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Post-ASCT brentuximab vedotin (BV) consolidation improves PFS in pts with high-risk relapse as per ATHERA criteria: early relapse [ER], primary refractory disease [PRD] or extra nodal disease (END). B Background: b Salvage chemotherapy and autologous stem cell transplant (ASCT) have cure rates of 60-70% in relapsed refractory (R/R) classic Hodgkin lymphoma (cHL). In propensity score weighted analysis, BV consolidation was associated with better survival in the subgroup of pre-ASCT PMR but not pre-ASCT CMR. [Extracted from the article]

Type 1 diabetes (T1D) remains a major health problem worldwide, with a steadily rising incidence yet no cure. Phosphoinositide 3-kinase-γ (PI3Kγ), a member of a family of lipid kinases expressed primarily in leukocytes, has been the subject of substantial research for its role in inflammatory diseases. However, the role of PI3Kγ inhibition in suppressing autoimmune T1D remains to be explored. We tested the role of the PI3Kγ inhibitor AS605240 in preventing and reversing diabetes in NOD mice and assessed the mechanisms by which this inhibition abrogates T1D. Our data indicate that the PI3Kγ pathway is highly activated in T1D. In NOD mice, we found upregulated expression of phosphorylated Akt (PAkt) in splenocytes. Notably, T regulatory cells (Tregs) showed significantly lower expression of PAkt compared with effector T cells. Inhibition of the PI3Kγ pathway by AS605240 efficiently suppressed effector T cells and induced Treg expansion through the cAMP response element-binding pathway. AS605240 effectively prevented and reversed autoimmune diabetes in NOD mice and suppressed T-cell activation and the production of inflammatory cytokines by autoreactive T cells in vitro and in vivo. These studies demonstrate the key role of the PI3Kγ pathway in determining the balance of Tregs and autoreactive cells regulating autoimmune diabetes. [ABSTRACT FROM AUTHOR]

Presents a case study of tax reform in Lebanon in the 1990's. Outline of debt servicing cost incurred by Lebanese government; Examination of investment and income tax structure; Possible direct and indirect corporate tax reform options that may be implemented in the short-to-medium term.

Efforts to produce adoptive cell therapies in AML have been largely unfruitful, despite the success seen in lymphoid malignancies. Identifying targetable antigens on leukemic cells that are absent on normal progenitor cells remains a major obstacle, as is the hostile tumor microenvironment created by AML blasts. In this review, we summarize the challenges in the development of adoptive cell therapies such as CAR-T, CAR-NK, and TCR-T cells in AML, discussing both autologous and allogeneic therapies. We also discuss methods to address myelotoxicity associated with these therapies, including rapidly switchable CAR platforms and CRISPR-Cas9 genetic engineering of hematopoietic stem cells. Finally, we present the current clinical landscape in these areas, along with future directions in the field.

Children with cancer previously treated with radiotherapy face the likelihood of side effects that can be debilitating or fatal. This study aimed to assess the long-term effect of medulloblastoma radiotherapy on the DNA double-strand break (DSB) repair capability of primary fibroblasts derived from lung biopsies of previously irradiated young sheep. This study included biopsies from three control and five irradiated sheep. The treated sheep had previously received spinal radiotherapy at a total dose of 28 Gy, which is equivalent to pediatric medulloblastoma treatment. Lung biopsies were taken 4 years post-irradiation from high-dose (HD, >18 Gy) and low-dose (LD, <2 Gy) regions. Fifteen cell lines were extracted (six control, four LD and five HD). The cells were irradiated, and DNA DSB repair was analyzed by immunofluorescence. Clonogenic, trypan blue and micronuclei assays were performed. Both the HD and LD cell lines had a significantly higher number of residual γH2AX foci 24 h and a significant decrease in pATM activity post-irradiation compared to the control. There was no statistically significant difference in the clonogenic assay, trypan blue and micronuclei results. Our study showed that a previous irradiation can impair the DNA DSB repair mechanism of ovine lung fibroblasts.

Tolerance of mouse kidney allografts arises in grafts that develop regulatory tertiary lymphoid organs (rTLOs). Single-cell RNA-seq (scRNA-seq) data and adoptive transfer of alloreactive T cells after transplantation showed that cytotoxic CD8+ T cells are reprogrammed within the accepted graft to an exhausted/regulatory-like phenotype mediated by IFN-γ. Establishment of rTLOs was required because adoptive transfer of alloreactive T cells prior to transplantation results in kidney allograft rejection. Despite the presence of intragraft CD8+ cells with a regulatory phenotype, they were not essential for the induction and maintenance of kidney allograft tolerance since renal allotransplantation into CD8-KO recipients resulted in acceptance and not rejection. Analysis of scRNA-seq data from allograft kidneys and malignant tumors identified similar regulatory-like cell types within the T cell clusters and trajectory analysis showed that cytotoxic CD8+ T cells are reprogrammed into an exhausted/regulatory-like phenotype intratumorally. Induction of cytotoxic CD8+ T cell dysfunction of infiltrating cells appears to be a beneficial mechanistic pathway that protects the kidney allotransplant from rejection through a process we call "defensive tolerance." This pathway has implications for our understanding of allotransplant tolerance and tumor resistance to host immunity.

Background: GPP is a rare, chronic, neutrophilic skin disease, with limited real-world data characterizing patients with flares and the impact of flares on disease progression and morbidity., Objective: Describe the clinical characteristics of patients with GPP, comorbidities, disease epidemiology and frequency and severity of flares, and compare patients with GPP with a matched severe psoriasis population., Methods: In this population-based real-world cohort study an algorithm was developed to identify patients with GPP flares. Three cohorts were identified using the Système National des Données de Santé (SNDS) database covering almost the entire French population; a prevalent cohort (2010-2018), an incident cohort (2012-2015). A severe psoriasis cohort was compared with the GPP incident cohort using propensity score matching., Results: The prevalent and incident cohorts comprised 4195 and 1842 patients, respectively. In both cohorts, mean age was 58 years; 53% were male. Comorbidities were significantly more common in the incident cohort versus matched psoriasis cohort, respectively, including hypertension (44% vs. 26%), ischaemic heart disease (26% vs. 18%) and hyperlipidaemia (25% vs. 15%). In the incident cohort, the flare rate was 0.1 flares/person-year and 0.4 flares/person-year among the 569 out of 1842 patients hospitalized with flares. These patients had a mean (±SD) stay of 11.6 ± 10.4 days; 25% were admitted to the intensive care unit. In 2017, the cumulative incidence and cumulative GPP age-sex standardized prevalence were 7.1 and 45.2 per million, respectively., Conclusions: Patients with GPP had a distinct comorbidity profile compared to patients with severe psoriasis, and GPP flares were associated with long hospitalizations., (© 2024 Boehringer Ingelheim International GmbH and The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltdon behalf of European Academy of Dermatology and Venereology.)

Background: Early-stage breast cancer is usually treated with breast-conserving surgery followed by adjuvant radiation therapy. Acute skin toxicity is a common radiation-induced side effect experienced by many patients. Recently, a combination of bisphosphonates (zoledronic acid) and statins (pravastatin), or ZOPRA, was shown to radio-protect normal tissues by enhancing DNA double-strand breaks (DSB) repair mechanism. However, there are no studies assessing the effect of ZOPRA on cancerous cells. The purpose of this study is to characterize the in vitro effect of the zoledronic acid (ZO), pravastatin (PRA), and ZOPRA treatment on the molecular and cellular radiosensitivity of breast cancer cell lines., Materials: Two breast cancer cell lines, MDA MB 231 and MCF-7, were tested. Cells were treated with different concentrations of pravastatin (PRA), zoledronate (ZO), as well as their ZOPRA combination, before irradiation. Anti-γH2AX and anti-pATM immunofluorescence were performed to study DNA DSB repair kinetics. MTT assay was performed to assess cell proliferation and viability, and flow cytometry was performed to analyze the effect of the drugs on the cell cycle distribution. The clonogenic assay was used to assess cell survival., Results: ZO, PRA, and ZOPRA treatments were shown to increase the residual number of γH2AX foci for both cell lines. ZOPRA treatment was also shown to reduce the activity of the ATM kinase in MCF-7. ZOPRA induced a significant decrease in cell survival for both cell lines., Conclusions: Our findings show that pretreatment with ZOPRA can decrease the radioresistance of breast cancer cells at the molecular and cellular levels. The fact that ZOPRA was previously shown to radioprotect normal tissues, makes it a good candidate to become a therapeutic window-widening drug., (© 2023. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

In the pre-novel agent era, the median postprogression overall survival (PPS) of patients with classic Hodgkin lymphoma (cHL) who progress after autologous stem cell transplant (ASCT) was 2 to 3 years. Recently, checkpoint inhibitors (CPI) and brentuximab vedotin (BV) have improved the depth and durability of response in this population. Here, we report the estimate of PPS in patients with relapsed cHL after ASCT in the era of CPI and BV. In this multicenter retrospective study of 15 participating institutions, adult patients with relapsed cHL after ASCT were included. Study objective was postprogression overall survival (PPS), defined as the time from posttransplant progression to death or last follow-up. Of 1158 patients who underwent ASCT, 367 had progressive disease. Median age was 34 years (range, 27-46) and 192 were male. Median PPS was 114.57 months (95% confidence interval [CI], 91-not achieved) or 9.5 years. In multivariate analysis, increasing age, progression within 6 months, and pre-ASCT positive positron emission tomography scan were associated with inferior PPS. When adjusted for these features, patients who received CPI, but not BV, as first treatment for post-ASCT progression had significantly higher PPS than the no CPI/no BV group (hazard ratio, 3.5; 95% CI, 1.6-7.8; P = .001). Receipt of allogeneic SCT (Allo-SCT) did not improve PPS. In the era of novel agents, progressive cHL after ASCT had long survival that compares favorably with previous reports. Patients who receive CPI as first treatment for progression had higher PPS. Receipt to Allo-SCT was not associated with PPS in this population., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: To provide EuroQoL EQ-5D-5L French population norms based on a sample of 15,000 responders., Methods: Based on the National Health and Wellness Survey, an international, annual, selfadministered Internet-based survey, this study extracted data from France for 2018 involving a sample of 15,000 respondents stratified by age and gender. Responses to the EQ-5D-5L questionnaire and the Visual Analog Scale (VAS) score, together with sociodemographic, health behavior, and disease status variables were collected. VAS, value indexes, the level sum score, and the distribution of levels per dimension were described. Multivariate regression analyses were performed to identify covariates with a statistically significant effect on the five dimensions and the three scores., Results: The mean [standard deviation (SD)] VAS was 73.4 (22.2) for the entire sample (male 74.8 vs female 72.2, p < 0.0001). The Mean SD value index was 0.905 (0.158) (male 0.915 vs female 0.895, p < 0.0001). The mean SD level sum score was 7.6 (3.0) (7.4 for males vs. 7.9 for females p < 0.0001). Health state 11,111 (no problem in any dimension) represented 25.1% of all responses. "No problem" responses' proportions were Self Care (91.3%), Usual Activities (74.2%), Mobility (72.4%), Anxiety/Depression (52.6%) and Pain/Discomfort (37.7%). Multivariate regressions revealed a significant relationship for health states, value indexes, and VAS with age, income, employment, marital status, smoking and alcohol consumption, obesity, and the presence of one or more health problems., Conclusion: Based on a large sample, this study is the first to report EQ-5D-5L population norms for France., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)