Potential mechanisms of gut microbiota influence on different types of vertigo: a bidirectional Mendelian randomization and mediation analysis.

BACKGROUND: The relationship between gut microbiota and vertigo, specifically Benign Paroxysmal Vertigo (BPV) and Vertigo of Central (VC), remains underexplored. AIM AND HYPOTHESES: This study aims to investigate the causal relationships between gut microbiota and two types of vertigo, BPV and VC. Additionally, the study seeks to explore the mediation effects of metabolic, inflammatory, and psychological factors on these relationships. We hypothesize that specific taxa of gut microbiota have a causal effect on the risk of developing BPV and VC. The mediation effects of HbA1c, obesity, major depression, and interleukin-18 levels significantly influence the relationships between gut microbiota and vertigo. METHOD: Utilizing a bidirectional two-sample Mendelian randomization approach, this study investigated causal associations between gut microbiota and the two types of vertigo. A network MR assessed mediation effects of HbA1c, major depression, obesity, and interleukin-18 levels, with data sourced from several consortia, including MiBioGen. RESULTS: Distinct gut microbiota displayed varying influences on BPV and VC risks. A total of ten taxa affect BPV. Among these, two taxa have an odds ratio (OR) greater than 1, including one class, one order. Conversely, eight taxa have an OR less than 1, encompassing four families, three genera, and one order. The OR for these taxa ranges from 0.693 to 0.930, with p-values between 0.006 and 0.048. For VC, eight taxa were found to have an impact. Five of these taxa exhibit an OR greater than 1, including four genera and one phylum. The OR for these taxa ranges from 1.229 to 2.179, with p-values from 0.000 to 0.046. The remaining three taxa have an OR less than 1, comprising one family and two genera, with an OR range of 0.445 to 0.792 and p-values ranging from 0.013 to 0.050. The mediation analysis for BPV shows that major depression, obesity, and HbA1c are key mediators between specific taxa and BPV. Major depression mediates 28.77% of the effect of family Rhodospirillaceae on BPV. Obesity mediates 13.90% of the effect of class Lentisphaeria/order Victivallales. HbA1c mediates 11.79% of the effect of genus Bifidobacterium, 11.36% of family Bifidobacteriaceae/order Bifidobacteriales. For VC, interleukin-18 levels and major depression are significant mediators. Interleukin-18 levels mediate 6.56% of the effect of phylum Actinobacteria. Major depression mediates 6.51% of the effect of genus Alloprevotella. CONCLUSION: The study highlights potential causal links between gut microbiota and vertigo, emphasizing metabolic and psychological mediators. These insights underscore the therapeutic potential of targeting gut health in vertigo management.

Design and Development of a Multimodal Digital Intervention (SHIFT App) to Address Sexual Dysfunction in Hematopoietic Stem Cell Transplant (HSCT) Survivors.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) survivors frequently experience persistent sexual dysfunction, which is associated with impaired quality of life (QOL) and increased psychological distress. The lack of availability of clinicians with expertise in sexual health limits the capacity to address sexual health concerns in HSCT survivors. Digital health applications may offer a patient-centered and scalable solution to address sexual health concerns in cancer survivors. The objective of this report is to delineate the iterative process of adapting an in-person sexual health intervention into a self-administered digital application called "Sexual Health and Intimacy Following Transplant (SHIFT)" and the refinement of SHIFT using stakeholder feedback. METHODS: We used a five-step development model to adapt SHIFT that included: 1) implementation of a multimodal bio-psycho-social conceptual framework, 2) development of a comprehensive intervention manual and SHIFT content, 3) translation of the intervention manual into an interactive storyline with a focus on enhancing patient engagement, 4) creation of initial SHIFT wireframes, and 5) refinement of SHIFT through iterative alpha and beta testing. At each step, key stakeholders including HSCT survivors, HSCT clinicians, and experts in sexual health, psychology, and digital health provided iterative feedback. RESULTS: We adapted SHIFT based on our conceptual framework, prior in-person intervention work, and iterative stakeholder feedback in each application development stage. SHIFT incorporates medical information, educational materials, intimacy exercises, and activities to address the multiple etiologies of sexual health concerns in HSCT survivors. SHIFT includes strategies to enhance engagement including gamification, personalization, and incorporation of video from HSCT survivors and clinicians. Based on stakeholder feedback, SHIFT was refined with a focus on inclusivity of gender, sexual orientation, relationship status, and body image concerns. CONCLUSIONS: SHIFT is novel, patient-centered digital application to address sexual dysfunction in HSCT survivors. Iterative feedback from key stakeholders including HSCT survivors guided SHIFT adaptation and refinement, to optimize patient engagement and ensure inclusivity. The final prototype of SHIFT was initially acceptable to key stakeholders and is now under further testing in a pilot randomized trial to assess its feasibility and preliminary efficacy for improving sexual health outcomes in HSCT survivors.

Fusible and Radiopaque Microspheres for Embolization.

In this work, fusible microspheres loaded with radiopaque agents as an embolic agent for transcatheter arterial embolization (TAE) are developed. A poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) multi-block copolymer basing polyurethane (PCEU) is synthesized and fabricated into blank microspheres (BMs). The microspheres are elastic in compression test. A clinical contrast agent lipiodol is encapsulated in the microspheres to receive fusible radiopaque microspheres (FRMs). The sizes of FRMs are uniform and range from 142.2 to 343.1 µm. The encapsulated lipiodol acts as the plasticizer to reduce the melting temperature point (Tm) of PECU microspheres, thus, leading to the fusion of microspheres to exhibit efficient embolization in vivo. The performance of FRMs is carried out on a rabbit ear embolization model. Serious ischemic necrosis is observed and the radiopacity of FRMs sustains much longer time than that of commercial contrast agent Loversol in vivo. The fusible and radiopaque microsphere is promising to be developed as an exciting embolic agent.

Health-Related Quality of Life with Gilteritinib versus Placebo Post-Transplant for FLT3-ITD+ Acute Myeloid Leukemia.

BMT CTN 1506 was a phase III randomized trial comparing gilteritinib versus placebo after allogeneic HCT for FLT3-ITD-positive AML. The primary analysis comparing relapse-free survival (RFS) was not statistically significant, however, patients with detectable FLT3-ITD MRD peri-HCT had significantly longer RFS with gilteritinib. The aim of this analysis is to describe the effect of post-HCT gilteritinib versus placebo on health-related quality of life (HRQOL). HRQOL was measured using the Functional Assessment of Cancer Therapy (FACT)-BMT, FACT-Leukemia (-Leu), and EQ-5D-5L at post-HCT randomization, day 29, month 3, 6, 12, 18, 24, and/or end of therapy. HRQOL and clinically meaningful differences were summarized using descriptive statistics and compared using mixed model repeated measures to evaluate longitudinal change from baseline and stratified Cox model to evaluate time to improvement. Between 8/2017 and 7/2020, 356 patients were randomized. HRQOL completion rate was acceptable (>70%) across all time points and measures. There were no differences in FACT-BMT, FACT-Leu, or EQ-5D-5L scores at any time point between cohorts. There was an increase in scores over time, indicating improvement in HRQOL post-HCT. Clinically meaningful improvement and time to improvement in HRQOL was similar in both arms. Despite higher TEAEs with gilteritinib, response to the question of being "bothered by side effects of treatment" did not differ between groups. Subgroup analysis of MRD detectable and negative patients demonstrated no differences in HRQOL between arms. For FLT3-ITD+ AML patients undergoing HCT, gilteritinib maintenance was not associated with any difference in HRQOL or patient-reported impact of side effects. Trial Registration: NCT02997202.

Novel MAGIC composite scores using both clinical symptoms and biomarkers best predict treatment outcomes of acute GVHD.

ABSTRACT: Acute graft-versus-host disease (GVHD) grading systems that use only clinical symptoms at treatment initiation such as the Minnesota risk identify standard and high-risk categories but lack a low-risk category suitable to minimize immunosuppressive strategies. We developed a new grading system that includes a low-risk stratum based on clinical symptoms alone and determined whether the incorporation of biomarkers would improve the model's prognostic accuracy. We randomly divided 1863 patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) who were treated for GVHD into training and validation cohorts. Patients in the training cohort were divided into 14 groups based on similarity of clinical symptoms and similar nonrelapse mortality (NRM); we used a classification and regression tree (CART) algorithm to create three Manhattan risk groups that produced a significantly higher area under the receiver operating characteristic curve (AUC) for 6-month NRM than the Minnesota risk classification (0.69 vs 0.64, P = .009) in the validation cohort. We integrated serum GVHD biomarker scores with Manhattan risk using patients with available serum samples and again used a CART algorithm to establish 3 MAGIC composite scores that significantly improved prediction of NRM compared to Manhattan risk (AUC, 0.76 vs 0.70, P = .010). Each increase in MAGIC composite score also corresponded to a significant decrease in day 28 treatment response (80% vs 63% vs 30%, P < .001). We conclude that the MAGIC composite score more accurately predicts response to therapy and long-term outcomes than systems based on clinical symptoms alone and may help guide clinical decisions and trial design.

Allogeneic B cell immunomodulatory therapy in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease. Immune system dysregulation plays an essential role in ALS onset and progression. Our preclinical studies have shown that the administration of exogenous allogeneic B cells improves outcomes in murine models of skin and brain injury through a process termed pligodraxis, in which B cells adopt an immunoregulatory and neuroprotective phenotype in an injured environment. Here, we investigated the effects of B-cell therapy in the SOD1G93A mouse preclinical model of ALS and in a person living with ALS. Purified splenic mature naïve B cells from haploidentical donor mice were administered intravenously in SOD1G93A mice for a total of 10 weekly doses. For the clinical study in a person with advanced ALS, IgA gammopathy of unclear significance, and B lymphopenia, CD19+ B cells were positively selected from a healthy haploidentical donor and infused intravenously twice, at a 60-day interval. Repeated intravenous B-cell administration was safe and significantly delayed disease onset, extended survival, reduced cellular apoptosis, and decreased astrogliosis in SOD1G93A mice. Repeated B-cell infusion in a person with ALS was safe and did not appear to generate a clinically evident inflammatory response. An improvement of 5 points on the ALSFRS-R scale was observed after the first infusion. Levels of inflammatory markers showed persistent reduction post-infusion. This represents a first demonstration of the efficacy of haploidentical B-cell infusion in the SOD1G93A mouse and the safety and feasibility of using purified haploidentical B lymphocytes as a cell-based therapeutic strategy for a person with ALS.

RNA 2'-O-methylation promotes persistent R-loop formation and AID-mediated IgH class switch recombination.

BACKGROUND: RNA-DNA hybrids or R-loops are associated with deleterious genomic instability and protective immunoglobulin class switch recombination (CSR). However, the underlying phenomenon regulating the two contrasting functions of R-loops is unknown. Notably, the underlying mechanism that protects R-loops from classic RNase H-mediated digestion thereby promoting persistence of CSR-associated R-loops during CSR remains elusive. RESULTS: Here, we report that during CSR, R-loops formed at the immunoglobulin heavy (IgH) chain are modified by ribose 2'-O-methylation (2'-OMe). Moreover, we find that 2'-O-methyltransferase fibrillarin (FBL) interacts with activation-induced cytidine deaminase (AID) associated snoRNA aSNORD1C to facilitate the 2'-OMe. Moreover, deleting AID C-terminal tail impairs its association with aSNORD1C and FBL. Disrupting FBL, AID or aSNORD1C expression severely impairs 2'-OMe, R-loop stability and CSR. Surprisingly, FBL, AID's interaction partner and aSNORD1C promoted AID targeting to the IgH locus. CONCLUSION: Taken together, our results suggest that 2'-OMe stabilizes IgH-associated R-loops to enable productive CSR. These results would shed light on AID-mediated CSR and explain the mechanism of R-loop-associated genomic instability.

Construction of a digital twin of chronic graft vs. host disease patients with standard of care.

There is an unmet medical need for new clinical trials to evaluate novel therapies in chronic graft-versus-host disease (cGvHD). Disease rarity, ethical issues regarding placebo arms, time, and cost impede clinical trial conduct. Digital twin (DT) technology enables virtual clinical trial arm construction using historical data, circumventing these obstacles. We evaluated the feasibility of constructing a DT trial arm using a large database of real-world clinical trial data and performed an efficacy assessment of a standard-of-care (SOC) drug to examine agreement with literature data. We constructed a flGvHD DT cohort (cGvHD patients at first-line treatment) (2042 patients; 32 cohorts) using the Trial Accelerator™ Digital Twin platform and derived an SOC arm from this cohort (flGvHD DT SOC cohort) (438 patients; eight cohorts); we analyzed the efficacy of SOC (prednisone) (overall response rate (ORR)) at six months. Our analysis results are in agreement with literature: flGvHD DT: disease onset time: 7.58 months post-allogeneic hematopoietic cell transplantation; most used graft source: peripheral blood stem cells; flGvHD DT SOC: ORR at six months for prednisone: 52.7%. It is feasible to construct a DT cohort using existing clinical trial data; a DT SOC arm can potentially replace a control arm in clinical trials.

Vedolizumab for the prevention of intestinal acute GVHD after allogeneic hematopoietic stem cell transplantation: a randomized phase 3 trial.

Acute graft-versus-host disease (aGVHD) of the lower gastrointestinal (GI) tract is a major cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab is a gut-selective anti-α4ß7 integrin monoclonal antibody that reduces gut inflammation by inhibiting migration of GI-homing T lymphocytes. The efficacy and safety of vedolizumab added to standard GVHD prophylaxis (calcineurin inhibitor plus methotrexate/mycophenolate mofetil) was evaluated for prevention of lower-GI aGVHD after unrelated donor allo-HSCT in a randomized, double-blind, placebo-controlled phase 3 trial. Enrollment closed early during the COVID-19 pandemic with 343 patients randomized (n = 174 vedolizumab, n = 169 placebo), and 333 received ≥1 intravenous dose of 300 mg vedolizumab (n = 168) or placebo (n = 165) and underwent allo-HSCT. The primary end point was met; Kaplan-Meier (95% confidence interval) estimated rates of lower-GI aGVHD-free survival by day +180 after allo-HSCT were 85.5% (79.2-90.1) with vedolizumab versus 70.9% (63.2-77.2) with placebo (hazard ratio, 0.45; 95% confidence interval, 0.27-0.73; P < 0.001). For the 5 key secondary efficacy end points analyzed by day +180 after allo-HSCT, rates of lower-GI aGVHD-free and relapse-free survival and grade C-D aGVHD-free survival were significantly higher with vedolizumab versus placebo. No significant treatment differences were found for the other key secondary end points of non-relapse mortality, overall survival and grade B-D aGVHD-free survival, respectively. Incidence of treatment-related serious adverse events analyzed in patients receiving ≥1 dose of study treatment (n = 334) was 6.5% (n = 11 of 169) vedolizumab versus 8.5% (n = 14 of 165) placebo. When added to standard calcineurin inhibitor-based GVHD prevention, lower-GI aGVHD-free survival was significantly higher with vedolizumab versus placebo. ClinicalTrials.gov identifier: NCT03657160 .

PTEN status determines therapeutic vulnerability to celastrol in cholangiocarcinoma.

BACKGROUND: A balanced protein homeostasis network helps cholangiocarcinoma (CCA) maintain their oncogenic growth, and disrupting proteostasis therapeutically will induce proteotoxic stress. Phosphatase and tensin homolog (PTEN) have been reported to be involved in proteostasis, and PTEN-associated pathways are commonly altered in CCA. Celastrol, a triterpene from plants, exhibits cytotoxic effects in various types of cancer. However, the underlying mechanisms remain unclear. PURPOSE: We investigated the therapeutic effect of celastrol in CCA and identified the molecular characteristics of tumors that were sensitive to celastrol. The target of celastrol was explored. We then evaluated the candidate combination therapeutic strategy to increase the effectiveness of celastrol in celastrol-insensitive CCA tumors. METHODS: Various CCA cells were categorized as either celastrol-sensitive or celastrol-insensitive based on their response to celastrol. The molecular characteristics of cells from different groups were determined by RNA-seq. PTEN status and its role in proteasome activity in CCA cells were investigated. The CMAP analysis, molecular docking, and functional assay were performed to explore the effect of celastrol on proteasome activities. The correlation between PTEN status and clinical outcomes, as well as proteasomal activity, were measured in CCA patients. The synergistic therapeutic effect of autophagy inhibitors on celastrol-insensitive CCA cells were measured. RESULTS: Diverse responses to celastrol were observed in CCA cells. PTEN expression varied among different CCA cells, and its status could impact cell sensitivity to celastrol: PTENhigh tumor cells were resistant to celastrol, while PTENlow cells were more sensitive. Celastrol induced proteasomal dysregulation in CCA cells by directly targeting PSMB5. Cells with low PTEN status transcriptionally promoted proteasome subunit expression in an AKT-dependent manner, making these cells more reliant on proteasomal activities to maintain proteostasis. This caused the PTENlow CCA cells sensitive to celastrol. A negative correlation was found between PTEN levels and the proteasome signature in CCA patients. Moreover, celastrol treatment could induce autophagy in PTENhigh CCA cells. Disrupting the autophagic pathway in PTENhigh CCA cells enhanced the cytotoxic effect of celastrol. CONCLUSION: PTEN status in CCA cells determines their sensitivity to celastrol, and autophagy inhibitors could enhance the anti-tumor effect in PTENhigh CCA.

Phase 1 study of CAR-37 T cells in patients with relapsed or refractory CD37+ lymphoid malignancies.

We report on the first-in-human clinical trial using chimeric antigen receptor (CAR) T-cells targeting CD37, an antigen highly expressed in B- and T-cell malignancies (clinicaltrials.gov NCT04136275). Five patients with relapsed or refractory CD37+ lymphoid malignancies were enrolled and infused with autologous CAR-37 T-cells. CAR-37 T-cells expanded in the peripheral blood of all patients and, at peak, comprised >94% of the total lymphocytes in 4/5 patients. Tumor responses were observed in 4/5 patients, with 3 complete responses, 1 mixed response, and 1 patient whose disease progressed rapidly and with relative loss of CD37 expression. Three patients experienced prolonged and severe pancytopenia, and in two of these patients, efforts to ablate CAR-37 T-cells (which were engineered to co-express truncated EGFR) with cetuximab, were unsuccessful. Hematopoiesis was restored in these two patients following allogeneic hematopoietic stem cell transplantation. No other severe, non-hematopoietic toxicities occurred. We investigated the mechanisms of profound pancytopenia and did not observe activation of CAR-37 T-cells in response to hematopoietic stem cells in vitro or hematotoxicity in humanized models. Patients with pancytopenia had sustained high levels of IL-18, with low levels of IL-18 binding protein in their peripheral blood. IL-18 levels were significantly higher in CAR-37-treated patients relative to both cytopenic and non-cytopenic cohorts of CAR-19-treated cohorts of patients. In conclusion, CAR-37 T-cells exhibited anti-tumor activity, with significant CAR expansion and cytokine production. CAR-37 T-cells may be an effective therapy in hematologic malignancies as a bridge to hematopoietic stem cell transplant.

A Nomogram to Predict the Risk of Acute Ischemic Stroke in Patients with Maintenance Hemodialysis: A Retrospective Cohort Study.

INTRODUCTION: Acute ischemic stroke (AIS) stands as a leading cause of death and disability globally. This study aimed to investigate the risk factors and relevance linked with AIS in patients undergoing maintenance hemodialysis (MHD) and to create and validate nomogram models. METHODS: We examined the medical records of 314 patients with stage 5 chronic kidney disease (CKD 5) undergoing MHD, who sought neurology outpatient department consultation for suspected AIS symptoms between January 2018 and December 2023. These 314 patients were randomly divided into the training cohort (n = 222) and validation cohort (n = 92). The least absolute shrinkage selection operator (LASSO) regression model was employed for optimal feature selection in the AIS risk model. Subsequently, multivariable logistic regression analysis was used to construct a predictive model incorporating the features selected through LASSO. This predictive model's performance was assessed using the C-index and the area under the receiver operating characteristic curve (AUC). Additionally, calibration and clinical utility were evaluated through calibration plots and decision curve analysis (DCA). The model's internal validation was conducted using the validation cohort. RESULTS: Predictors integrated into the prediction nomogram encompassed cardiovascular disease (CVD) (odds ratio [OR] 7.95, 95% confidence interval [CI] 2.400-29.979), smoking (OR 5.7, 95% CI: 1.661-21.955), dialysis time (OR: 5.91, 95% CI: 5.866-29.979), low-density lipoprotein (OR: 2.99, 95% CI: 0.751-13.007), and fibrin degradation products (OR: 5.47, 95% CI: 1.563-23.162). The model exhibited robust discrimination, with a C-index of 0.877 and 0.915 in the internal training and validation cohorts, respectively. The AUC for the training set was 0.857, and a similar AUC of 0.905 was achieved in the validation cohort. DCA demonstrated a positive net benefit within a threshold risk range of 2-96%. CONCLUSION: The proposed nomogram effectively identifies MHD patients at high risk of AIS at an early stage. This model holds the potential to aid clinicians in making preventive recommendations.

Amphiregulin, ST2, and REG3α biomarker risk algorithms as predictors of nonrelapse mortality in patients with acute GVHD.

ABSTRACT: Graft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.

The MAGIC algorithm probability predicts treatment response and long-term outcomes to second-line therapy for acute GVHD.

ABSTRACT: The significance of biomarkers in second-line treatment for acute graft-versus-host disease (GVHD) has not been well characterized. We analyzed clinical data and serum samples at the initiation of second-line systemic treatment of acute GVHD from 167 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC) between 2016 and 2021. Sixty-two patients received ruxolitinib-based therapy, whereas 102 received other systemic agents. In agreement with prospective trials, ruxolitinib resulted in a higher day 28 (D28) overall response Frate than nonruxolitinib therapies (55% vs 31%, P = .003) and patients who received ruxolitinib had significantly lower nonrelapse mortality (NRM) than those who received nonruxolitinib therapies (point estimates at 2-year: 35% vs 61%, P = .002). Biomarker analyses demonstrated that the benefit from ruxolitinib was observed only in patients with low MAGIC algorithm probabilities (MAPs) at the start of second-line treatment. Among patients with a low MAP, those who received ruxolitinib experienced significantly lower NRM than those who received nonruxolitinib therapies (point estimates at 2-year: 12% vs 41%, P = .016). However, patients with high MAP experienced high NRM regardless of treatment with ruxolitinib or nonruxolitinib therapies (point estimates at 2-year: 67% vs 80%, P = .65). A landmark analysis demonstrated that the relationship between the D28 response and NRM largely depends on the MAP level at the initiation of second-line therapy. In conclusion, MAP measured at second-line systemic treatment for acute GVHD predicts treatment response and NRM. The outcomes of patients with high MAP are poor regardless of treatment choice, and ruxolitinib appears to primarily benefit patients with low MAP.

Outcomes of a Formal Hematopoietic Cell Transplantation Survivorship Program on Screening for Late Effects.

Allogeneic hematopoietic cell transplantation (HCT) survivors may benefit from routine screening for post-transplant complications. However, the impact of formal survivorship efforts to promote screening adherence is uncertain. The effect of a formal HCT survivorship program to promote screening adherence was evaluated. We conducted a retrospective analysis of an academic formal HCT survivorship program with primary and specialty consult components. We included patients who underwent allogeneic HCT and were alive and relapse-free 1-year post-HCT. We excluded patients who died <2-year post-HCT or transferred care. We measured screening adherence to cardiovascular, pulmonary, ocular, secondary cancer, and endocrine evaluations. The primary outcome was proportion of patients completing ≥1 evaluation per screening domain prior to 2-year post-HCT. We examined screening adherence during 3 time periods: presurvivorship (2012 to 2014) and 2 postsurvivorship (2016 to 2018 and 2019 to 2021) using multivariate logistic and Cox proportional hazards regression. Four hundred ten patients (2012 to 2014: n = 136, 2016 to 2018: n = 153, 2019 to 2021: n = 121) were included. Compared to the presurvivorship period (16.9%), patients in 2016 to 2018 (47.7%, odds ratio [OR] = 4.9, P < .0001) and 2019 to 2021 (34.7%, OR = 2.7, P = .001) were more likely to complete ≥1 evaluation per screening domain. Except for pulmonary function tests in 2019 to 2021, median time to completion of survivorship evaluations was shorter in the survivorship periods compared to presurvivorship. Patients who completed a formal HCT survivorship consult in 2016 to 2018 and 2019 to 2021 were more likely to complete ≥1 evaluation per screening domain (OR = 5.1, P = .0004). Survivorship consult had similar effect on the primary screening outcome in 2016 to 2018 and 2019 to 2021 (consult × time interaction OR: 2.5, P = .2). However, patients who received a consult in 2019 to 2021 were more likely to complete all screenings (consult × time interaction: OR = 5.7, P = .03). Our HCT survivorship program with primary and specialty components improved screening adherence. Additional studies are needed to evaluate efficacy, dissemination, and implementation of formal HCT survivorship programs.

Arsenic trioxide augments immunogenic cell death and induces cGAS-STING-IFN pathway activation in hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) is particularly challenging due to the inherent tumoral heterogeneity and easy resistance towards chemotherapy and immunotherapy. Arsenic trioxide (ATO) has emerged as a cytotoxic agent effective for treating solid tumors, including advanced HCC. However, its effectiveness in HCC treatment remains limited, and the underlying mechanisms are still uncertain. Therefore, this study aimed to characterize the effects and mechanisms of ATO in HCC. By evaluating the susceptibilities of human and murine HCC cell lines to ATO treatment, we discovered that HCC cells exhibited a range of sensitivity to ATO treatment, highlighting their inherent heterogeneity. A gene signature comprising 265 genes was identified to distinguish ATO-sensitive from ATO-insensitive cells. According to this signature, HCC patients have also been classified and exhibited differential features of ATO response. Our results showed that ATO treatment induced reactive oxygen species (ROS) accumulation and the activation of multiple cell death modalities, including necroptosis and ferroptosis, in ATO-sensitive HCC cells. Meanwhile, elevated tumoral immunogenicity was also observed in ATO-sensitive HCC cells. Similar effects were not observed in ATO-insensitive cells. We reported that ATO treatment induced mitochondrial injury and mtDNA release into the cytoplasm in ATO-sensitive HCC tumors. This subsequently activated the cGAS-STING-IFN axis, facilitating CD8+ T cell infiltration and activation. However, we found that the IFN pathway also induced tumoral PD-L1 expression, potentially antagonizing ATO-mediated immune attack. Additional anti-PD1 therapy promoted the anti-tumor response of ATO in ATO-sensitive HCC tumors. In summary, our data indicate that heterogeneous ATO responses exist in HCC tumors, and ATO treatment significantly induces immunogenic cell death (ICD) and activates the tumor-derived mtDNA-STING-IFN axis. These findings may offer a new perspective on the clinical treatment of HCC and warrant further study.

Gilteritinib as Post-Transplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3.

PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 (FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS: Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS: Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION: Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.