Direct immunofluorescence on plucked hair outer root sheath can predict relapse in pemphigus vulgaris.

BACKGROUND: Prospective research is lacking on the utility of plucked hair outer root sheath direct immunofluorescence (ORS DIF) in the prediction of relapse in pemphigus vulgaris (PV) and the correlation of ORS DIF positivity with serum desmoglein antibody titers. METHODS: We performed a prospective cohort study enrolling 80 PV patients in complete clinical remission at a tertiary care center in North India. Study participants underwent ORS DIF at baseline, which was repeated every 3 months. Skin biopsy DIF was done at study inclusion, repeated at 3 months, and upon clinical relapse. An antidesmoglein antibody titer was assessed concurrently with ORS DIF in a subset of patients. Patients on adjuvant therapy had their adjuvant therapy withdrawn either at the initial visit, at 3 months, or at a 6-month follow-up. Our objectives were to determine the association between positive ORS DIF and clinical relapse, the correlation between positive ORS DIF and skin biopsy DIF, and between positive ORS DIF and positive antidesmoglein antibody titers (when concurrently done). RESULTS: Twenty-two patients (27.5%) had a clinical relapse. Baseline immunological markers significantly associated with relapse are ORS DIF positivity with IgG (16/36 [45.44%] P = 0.005) and C3 (12/29 [41.37%] P = 0.047) and greater intensity of baseline IgG and C3 positivity in ORS DIF (IgG, P = 0.002; C3, P = 0.033). Notably, a significant correlation was observed between baseline positive ORS DIF and skin biopsy DIF (IgG, ρ = 0.695; C3, ρ = 0.498). Positive ORS DIF strongly correlated with positive anti-Dsg3 antibody titers (φs = 0.815; P < 0.01). Early withdrawal of adjuvant immunosuppressant (within 3 months) (P = 0.007) and positive ORS DIF were also associated with relapse (P = 0.017). CONCLUSION AND RELEVANCE: ORS DIF is a reliable predictor of PV clinical relapse and demonstrated robust correlations with skin biopsy DIF and antidesmoglein antibody titers. Periodic assessment of ORS DIF aids in determining new-onset positivity that heralds clinical relapse.

Synthesized alternative reinforcement and resurgence.

In treatments based on differential reinforcement of alternative behavior, applied researchers and clinicians often provide multiple, qualitatively different reinforcers (i.e., synthesized reinforcement) rather than a single reinforcer (i.e., isolated reinforcement) contingent on alternative behavior. Some research shows that providing synthesized reinforcement for alternative responses within such treatments produces more rapid and complete suppression of target behavior; however, there is limited research evaluating the durability of these effects during treatment disruptions. Conceptual explanations of resurgence (e.g., resurgence as choice, context theory) suggest that treatments that include synthesized alternative reinforcement may lead to more resurgence of target behavior when alternative reinforcement is disrupted relative to treatments using isolated reinforcement. We evaluated this hypothesis within a three-phase resurgence evaluation. We exposed rats to isolated or synthesized reinforcement for alternative responding in the second phase, and we exposed rats to extinction in the third phase. Synthesized alternative reinforcement produced more rapid and complete suppression of target behavior than did isolated reinforcement in the second phase; however, exposure to extinction following synthesized reinforcement produced more resurgence. We discuss these results in terms of their implications for applied research and their support for current conceptual explanations for resurgence.

CRISPR-Cas9 Knockout Screens Identify DNA Damage Response Pathways and BTK as Essential for Cisplatin Response in Diffuse Large B-Cell Lymphoma.

The recurrence of diffuse large B-cell lymphoma (DLBCL) has been observed in 40% of cases. The standard of care for refractory/relapsed DLBCL (RR-DLBCL) is platinum-based treatment prior to autologous stem cell transplantation; however, the prognosis for RR-DLBCL patients remains poor. Thus, to identify genes affecting the cisplatin response in DLBCL, cisplatin-based whole-genome CRISPR-Cas9 knockout screens were performed in this study. We discovered DNA damage response (DDR) pathways as enriched among identified sensitizing CRISPR-mediated gene knockouts. In line, the knockout of the nucleotide excision repair genes XPA and ERCC6 sensitized DLBCL cells to platinum drugs irrespective of proliferation rate, thus documenting DDR as essential for cisplatin sensitivity in DLBCL. Functional analysis revealed that the loss of XPA and ERCC6 increased DNA damage levels and altered cell cycle distribution. Interestingly, we also identified BTK, which is involved in B-cell receptor signaling, to affect cisplatin response. The knockout of BTK increased cisplatin sensitivity in DLBCL cells, and combinatory drug screens revealed a synergistic effect of the BTK inhibitor, ibrutinib, with platinum drugs at low concentrations. Applying local and external DLBCL cohorts, we addressed the clinical relevance of the genes identified in the CRISPR screens. BTK was among the most frequently mutated genes with a frequency of 3-5%, and XPA and ERCC6 were also mutated, albeit at lower frequencies. Furthermore, 27-54% of diagnostic DLBCL samples had mutations in pathways that can sensitize cells to cisplatin. In conclusion, this study shows that XPA and ERCC6, in addition to BTK, are essential for the response to platinum-based drugs in DLBCL.

Treatment Outcomes in Patients with Conjunctival Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma.

Purpose: To report the outcomes of different therapies in patients with conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma. Patients and Methods: This retrospective study included patients diagnosed with conjunctival MALT lymphoma between August 2000 and April 2022. Patients were classified into three groups according to their treatment: an observation group, a radiation therapy (RT) group, and a rituximab group (rituximab with or without chemotherapy). We analyzed overall survival (OS), overall, local, and systemic relapse-free survival (RFS), and adverse events after treatment. Results: This study included 15 patients (22 eyes). The 10-year OS was 100%. The 2-, 5-, and 10-year overall RFS rates were 80.1%, 41.2%, and 41.2% in all patients, respectively. The 2- and 5-year local RFS rates in the observation group were 100% and 0%, respectively. The 2-, 5-, and 10-year local RFS rates were 87%, 87%, and 87% in the RT group and 83%, 67%, and 67% in the rituximab group, respectively. The 2- and 5-year systemic RFS rates in the observation group were both 100%, and the 2-, 5-, and 10-year systemic RFS rates were 92%, 55%, and 55% in the RT group, and 100%, 60%, and 60% in the rituximab group, respectively. After RT, 53.3% of the eyes developed cataracts and 75% of these were treated with cataract surgery. In addition, 53.3% of the eyes developed dry eyes and were treated with eye drops. Rituximab with or without chemotherapy resulted in some systemic adverse events, but these improved following symptomatic therapies. Conclusion: RT resulted in good local control of conjunctival MALT lymphoma; however, systemic relapse may occur during long-term follow-up. Local and/or systemic relapse may also occur during long-term follow-up in patients treated by observation or rituximab with or without chemotherapy. Patients with conjunctival MALT lymphoma should be followed-up carefully for as long as possible after treatment.

Risk factors for relapse after discontinuation of tenofovir or entecavir in hepatitis B e antigen-negative patients.

Background and Aim: This study aimed to define the relapse frequency and risk determinants in chronic hepatitis B (CHB) patients who discontinued nucleoside analog (NA) treatment, were HBeAg-negative, and had achieved both a virological and biochemical response. Materials and Methods: This retrospective cohort study reviewed patients with HBeAg-negative CHB who received antiviral therapy for at least 65 months between January 1, 2013, and December 31, 2020. These patients discontinued treatment after demonstrating a biochemical and virological response and were evaluated at 6, 12, and 24 months post-treatment discontinuation. Results: Sixty-seven patients with CHB who received NA therapy for at least 65 months, discontinued treatment, and had undetectable HBV DNA and normal ALT values were evaluated. After cessation of NA therapy, a relapse was observed in 38 patients (56.7%). The relapse rate was 71.0% in patients treated with tenofovir disoproxil fumarate (TDF) as the last NA type and 37.9% in patients treated with entecavir (ETV) (p=0.017). The cutoff value for the best estimate of age for predicting relapse was 42 years. The relapse rate was 69.2% in patients aged ≥42 years and 39.2% in patients aged <42 years (p=0.007). The relapse rate was 51.3% in patients with a pre-treatment fibrosis score of 2, 56.0% in those with a fibrosis score of 3, and 100% in those with a fibrosis score of 4 (p=0.089). Conclusion: Among HBeAg-negative CHB patients who achieved a virological and biochemical response to long-term antiviral therapy, those aged 42 years and older, those with high fibrosis scores before treatment, and those who used TDF before treatment cessation should be closely monitored for relapse, especially in the first 12 months after stopping NA treatment.

Double trouble: insights from a rare case of extranodal composite lymphoma in an elderly man, with comprehensive literature review.

Composite lymphoma (CL) is a rare cancer characterized by the concurrent occurrence of more than one type of lymphoma within the same organ or tissue in an individual. Its occurrence at extranodal sites is exceptional, with only a few cases documented in the literature. A 62-year-old gentleman presented with dystonia, dysphagia, and irregular enlargement of the right tonsil for the last three months. Based on a clinical suspicion of tonsillar malignancy, tonsillectomy was done. The histopathologic examination revealed effacement of the architecture by large irregular lymphoid nodules with interfollicular expansion. The nodules showed sheets of small atypical lymphoid cells, while the interfollicular areas showed large atypical lymphoid cells with scattered typical binucleate Reed-Sternberg cells. Immunohistochemistry confirmed mantle cell lymphoma (MCL) in the nodules and classical HL (cHL) in the interfollicular areas. Based on these features, a diagnosis of composite MCL with cHL was rendered. He was treated with bendamustine and rituximab chemotherapy and remained in complete remission for five years when he presented with significant right-sided neck swelling. Percutaneous fine needle aspiration and subsequent flow cytometry confirmed a relapse of the MCL component of the CL. The index report documents an exceptional case of CL, comprising MCL and cHL, presenting at an uncommon extranodal site. In addition, it also emphasizes the importance of adequate sampling and the simultaneous use of immunochemistry and/or flow cytometry to confirm the presence of more than a single type of lymphoma, which may be easily overlooked on microscopy alone.

Safety and Effectiveness of Satralizumab in Japanese Patients with Neuromyelitis Optica Spectrum Disorder: A 6-month Interim Analysis of Post-marketing Surveillance.

INTRODUCTION: Satralizumab, an anti-interleukin-6 receptor antibody, is approved in Japan for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and is undergoing post-marketing surveillance (PMS) of clinical use. We aimed to describe the real-world safety and effectiveness of satralizumab in Japanese patients with NMOSD. METHODS: This is an ongoing PMS (planned completion: February 2027). This 6-month interim analysis assessed the safety and effectiveness of satralizumab in Japanese patients with NMOSD using data collected from August 2020 to July 2021. RESULTS: Among 570 patients who participated, 523 (91.75%) were female and the mean ± standard deviation (SD) age was 52.4 ± 14.1 years. At baseline, NMOSD expanded disability status scale mean ± SD was 4.19 ± 2.19; 490 (85.96%) patients used glucocorticoids and 277 (48.59%) patients used immunosuppressants concomitantly. Of 570 satralizumab-treated patients, 85 (14.91%) had discontinued satralizumab treatment at 6 months. For the overall adverse drug reactions (ADRs), 76.22 (66.07-87.48) events/100 person-years occurred in 118 (20.70%) patients, and infections occurred in 28 (4.91%) patients. Serious infections occurred in 18 (3.15%) patients, with an event rate of 9.05 (5.80-13.47) events/100 person-years. Of the 24 events of serious infections, respiratory tract infections (29.17%; 7) and urinary tract infections (25.00%; 6) were the most common serious infection events. One fatal ADR (septic shock) suspected to be related to satralizumab was reported. The mean ± SD glucocorticoid dose reduced from 12.28 ± 10.17 mg/day at the index date to 8.11 ± 7.30 mg/day at 6 months. The Kaplan-Meier cumulative relapse-free rate (95% confidence interval) was 94.59% (92.25-96.23) at 6 months. CONCLUSION: In this study, satralizumab was found to be safe, well tolerated, and effective in patients with NMOSD in routine clinical practice. The results are consistent with those of previous clinical trials. The safety and effectiveness of satralizumab in Japanese patients with NMOSD will be analyzed over the 6-year surveillance period. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000041047.

PRIORITI: Phase 4 study of triptorelin or active surveillance in high-risk prostate cancer.

AIM: To evaluate the efficacy and safety of triptorelin after radical prostatectomy (RP) in patients with negative lymph nodes. METHODS: PRIORITI (NCT01753297) was a prospective, open-label, randomized, controlled, phase 4 study conducted in China and Russia. Patients with high-risk (Gleason score ≥ 8 and/or pre-RP prostate-specific antigen [PSA] ≥ 20 ng/mL and/or primary tumor stage 3a) prostate adenocarcinoma without evidence of lymph node or distant metastases were randomized to receive triptorelin 11.25 mg at baseline (≤ 8 weeks after RP) and at 3 and 6 months, or active surveillance. The primary endpoint was biochemical relapse-free survival (BRFS), defined as the time from randomization to biochemical relapse (BR; increased PSA > 0.2 ng/mL). Patients were monitored every 3 months for at least 36 months; the study ended when 61 BRs were observed. RESULTS: The intention-to-treat population comprised 226 patients (mean [standard deviation] age, 65.3 [6.4] years), of whom 109 and 117 were randomized to triptorelin or surveillance, respectively. The median BRFS was not reached. The 25th percentile time to BRFS (95% confidence interval) was 39.1 (29.9-not estimated) months with triptorelin and 30.0 (18.6-42.1) months with surveillance (p = 0.16). There was evidence of a lower risk of BR with triptorelin versus surveillance but this was not statistically significant at the 5% level (p = 0.10). Chemical castration was maintained at month 9 in 93.9% of patients who had received triptorelin. Overall, triptorelin was well tolerated and had an acceptable safety profile. CONCLUSION: BRFS was observed to be longer with triptorelin than surveillance, but the difference was not statistically significant.

The ReCoDe addiction research consortium: Losing and regaining control over drug intake-Findings and future perspectives.

Substance use disorders (SUDs) are seen as a continuum ranging from goal-directed and hedonic drug use to loss of control over drug intake with aversive consequences for mental and physical health and social functioning. The main goals of our interdisciplinary German collaborative research centre on Losing and Regaining Control over Drug Intake (ReCoDe) are (i) to study triggers (drug cues, stressors, drug priming) and modifying factors (age, gender, physical activity, cognitive functions, childhood adversity, social factors, such as loneliness and social contact/interaction) that longitudinally modulate the trajectories of losing and regaining control over drug consumption under real-life conditions. (ii) To study underlying behavioural, cognitive and neurobiological mechanisms of disease trajectories and drug-related behaviours and (iii) to provide non-invasive mechanism-based interventions. These goals are achieved by: (A) using innovative mHealth (mobile health) tools to longitudinally monitor the effects of triggers and modifying factors on drug consumption patterns in real life in a cohort of 900 patients with alcohol use disorder. This approach will be complemented by animal models of addiction with 24/7 automated behavioural monitoring across an entire disease trajectory; i.e. from a naïve state to a drug-taking state to an addiction or resilience-like state. (B) The identification and, if applicable, computational modelling of key molecular, neurobiological and psychological mechanisms (e.g., reduced cognitive flexibility) mediating the effects of such triggers and modifying factors on disease trajectories. (C) Developing and testing non-invasive interventions (e.g., Just-In-Time-Adaptive-Interventions (JITAIs), various non-invasive brain stimulations (NIBS), individualized physical activity) that specifically target the underlying mechanisms for regaining control over drug intake. Here, we will report on the most important results of the first funding period and outline our future research strategy.

Long-term clinicopathological characteristics of TAFRO syndrome and its relapse: a case series study.

Introduction: This study aimed to analyze the clinical course of TAFRO syndrome in patients through extended follow-up, focusing on recurrent cases and long-term remission. Methods: This was a retrospective case series study. We assessed the clinical course of patients diagnosed with TAFRO syndrome between January 2012 and September 2022 at Toranomon Hospital or Toranomon Hospital Kajigaya, excluding those patients who died during the initial hospitalization. Results: Twelve patients were included. Baseline characteristics, laboratory findings, treatment modalities, and outcomes were assessed. During the median follow-up period of 1474 days, two patients experienced recurrence following a reduction in tocilizumab (TCZ) dose, whereas two achieved remission for >400 days without TCZ treatment. The remaining eight patients maintained remission under the continued TCZ therapy. Recurrence diagnosis was complicated by the non-simultaneous presentation of the five manifestations of TAFRO syndrome. The patients who experienced recurrence showed milder manifestations and faster recovery than the initial onset. Glomerular endotheliopathy was evident in kidney biopsies during recurrence, which was similar to the initial presentation. In a case where only inflammation preceded other manifestation, a kidney biopsy was pivotal in distinguishing TAFRO syndrome relapse from other inflammatory conditions such as infection. Pretreatment serum IL-6 levels were within the reference range only in patients who experienced long-term remission without TCZ treatment. Conclusions: This is the first study to perform kidney biopsies on recurrent TAFRO cases, highlighting recurrence after TCZ dosage reduction, non-simultaneous manifestation of symptoms, the utility of kidney biopsies in recurrence diagnosis, and potential non-IL-6 pathogenesis factors. Pretreatment serum IL-6 levels may help identify patients suitable for maintenance therapy without TCZ. Further investigation is warranted to identify stratified treatment approaches based on individual etiologic factors.

Myocardial Recovery and Relapse in Heart Failure With Improved Ejection Fraction.

Purpose of review: The purpose of this review is to discuss myocardial recovery in heart failure with reduced ejection fraction (HFrEF) and to summarize the contemporary insights regarding heart failure with improved ejection fraction (HFimpEF). Recent findings: Improvement in left ventricular ejection fraction (LVEF ≥ 40%) with improved prognosis can be achieved in one out of three (10-40%) patients with HFrEF treated with guideline-directed medical therapy. Clinical predictors include non-ischemic etiology of HFrEF, less abnormal blood or imaging biomarkers, and lack of specific pathogenic genetic variants. However, a subset of patients may ultimately relapse, suggesting that many patients are merely in remission rather than having fully recovered. Summary: Patients with HFimpEF have improved prognosis but nonetheless remain at risk of relapse and long-term adverse events. Future studies will hopefully chart the natural history of HFimpEF and identify clinical predictors such as blood or novel imaging biomarkers that distinguish subgroups of patients based on differential trajectory and prognosis.

Nephrons and non-relapse mortality: simplified comorbidity index and acute kidney injury are associated with NRM in adults undergoing allogeneic hematopoietic cell transplant.

The Simplified Comorbidity Index (SCI) is a recently published 5-component, pre-transplant tool to predict non-relapse mortality (NRM) in allogeneic hematopoietic cell transplantation (alloHCT) patients. The SCI captures chronic kidney disease (CKD) using estimated glomerular filtration rate (eGFR) based on the CKD-EPI equation (KDIGO 2021 CKD-EPI), which may be more sensitive to predict risk of NRM than the creatinine cut-off in the 16-component, Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI). We retrospectively assessed the ability of the SCI to risk-stratify patients and the impact of acute kidney injury (AKI) to NRM in adults who underwent alloHCT at the University of Minnesota. We included 373 patients who underwent their first alloHCT between 2015 and 2019. Through multivariate analysis, we found that patients with an SCI of greater than 4 had a higher risk of NRM. Additionally, we noted that AKIs stages 2-3 prior to day +100 was independently associated with a 3-fold greater NRM than patients who did not experience clinically significant AKI.

The relationship between neuromyelitis optica spectrum disorder and autoimmune diseases.

Objective: There have been reports of neuromyelitis optica spectrum disorder (NMOSD) coexisting with connective tissue disorders. The objective of this study was to describe the characteristics of NMOSD coexisting with autoimmune diseases (AID). Methods: This retrospective study evaluated NMOSD patients with and without AID. The enrolled patients had at least one attack, with duration of more than 1 year. Data on the demographics, clinical features, and laboratory findings were assessed. The Poisson model was used to investigate the risk factors associated with the annualized relapse rate (ARR), whereas the Cox model was used to evaluate the risk factors for the first relapse. Results: A total of 180 patients (154 women and 26 men) with NMOSD were identified: 45 had AID and 135 did not. Female patients had a higher prevalence of concomitant AID (p = 0.006) and a greater relapse rate within the first year. There were no statistically significant differences in the characteristics of patients. Kaplan-Meier analysis revealed that NMOSD patients with seropositive aquaporin 4 antibodies (AQP4-Ab; log-rank: p = 0.044), had a shorter time to relapse. Patients seropositive for AQP4-Ab (HR = 2.402, 95%CI = 1.092-5.283, p = 0.029) had a higher risk of suffering a first relapse, according to the Cox model. Patients with and without AID showed a similar declining tendency in terms of change in ARR throughout the first 5 years of the disease. The ARR was greater in the first year [incidence rate ratio (IRR) = 1.534, 95%CI = 1.111-2.118] and the first 2 years (IRR = 1.474, 95%CI = 1.056-2.058) in patients with coexisting AID diagnosis prior to the NMOSD onset. Conclusions: Patients with NMOSD with coexisting AID had similar characteristics when compared with those without AID. NMOSD patients with AID diagnosed before onset had a higher risk of relapse in the early stage of the disease.

Neuromyelitis optica spectrum disorder with acute brainstem manifestations as initial symptoms.

Objective: To explore the clinical features and prognosis of patients with neuromyelitis optica spectrum disorder (NMOSD) initially presenting with acute brainstem symptoms. Methods: The clinical data of NMOSD patients admitted to two medical centers were collected. The clinical characteristics, laboratory data, neuroimaging features and prognoses of patients with NMOSD with acute brainstem manifestations as initial symptoms (NMOSD-BSMIS) were analyzed. The clinical features and prognosis of patients with NMOSD-BSMIS and patients with NMOSD with other manifestations as initial symptoms (NMOSD-OMIS) were compared. Results: Fifty-two patients (18.37 %, 52/283) initially presented with acute brainstem symptoms. Intractable nausea, vomiting or hiccups, diplopia, vertigo, headache, and facial hypoesthesia were the initial symptoms in most of the patients. The percentage of patients who were positive for serum aquaporin 4 (AQP4)-IgG antibodies was 81.63 % (40/49). MRI revealed that the lesions were usually located in the postrema, dorsal medulla oblongata, pons and other areas around the fourth ventricle. The early-stage misdiagnosis rate was 46.15 %. Compared with those in the non-misdiagnosed group, the age of onset of patients in the NMOSD-BSMIS group was older, and the proportion of patients admitted to the neurology department as the first department was lower in the misdiagnosed group. The annual relapse rate of patients who underwent NMOSD-BSMIS was significantly greater than that of patients who underwent NMOSD-OMIS (P < 0.01). Conclusions: NMOSD patients can initially present with different brainstem symptoms. The early misdiagnosis rate of NMOSD-BSMIS is high. Moreover, if patients are older or initially admitted to nonneurological departments, they are more likely to be misdiagnosed. Moreover, the annual recurrence rate of NMOSD-BSMIS is greater in the early stage.

First-line immunosuppressive therapies for acquired hemophilia A: A 25-year cohort experience and network meta-analysis.

Acquired hemophilia A (AHA) presents a significant bleeding risk. Management involves bleeding control and immunosuppressive therapy (IST) to eliminate inhibitors. This study, encompassing a retrospective cohort of 76 newly diagnosed AHA patients (1997-2022), evaluated IST outcomes such as complete remission (CR), relapse, and mortality rates, alongside influencing factors. Supplementing these findings, a systematic review and network meta-analysis compared CR and relapse rates across ISTs, sourcing from Embase, Scopus, and ScienceDirect up to November 2023. In our cohort, demarcated by a 20 Bethesda-unit titer threshold, cyclophosphamide plus prednisolone (CP; n = 64) was the predominant initial IST. Lower inhibitor levels significantly correlated with higher CR rates (86.8 % vs 62.2 %; P = .014) and showed an odds ratio of 0.26 for CR (P = .021). Median relapse-free survival (RFS) extended to 37.13 months, significantly enhanced by CP (hazard ratio, 0.24; 95 % confidence interval, 0.10-0.60; P = .002). Our network meta-analysis, including 1476 CR and 636 relapse patients, indicated CP and rituximab-based ISTs significantly outperformed steroid monotherapy in terms of CR and lower relapse rates (risk differences of 0.15 and -0.13/-0.15, respectively; P < .05), without significant differences between CP and rituximab. Moreover, adding rituximab to the front-line treatment did not produce superior outcomes compared to the CP regimen alone, positioning CP as a viable first-line choice, particularly where rituximab is less accessible. The consideration of IST toxicity remains critical in treatment decisions.

Targeting cancer stem cells in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy of bone marrow (BM) plasma cells with excessive clonal expansion and is associated with the overproduction of light-chain or monoclonal immunoglobulins (Igs). MM remains incurable, with high rates of relapses and refractory disease after first-line treatment. Cancer stem cells (CSCs) have been implicated in drug resistance in MM; however, the evidence for CSCs in MM is not adequate, partly due to a lack of uniformity in the definitions of multiple myeloma stem cells (MMSCs). We review advances in understanding MMSCs and their role in drug resistance to MM therapies. We also discuss novel therapeutic strategies to overcome MMSC-mediated relapses and drug resistance.

Cardiotoxicity of CPX-351 in children and adolescents with relapsed AML: a Children's Oncology Group report.

Introduction: Anthracyclines are effective in treating acute myeloid leukemia (AML) but limited by cardiotoxicity. CPX-351, a liposomal daunorubicin and cytarabine, may provide therapeutic benefit with less cardiotoxicity. Acute changes in left ventricular systolic function and cardiac biomarkers were evaluated after a cycle of CPX-351 in children with relapsed AML treated on the phase 1/2 Children's Oncology Group study, AAML1421. Methods: Subjects received 135 units/m2/dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/- 1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 left ventricular ejection fraction (LVEF) with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of ≥10%-<50%. Results: Twenty-five of 38 heavily anthracycline pre-treated (median 348 mg/m2 daunorubicin equivalents) subjects enrolled on AAML1421 were included in the cardiac analyses. At baseline, centrally quantitated LVEF was <50% in 8 of 25 subjects (32%) with a median LVEF of 53.8% [48.0, 56.9]. Following CPX-351, LVEF declined significantly (ΔLVEF -3.3% [-7.8, 0]) and 6 of 25 subjects (24%) experienced CTRCD. Amongst all subjects, hs-cTnT was modestly increased at end of cycle 1 compared to baseline [baseline hs-cTnT 7.2 (3, 10.6); ΔcTnT 1.80 (0, 6.1), p = 0.03]. NT-proBNP remained stably elevated without significant change. No significant associations were seen between NT-proBNP or cTnT levels and post-CPX-351 LVEF. Discussion: In this single arm study of anthracycline pre-treated children exposed to CPX-351, baseline abnormalities in cardiovascular function were prevalent. Following CPX-351, LVEF decreased, cTnT increased, and NT-proBNP did not change. Longer follow-up is needed to determine whether these changes result in clinically meaningful long-term decrements in cardiac function. An ongoing randomized trial of CPX-351 compared to standard anthracyclines in anthracycline naïve patients will provide further insight into the cardiac effects of CPX-351 (ClinicalTrials.gov; NCT04293562).

Ostracism Predicting Suicidal Behavior and Risk of Relapse in Substance Use Disorders.

INTRODUCTION: The present study investigated the predictive relationship between ostracism and suicidal behaviors in individuals with substance use disorders. It also attempts to highlight the mediating role of the risk of relapse between ostracism and suicidal behavior. METHODS: The study was based on a cross-sectional survey design. The sample comprised 100 men aged between 30 to 45 years (M = 35.25, SD = 3.06) from Karachi. The purposive sampling technique was employed. The study employed demographic forms and three self-reporting measures: the Ostracism Experience Scale (OES-A), the Advance Warning of Relapse Questionnaire 3.0 (AWARE), and the Suicide Behaviors Questionnaire-Revised (SBQ-R). RESULTS: Ostracism significantly predicted relapse risk and suicidal behavior. Risk of relapse positively predicted both dimensions of ostracism (ignored: r = 0.33, p < 0.01; excluded: r = 0.43, p < 0.01) and suicidal behavior (r = 0.35, p < 0.01). Additionally, the risk of relapse strongly correlated with overall ostracism score (r = 0.43, p < 0.01). However, no significant mediating effect of ostracism on suicidal behavior was found. The effect was mediated through the risk of relapse (B indirect = 0.12, 95% CI = 0.04, 0.23). These findings suggest that ostracism increases the likelihood of recurrence, which in turn is associated with suicidal behavior. The mediation model explained 17% of the variation in suicidal behavior. CONCLUSION: The findings propose the importance of addressing ostracism as a risk factor for suicidal behavior and relapse in substance use disorders. The results suggest that reducing the adverse effects of ostracism and improving social support for individuals can have a significant impact on their mental health.

A Descriptive Review and Meta-Regression Study of Demographic and Study Context Factors in US Clinical Trials of Cognitive Behavioral Interventions for Alcohol or Other Drug Use.

Objectives. Cognitive-Behaviorally Based Interventions (CBIs) are evidence-based treatments for alcohol and other drug (AOD) use with potential variable effectiveness by population sub-groups. This study used evidence synthesis to examine treatment effect by demographic and study context factors in clinical trials of CBI for AOD. Methods. Studies were systematically identified, and their characteristics and outcome data were extracted and summarized. Standardized mean differences were calculated for within- and between-condition effects on substance use outcomes. Demographic and study context moderators were identified during data acquisition and several sensitivity analyses were conducted. Results. The sample included K = 29 trials and a total of 15 study-level moderators were examined. Information on participants' age, biological sex, and race were reported in at least 26 trials, but information on gender identity, sexual orientation, and ethnicity were reported infrequently or in non-inclusive ways. The mean between-condition effect size was small and moderately heterogenous (d = 0.158, 95% CI = 0.079, 0.238, I2 = 46%) and the mean within-condition effect size was large and showed high heterogeneity (dz = 1.147, 95% CI = 0.811, 1.482, - I2 = 96%). The specific drug targeted in the study and whether biological assay-based outcomes were used moderated between-condition CBI efficacy and the inclusion of co-occurring mental health conditions and study publication date moderated within-condition CBI effects. Conclusions. Results provide preliminary data on study context factors associated with effect estimates in United States based clinical trials of CBI for AOD.