Secondary outcomes were inpatient morbidities, mean length of stay (LOS), and mean total hospital charge (THC). A multivariate logistic regression and linear regression analyses were used to adjust for potential confounders. Results: Out of 359655 patients hospitalized with SCC, only 4.6% had concomitant sarcoidosis. Of these, 70% were females, with a mean age of 38.4 compared to an average age of 32 in patients without sarcoidosis (p-value <0.05). The mean LOS for patients with sarcoidosis and SCC was 6.4 days, while it was 5.1 days for patients without sarcoidosis (p-value 0.001). While adjusting for common comorbidities and patients' characteristics, patients with SCC and sarcoidosis did not have a statistical mortality difference compared to patients without sarcoidosis [adjusted odds ratio (aOR): 2.3, CI: 0.4-14). On stratified analysis, patients with ACS and sarcoidosis had increased odds of mortality with an aOR of 6.68, CI: 1.1-39.7, and a p-value of 0.037. Moreover, amongst patients who had SCC, patients with concomitant sarcoidosis had a higher risk of acute coronary syndrome (aOR: 5.1, CI 1.24-21.0) and avascular necrosis (aOR: 1.57, CI: 1.12-2.20). There were no statistically significant differences in the odds of ischemic strokes, transient ischemic attacks, acute and chronic kidney disease, risk of intubation, pulmonary edema, osteoporosis, venous thrombosis, and THC. Figure 1 shows the Forrest plot for multivariate analysis of in-hospital morbidities when adjusted for patient demographics, comorbidities, and hospital characteristics. Conclusion: Patients admitted with ACS and sarcoidosis had higher odds of mortality. Patients with SCC and sarcoidosis also had higher odds of acute coronary syndrome, avascular necrosis, and mean LOS. Nevertheless, this has not impacted other inpatient comorbidity.