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Andrew Bodiford,1 Mahsa S Talbott,1 Nishitha M Reddy,2 1Department of Pharmacy, 2Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA Abstract: The histone deacetylase inhibitor (HDACi), belinostat, is an emerging and novel therapeutic option for patients diagnosed with relapsed/refractory peripheral T-cell lymphoma (PTCL). The PTCLs are comprised of multiple subtypes that occur in less than one per 100,000 cases in the USA. The incidence of these malignancies is rare, thus limited evidence is available. The most appropriate treatment modality has not been established. The most current recommended option is combination chemotherapy or enrollment in a clinical trial. T-cell lymphomas have emerged as a disease with marked epigenetic dysregulation. HDACi are an innovative and emerging medication class gaining increased attention in the treatment of T-cell lymphomas. There is a need to evaluate their potential place in the treatment of patients diagnosed with PTCL. Currently, the largest study evaluating belinostat use in this patient population is the BELIEF study. The BELIEF study is a single-arm, Phase II clinical trial, evaluating the use of belinostat in patients with refractory or relapsed PTCL. The primary outcome, objective response rate, was 26%, with 11% achieving a complete response and 15% a partial response. This study presents a potential novel therapeutic option in the treatment of these patients. In this paper, we review therapeutic options for PTCL and present the recent data on the role of HDACi, specifically belinostat, in the treatment of patients with relapsed/refractory PTCL. Keywords: peripheral T-cell lymphoma, novel agents, histone deacetylase inhibitor

Andrew Bodiford,1 Megan Bodge,1 Mahsa S Talbott,1 Nishitha M Reddy2 1Department of Pharmacy, 2Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USAAbstract: The peripheral T-cell lymphomas are a rare and heterogeneous group of mature T-cell lymphomas with limited available therapies. The outcome of frontline chemotherapy regimens has been disappointing, with a long-term survival of only 20%–30%. There is an urgent need to optimize induction therapy by incorporating novel agents that target the dysregulated pathways. Histone deacetylase inhibitors that induce acetylation of histones and enhance apoptosis have shown promising activity. In this article, we summarize the role of histone deacetylase inhibitors and specifically discuss pharmacokinetics, efficacy, and toxicity of the recently US Food and Drug Administration-approved agent belinostat for its use in patients with relapsed/refractory peripheral T-cell lymphoma.Keywords: histone deacetylase inhibitor, pharmacokinetics, cutaneous T-cell lymphoma

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Rationale: Oxygen supplementation (e.g., hyperoxia) is used to support critically ill patients with noninfectious and infectious acute lung injury (ALI); however, hyperoxia exposure can potentially further contribute to and/or perpetuate preexisting ALI. Thus, developing novel therapeutic agents to minimize the side effects of hyperoxia is essential to improve the health of patients with severe ALI and respiratory dysfunction. We have previously shown that mice with a genetic disruption of the Nrf2 transcription factor, which squelches cellular stress by up-regulating the induction of several antioxidant enzymes and proteins, have greater susceptibility to hyperoxic lung injury. Moreover, we have recently demonstrated that Nrf2-deficiency impairs the resolution of lung injury and inflammation after nonlethal hyperoxia exposure.Objectives: To test the hypothesis that amplification of endogenous Nrf2 activity would prevent or dampen ALI induced by hyperoxia.Methods: Here, we tested our hypothesis using a synthetic triterpenoid compound CDDO-imidazole (CDDO-Im) (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole) in Nrf2-sufficient and Nrf2-deficient mice subjected to hyperoxia-induced ALI.Measurements and Main Results: We demonstrate that oral administration of CDDO-Im at a dose of 30 micromol/kg body weight during the hyperoxic exposure is sufficient to markedly attenuate hyperoxia-induced ALI in Nrf2-sufficient but not Nrf2-deficient mice. This protection by the CDDO-Im against hyperoxic insult was accompanied by increased levels of Nrf2-regulated cytoprotective gene expression and reduced levels of DNA damage in the lung.Conclusions: These results suggest that up-regulation of Nrf2 signaling by CDDO-Im or its analogs may provide a novel therapeutic strategy to minimize the adverse effects of hyperoxia. [ABSTRACT FROM AUTHOR]

Mechanical ventilation (MV) is used as therapy to support critically ill patients; however, the mechanisms by which MV induces lung injury and inflammation remain unclear. Epidermal growth factor receptor (EGFR)-mediated signaling plays a key role in various physiologic and pathologic processes, which include those modulated by mechanical and shear forces, in various cell types. We hypothesized that EGFR-activated signaling plays a key role in ventilator-induced lung injury and inflammation (VILI). To test this hypothesis, we assessed lung vascular and alveolar permeability as well as inflammation, which are cardinal features of VILI, in mice treated with the EGFR inhibitor AG1478. Inhibition of EGFR activity greatly diminished MV-induced lung alveolar permeability and neutrophil accumulation in the bronchoalveolar lavage (BAL) fluid, as compared with vehicle-treated controls. Similarly, AG1478 inhibition diminished lung vascular leak (as assessed by Evans blue extravasation), but it did not affect interstitial neutrophil accumulation. Inhibition of the EGFR pathway also blocked expression of genes induced by MV. However, intratracheal instillation of EGF alone failed to induce lung injury. Collectively, our findings suggest that EGFR-activated signaling is necessary but not sufficient to produce acute lung injury in mice. [ABSTRACT FROM AUTHOR]

Accurately predicting the power conversion efficiency (PCE) in dye-sensitized solar cells (DSSCs) represents a crucial challenge, one that is pivotal for the high throughput rational design and screening of promising dye sensitizers. This study presents precise, predictive, and interpretable machine learning (ML) models specifically designed for Zn-porphyrin-sensitized solar cells. The model leverages theoretically computable, effective, and reusable molecular descriptors (MDs) to address this challenge. The models achieve excellent performance on a "blind test" of 17 newly designed cells, with a mean absolute error (MAE) of 1.02%. Notably, 10 dyes are predicted within a 1% error margin. These results validate the ML models and their importance in exploring uncharted chemical spaces of Zn-porphyrins. SHAP analysis identifies crucial MDs that align well with experimental observations, providing valuable chemical guidelines for the rational design of dyes in DSSCs. These predictive ML models enable efficient in silico screening, significantly reducing analysis time for photovoltaic cells. Promising Zn-porphyrin-based dyes with exceptional PCE are identified, facilitating high-throughput virtual screening. The prediction tool is publicly accessible at https://ai-meta.chem.ncu.edu.tw/dsc-meta., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

This study examined and addressed climate change's effects on hydrological patterns, particularly in critical places like the Godavari River basin. This study used daily gridded rainfall and temperature datasets from the Indian Meteorological Department (IMD) for model training and testing, 70% and 30%, respectively. To anticipate future hydrological shifts, the study harnessed the EC-Earth3 data, presenting an innovative methodology tailored to the unique hydrological dynamics of the Godavari River basin. The Sacramento model provided initial streamflow estimates for Kanhargaon, Nowrangpur, and Wairagarh. This approach melded traditional hydrological modeling with advanced multi-layer perceptron (MLP) capabilities. When combined with parameters like lagged rainfall, lagged streamflow, potential evapotranspiration (PET), and temperature variations, these initial outputs were further refined using the Sac-MLP model. A comparison with Sacramento revealed the superior performance of the Sac-MLP model. For instance, during training, the Nash Sutcliffe efficiency (NSE) values for the Sac-MLP witnessed an improvement from 0.610 to 0.810 in Kanhargaon, 0.580 to 0.692 in Nowrangpur, and 0.675 to 0.849 in Wairagarh. The results of the testing further corroborated these findings, as evidenced by the increase in the NSE for Kanhargaon from 0.890 to 0.910. Additionally, Nowrangpur and Wairagarh experienced notable improvements, with their NSE values rising from 0.629 to 0.785 and 0.725 to 0.902, respectively. Projections based on EC-Earth3 data across various scenarios highlighted significant shifts in rainfall and temperature patterns, especially in the far future (2071-2100). Regarding the relative change in annual streamflow, Kanhargaon projections under SSP370 and SSP585 for the far future indicate increases of 584.38% and 662.74%. Similarly, Nowrangpur and Wairagarh are projected to see increases of 98.27% and 114.98%, and 81.68% and 108.08%, respectively. This study uses EC-Earth3 estimates to demonstrate the Sac-MLP model's accuracy and importance in climate change water resource planning. The unique method for region-specific hydrological analysis provides vital insights for sustainable water resource management. This research provides a deeper understanding of climate-induced hydrological changes and a robust modeling approach for accurate predictions in changing environmental conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Microvascular endothelial hyperpermeability is an earliest pathological hallmark in Acute Lung Injury (ALI), which progressively leads to Acute Respiratory Distress Syndrome (ARDS). Recently, vascular protective and anti-inflammatory effect of metformin, irrespective of glycemic control, has garnered significant interest. However, the underlying molecular mechanism(s) of metformin's barrier protective benefits in lung-endothelial cells (ECs) has not been clearly elucidated. Many vascular permeability-increasing agents weakened adherens junctions (AJ) integrity by inducing the reorganization of the actin cytoskeleton and stress fibers formation. Here, we hypothesized that metformin abrogated endothelial hyperpermeability and strengthen AJ integrity via inhibiting stress fibers formation through cofilin-1-PP2AC pathway. Methods: We pretreated human lung microvascular ECs (human-lung-ECs) with metformin and then challenged with thrombin. To investigate the vascular protective effects of metformin, we studied changes in ECs barrier function using electric cell-substrate impedance sensing, levels of actin stress fibers formation and inflammatory cytokines IL-1β and IL-6 expression. To explore the downstream mechanism, we studied the Ser 3 -phosphorylation-cofilin-1 levels in scramble and PP2AC-siRNA depleted ECs in response to thrombin with and without metformin pretreatment. Results: In-vitro analyses showed that metformin pretreatment attenuated thrombin-induced hyperpermeability, stress fibers formation, and the levels of inflammatory cytokines IL-6 and IL-β in human-lung-ECs. We found that metformin mitigated Ser 3 -phosphorylation mediated inhibition of cofilin-1 in response to thrombin. Furthermore, genetic deletion of PP2AC subunit significantly inhibited metformin efficacy to mitigate thrombin-induced Ser 3 -phosphorylation cofilin-1, AJ disruption and stress fibers formation. We further demonstrated that metformin increases PP2AC activity by upregulating PP2AC-Leu 309 methylation in human-lung-ECs. We also found that the ectopic expression of PP2AC dampened thrombin-induced Ser 3 -phosphorylation-mediated inhibition of cofilin-1, stress fibers formation and endothelial hyperpermeability. Conclusion: Together, these data reveal the unprecedented endothelial cofilin-1/PP2AC signaling axis downstream of metformin in protecting against lung vascular endothelial injury and inflammation. Therefore, pharmacologically enhancing endothelial PP2AC activity may lead to the development of novel therapeutic approaches for prevention of deleterious effects of ALI on vascular ECs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Siddiqui, Reddy, Faridi, Shahid and Shanley.)

In this study, a comparison of 17 Coupled Model Intercomparison Project Phase 6 (CMIP6) data sets with Indian Meteorological Department (IMD) data in terms of finding out extreme precipitation indices obtained by the Expert Team on Climate Change Detection and Indices (ETCCDI) is done. The extreme indices considered were the consecutive dry days (CDD), consecutive wet days (CWD), maximum 1-day precipitation (RX1DAY), maximum 5-day precipitation (RX5DAY), precipitation > 2.5 mm (RR2.5), heavy precipitation > 10 mm (R10MM), very heavy precipitation > 20 mm (R20MM), and simple daily intensity (SDII) that have been calculated for 17 CMIP6 datasets from 1950 to 2014 with IMD-gridded precipitation datasets over India. Rankings were assigned using the TOPSIS method with evaluation metrics as CC and RMSE as conditions. Almost all datasets performed well for indices, i.e., CWD, R10MM, R20MM, and RR2.5. The top 5 performing models are EC-Earth3, EC-Earth3-Veg, MRI-ESM2-0, GFDL-ESM4, and MIROC6 which were ensembled and projected for future periods in the near (2015-2040), middle (2041-2070), and far future (2070-2100), and extreme indices were calculated under Shared Socioeconomic Pathways 126 (SSP126), SSP245, SSP370, and SSP585 scenarios. The ensemble mean shows that RX1DAY, RX5DAY, R10MM, R20MM, and CWD are observed to increase in western ghats and northeastern regions of India. Central India exhibits a dynamic influence on precipitation indices in different climate change scenarios. The temporal variation for the SSP585 scenario predicts significant increases of about 45.41%, 149.40%, 52.26%, and 45.92% in R10MM, R20MM, RX1DAY, and RX5DAY over the current climate. Future extreme precipitation indices help flood modelers and hydrologists with watershed management., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Laurence-Moon-Bardet-Biedl syndrome (LMBBS) is a rare autosomal recessive disorder characterised by polydactyly, retinitis pigmentosa, obesity, hypogonadism and mental retardation., Materials: A 20-year old male, who is morbidly obese [BMI = 41] with history of intellectual delay, speech impairment and progressive vision loss. Presented to Saveetha medical college, Chennai with chief complaints of breathlessness, oliguria, abdominal distension. On examination patient had short stature, obese, crowded teeth present, had polydactyly of feet, micro penis and retinitis pigmentosa, nystagmus. He had pedal edema and facial puffiness. Laboratory investigations revealed Hb-6.9, creatinine-12, urea 217, potassium-7.7, bicarbonate-8.3. Echo showed eccentric Left ventricular hypertrophy. CT abdomen revealed hepatomegaly, right contracted kidney with renal pelvic lipomatosis, left enlarged kidney with hydroureteronephrosis grade 4., Result: He presented with all the primary Pentad features of LMBBS along with CKD stage 5. He also had secondary features like speech delay, developmental delay, dental crowding, high arched palate, left ventricular hypertrophy., Conclusion: LMBBS is a disorder with an identified Pentad of symptoms which are obesity, hypogonadism, intellectual impairment, polydactyly and retinitis pigmentosa. Renal function loss is most common cause of mortality in these patients. Because of seemingly unrelated symptoms the disorder remains largely under diagnosed. Genetic counselling of effected families raise awareness about need to get the other family members assessed for renal and cardiovascular problems. References Khan PA, Nishaat J, Noor S, et al. Laurence Moon Bardet Biedl syndrome: a rare case report in a tertiary care teaching hospital, Hyderabad, Telangana, India. Int J Med Sci Public Health 2017;7(1):68-71. Katsanis N, Lupski JR, Beales PL. Exploring the molecular basis of Bardet-Biedl syndrome. Hum Mol Genet 2001;10(20):2293-2299., (© Journal of the Association of Physicians of India 2011.)

Tracheobronchial foreign body aspiration amongst paediatric population is one of the commonest challenges faced by the otolaryngologist. Subcutaneous emphysema is an uncommon presentation of this condition and the ENT specialist needs to have a high index of clinical suspicion of a foreign body. We report a case of 2-year old child presented with subcutaneous emphysema later diagnosed with a foreign body in the bronchus., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interests., (© Association of Otolaryngologists of India 2020.)

Hearing is an important sense organ for human beings essential for speech, language and overall development. Universal neonatal hearing screening programmes are mandatory in many developed countries. In India out of 1000 neonates approximately 5-6 infants are diagnosed with hearing impairment but still universal neonatal hearing screening programme is in its infancy. To screen all neonates delivered at our centre in three years, with secondary objective of determining the significance of risk factors with neonatal hearing loss and to provide appropriate intervention following the detection of a permanent hearing impairment. It is a non-randomised prospective cohort study conducted at a tertiary care centre to screen all neonates born between Jan 2017 and Dec 2019 with 2 stage protocol using distortion product otoacoustic emission and auditory brainstem response. The study population was also divided into two groups, ''at risk'' and ''no risk'' groups to determine the significance of risk factors on neonatal hearing loss. Total 2676 neonates were screened, OAE referral rate was 1.53%. There was a 94.12% follow up. The incidence of hearing impairment was found to be 7 per 1000(In the "no risk" group, 2.9 per 1000 and in the "at risk" group, 41.38 per 1000). Statistically, a significant difference was found in the incidence of hearing impairment between the two groups ( p  < 0.05, chi-square Test). Hospital based universal hearing screening of new born before discharge is feasible at a tertiary care centre. A high incidence of 0.7% congenital hearing impairment warrants universal newborn hearing screening programme. Considering the limitations and infrastructure in India, we should at least employ screening for all high risk neonates., Competing Interests: Conflict of InterestThe authors declare that they have no conflict of interests., (© Association of Otolaryngologists of India 2021.)

Background: Ofatumumab is a humanized type 1 anti-CD20 monoclonal antibody. Preclinical studies show improved complement-mediated cytotoxicity (CMC) compared to rituximab in mantle cell lymphoma (MCL). This study evaluates the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O-HyperCVAD) in newly diagnosed MCL., Methods: In this single-arm phase 2 study, 37 patients were treated with the combination of O-HyperCVAD for 4 or 6 cycles, followed by high dose chemotherapy and autologous stem cell transplant. Primary objectives were overall response rate (ORR) and complete response (CR) rate at the end of therapy. Secondary objectives included minimal residual disease (MRD) negativity, progression-free survival (PFS), and overall survival (OS)., Results: Median age was 60 years; ORR was 86% and 73% achieved a CR by modified Cheson criteria. The MRD negativity rate was 78% after 2 cycles of therapy, increasing to 96% at the end of induction; median PFS and OS were 45.5 months and 56 months, respectively. Achieving a post-induction CR by both imaging and flow cytometry was associated with improved PFS and OS. Early MRD negativity (post-2 cycles) was also associated with an improved PFS but not OS. There were 3 deaths while on therapy, and grades 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients., Conclusion: The addition of ofatumumab to HyperCVAD/HD-MA led to high rates of MRD negativity by flow cytometry in patients with newly diagnosed MCL. Achieving a CR post-induction by both imaging and flow cytometry is associated with improved overall survival., (© 2022 American Cancer Society.)

Background: Neighborhood-level racial residential segregation has been linked to several cardiovascular disease risk factors and outcomes in Black adults, but its impact on subclinical atherosclerosis remains unknown. In addition, although the impact of segregation on health may vary over the life course, most studies have examined segregation exposure at a single point in time. This article takes a life course approach by examining associations of exposure to neighborhood-level racial residential segregation in young adulthood and patterns of exposure from young adulthood to midlife with coronary artery calcification (CAC) incidence., Methods: We used data on 1125 Black CARDIA study (Coronary Artery Risk Development in Young Adults) participants free of CAC. Residential segregation was assessed using the G i * statistic and measured when participants were young adults (18-30 years old, in 1985-1986) and as the pattern from young adulthood to midlife (15 years later). Poisson regression with generalized estimating equations models was used to measure CAC incidence., Results: We found participants living in low segregation neighborhoods in young adulthood had 0.52 (rate ratio [95% CI: 0.28-0.98]) times lower risk of developing CAC compared with high segregation after adjusting for young adulthood sociodemographic characteristics and neighborhood poverty. Associations were attenuated and no longer statistically significant with adjustment for midlife CAC risk factors hypothesized to be on the causal pathway (rate ratio: 0.56 [95% CI: 0.29-1.09]). Findings for patterns of segregation over time suggest participants living in low segregation neighborhoods in young adulthood were less likely to develop CAC than those who started out in medium/high segregation neighborhoods, regardless of where they lived in midlife (rate ratio for increase from low to medium/high: 0.42 [95% CI: 0.19-0.95]; rate ratio for continuously low versus continuously medium/high segregation neighborhoods: 0.75 [95% CI: 0.31-1.83])., Conclusions: We found that participants living in more segregated neighborhoods in young adulthood were more likely to develop CAC due at least in part to differences in CAC risk factor burden accumulated over follow-up.

Recognition and clearance of apoptotic cells by phagocytes (also known as efferocytosis), primarily mediated by macrophages, are essential to terminate lung inflammatory responses and promote tissue repair after injury. The Nrf2 transcription factor is crucial for cytoprotection and host defense. Previously, we showed sustained neutrophilic lung inflammation in Nrf2-deficient ( Nrf2 -/- ) mice after hyperoxia-induced lung injury in vivo, but the mechanisms underlying this abnormal phenotype remain unclear. To examine whether Nrf2 regulates apoptotic neutrophil clearance, we used the alveolar macrophages (AMФs) and bone-marrow-derived macrophages (BMDMФs) of wild-type (WT) and Nrf2 -/- mice. We found that the efferocytic ability of AMФ was impaired in hyperoxia-exposed mice's lungs, but the effect was more pronounced in Nrf2 -/- mice. Importantly, AMФ-mediated efferocytosis remained impaired in Nrf2 -/- mice recovering from injury but was restored to the basal state in the wild-type counterparts. Hyperoxia affected apoptotic neutrophil binding, not internalization, in both WT and Nrf2 -/- BMDMФs, but the effect was more significant in the latter cells. Augmenting Nrf2 activity restored hyperoxia attenuated efferocytosis in WT, but not in Nrf2 -/- macrophages. However, the loss of Nrf2 in neutrophils affected their uptake by WT macrophages. Collectively, these results demonstrate that Nrf2 is required for optimal macrophage-mediated efferocytosis and that activating Nrf2 may provide a physiological way to accelerate apoptotic cell clearance after oxidant injury.

Bronchopulmonary dysplasia (BPD) is a chronic disease of preterm babies with poor clinical outcomes. Nrf2 transcription factor is crucial for cytoprotective response, whereas Keap1-an endogenous inhibitor of Nrf2 signaling-dampens these protective responses. Nrf2-sufficient (wild type) newborn mice exposed to hyperoxia develop hypoalveolarization, which phenocopies human BPD, and Nrf2 deficiency worsens it. In this study, we used PND1 pups bearing bearing hypomorphic Keap1 floxed alleles (Keap1 f/f ) with increased levels of Nrf2 to test the hypothesis that constitutive levels of Nrf2 in the premature lung are insufficient to mitigate hyperoxia-induced hypoalveolarization. Both wildtype and Keap1 f/f pups at PND1 were exposed to hyperoxia for 72 h and then allowed to recover at room air for two weeks (at PND18), sacrificed, and lung hypoalveolarization and inflammation assessed. Hyperoxia-induced lung hypoalveolarization was remarkably lower in Keap1 f/f pups than in wildtype counterparts (28.9% vs 2.4%, wildtype vs Keap1 f/f ). Likewise, Keap1 f/f pups were protected against prolonged (96 h) hyperoxia-induced hypoalveolarization. However, there were no differences in hyperoxia-induced lung inflammatory response immediately after exposure or at PND18. Lack of hypoalveolarization in Keap1 f/f pups was accompanied by increased levels of expression of antioxidant genes and GSH as assessed immediately following hyperoxia. Keap1 knockdown resulted in upregulation of lung cell proliferation postnatally but had opposing effects following hyperoxia. Collectively, our study demonstrates that augmenting endogenous Nrf2 activation by targeting Keap1 may provide a physiological way to prevent hypoalveolarization associated with prematurity.

Approximately 90% of limited-stage Hodgkin lymphoma (HL) patients are projected to be cured with standard therapy, but many do not live their expected life span because of late treatment-related complications. New treatment paradigms are needed to reduce the use of radiation therapy (RT) as well as conventional chemotherapy drugs while improving upon current standard-of-care survival outcomes. In this phase 2 multicenter study, patients with non-bulky limited-stage HL received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by brentuximab vedotin (BV) consolidation. Forty-one patients were enrolled, and patient characteristics included median age of 29 years (range, 19 to 67 years), 58% were female, 45% had unfavorable disease, and 98% had stage II disease. Based on positron emission tomography (PET)-based risk stratification, patients received 2 to 6 cycles of ABVD followed by 6 cycles of BV. After ABVD followed by BV, 95% of evaluable patients (37 out of 39; 95% confidence interval [CI], 83%-99%) achieved PET-negative status. In the intent-to-treat patient population, the estimated 3-year progression-free survival (PFS) rate was 92%, and the overall survival (OS) rate was 97%, with a median follow-up of 47 months. All 37 patients who achieved negative PET status after BV consolidation effectively avoided RT and remain in remission with estimated 3-year PFS and OS rates of 100%. In conclusion, BV demonstrates encouraging clinical activity when it follows ABVD therapy in limited-stage HL. Early incorporation of BV may reduce the use of RT as well as conventional chemotherapy drugs while achieving favorable survival outcomes in risk-stratified patients with non-bulky limited-stage HL. This trial was registered at www.clinicaltrials.gov as #NCT01578967., (© 2020 by The American Society of Hematology.)

Background: Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown., Methods: Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy., Results: In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy., Conclusions: Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients., (© 2019 American Cancer Society.)

Primary central nervous system lymphoma (PCNSL) patients have a poorer prognosis than systemic lymphoma. Gain-of-function MYD88 c.794T > C (p. L265P) mutation and programed cell death-1 (PD-1) pathway alterations are potential targetable pathways. Our study objective was to determine the clinicopathologic correlates of MYD88 mutation and PD-1 alterations in PCNSL and the impact of Epstein-Barr virus (EBV) infection. We studied 53 cases including 13 EBV-associated (EBV pos ) PCNSL, 49% harbored MYD88 mutation, none seen in EBV pos PCNSL. MYD88 protein expression did not correlate with MYD88 mutation. T-cell and macrophage infiltration was common. All PD-L1-positive tumors were EBV pos . Two PD-L1 positive tumors showed 9p24.1/PD-L1 locus alterations by Fluorescence In Situ Hybridization. T cells and macrophages expressed PD-1 and/or PD-L1 in 98% and 83% cases, respectively. MYD88 mutation or protein expression and PD-1 or PD-L1 expression did not predict outcome. We hypothesize that EBV pos PCNSL has a distinct activation mechanism, independent of genetic alterations.

Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707)., (© 2019 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)

Background: Ibrutinib has revolutionized treatment for several B-cell malignancies. However, a recent clinical trial where ibrutinib was used in a front-line setting showed increased mortality during treatment compared with conventional chemotherapy. Cardiovascular toxicities were suspected as the culprit but not directly assessed in the study., Objectives: The purpose of this study was to identify and characterize cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib., Methods: This study utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) and information component (IC) to determine whether CV-ADR and CV-ADR deaths were associated with ibrutinib. IC compares observed and expected values to find associations between drugs and adverse drug reactions using disproportionate Bayesian-reporting; IC 025 (lower end of the IC 95% credibility interval) >0 is significant., Results: This study identified 303 ibrutinib-associated cardiovascular deaths. Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVAs) (ROR: 23.1; 95% confidence interval: 21.6 to 24.7; p < 0.0001; IC 025 : 3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7; 95% confidence interval: 3.4 to 4.1; p < 0.0001; IC 025 : 1.63), heart failure (ROR: 3.5; 95% confidence interval: 3.1 to 3.8; p < 0.0001; IC 025 : 1.46), ventricular arrhythmias (ROR: 4.7; 95% confidence interval: 3.7 to 5.9; p < 0.0001; IC 025 : 0.96), conduction disorders (ROR: 3.5; 95% confidence interval: 2.7 to 4.6; p < 0.0001; IC 025 : 0.76), CNS ischemic events (ROR: 2.2; 95% confidence interval: 2.0 to 2.5; p < 0.0001; IC 025 : 0.73), and hypertension (ROR: 1.7; 95% confidence interval: 1.5 to 1.9; p < 0.0001; IC 025 : 0.4). CV-ADR often occurred early after ibrutinib administration. Importantly, CV-ADR were associated with fatalities that ranged from ∼10% (SVAs and ventricular arrhythmias) to ∼20% (CNS events, heart failure, and conduction disorders). Ibrutinib-associated SVA portends poor prognosis when CNS events occur concomitantly, with 28.8% deaths (15 of 52 cases)., Conclusions: Severe and occasionally fatal cardiac events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs. (Evaluation of Reporting of Cardio-vascular Adverse Events With Antineoplastic and Immunomodulating Agents [EROCA]; NCT03530215)., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: Alliance/CALGB 50303 (NCT00118209), an intergroup, phase III study, compared dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as frontline therapy for diffuse large B-cell lymphoma., Patients and Methods: Patients received six cycles of DA-EPOCH-R or R-CHOP. The primary objective was progression-free survival (PFS); secondary clinical objectives included response rate, overall survival (OS), and safety., Results: Between 2005 and 2013, 524 patients were registered; 491 eligible patients were included in the final analysis. Most patients (74%) had stage III or IV disease; International Prognostic Index (IPI) risk groups included 26% IPI 0 to 1, 37% IPI 2, 25% IPI 3, and 12% IPI 4 to 5. At a median follow-up of 5 years, PFS was not statistically different between the arms (hazard ratio, 0.93; 95% CI, 0.68 to 1.27; P = .65), with a 2-year PFS rate of 78.9% (95% CI, 73.8% to 84.2%) for DA-EPOCH-R and 75.5% (95% CI, 70.2% to 81.1%) for R-CHOP. OS was not different (hazard ratio, 1.09; 95% CI, 0.75 to 1.59; P = .64), with a 2-year OS rate of 86.5% (95% CI, 82.3% to 91%) for DA-EPOCH-R and 85.7% (95% CI, 81.4% to 90.2%) for R-CHOP. Grade 3 and 4 adverse events were more common ( P < .001) in the DA-EPOCH-R arm than the R-CHOP arm, including infection (16.9% v 10.7%, respectively), febrile neutropenia (35.0% v 17.7%, respectively), mucositis (8.4% v 2.1%, respectively), and neuropathy (18.6% v 3.3%, respectively). Five treatment-related deaths (2.1%) occurred in each arm., Conclusion: In the 50303 study population, the more intensive, infusional DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. The more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.

Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with <2 prior therapies, and the presence of TP53 or SF3B1 mutations showed a trend toward shorter PFS vs without these factors. Median duration of ibrutinib was 41 months, with 46% remaining on treatment at a median follow-up of 44 months. Grade ≥3 adverse events generally decreased over time, causing only a small proportion of patients to cease therapy. Ibrutinib was discontinued due to progressive disease in 27% of patients. This long-term study provides support for sustained efficacy and safety of ibrutinib in relapsed/refractory CLL and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated. This trial was registered at www.clinicaltrials.gov as #NCT01578707., (© 2019 by The American Society of Hematology.)

The efficacy of ibrutinib has been demonstrated in patients with chronic lymphocytic leukemia (CLL), including as first-line therapy. However, outcomes after ibrutinib discontinuation have previously been limited to higher-risk populations with relapsed/refractory (R/R) disease. The objective of this study was to evaluate outcomes of ibrutinib-treated patients based on prior lines of therapy, including after ibrutinib discontinuation. Data were analyzed from two multicenter phase 3 studies of single-agent ibrutinib: RESONATE (PCYC-1112) in patients with R/R CLL and RESONATE-2 (PCYC-1115) in patients with treatment-naive (TN) CLL without del(17p). This integrated analysis included 271 ibrutinib-treated non-del(17p) patients with CLL (136 TN and 135 R/R). Median progression-free survival (PFS) was not reached for subgroups with 0 and 1/2 prior therapies but was 40.6 months for patients with ≥3 therapies (median follow-up: TN, 36 months; R/R, 44 months). Median overall survival (OS) was not reached in any subgroup. Overall response rate (ORR) was 92% in TN and 92% in R/R, with depth of response increasing over time. Adverse events (AEs) and ibrutinib discontinuation due to AEs were similar between patient groups. Most patients (64%) remain on treatment. OS following discontinuation was 9.3 months in R/R patients (median follow-up 18 months, n = 51) and was not reached in TN patients (median follow-up 10 months, n = 30). In this integrated analysis, ibrutinib was associated with favorable PFS and OS, and high ORR regardless of prior therapies in patients with CLL. The best outcomes following ibrutinib discontinuation were for patients receiving ibrutinib in earlier lines of therapy., (© 2019 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)

Autoimmune hemolytic anemia occurs due to an interaction of IgG antibodies with protein antigens expressed on red blood corpuscles. Glucocorticoids are the mainstay of treatment for autoimmune hemolytic anemia. For patients not responding to initial therapy, other agents such as rituximab, immunosuppressive therapy, or splenectomy are considered. When refractory to these treatment options, alemtuzumab is an alternative agent. However, long-term outcomes of patients supporting its use are lacking. We present three patients with refractory autoimmune hemolytic anemia treated with alemtuzumab.

Primary central nervous lymphoma (PCNSL) is a rare extra-nodal subtype of non-Hodgkin lymphoma and most cases are of diffuse large B-cell lymphoma histology with an aggressive presentation. The treatment of PCNSL has evolved over the years from radiation alone to multi-agent chemotherapy with the goal of minimizing long-term toxicity. Recent studies have evaluated autologous stem cell transplant as consolidation in eligible patients with success. The prognosis of relapsed disease remains poor and hence the emphasis is on effective and less toxic frontline strategies. Our growing understanding of the pathogenetic pathways in PCNSL is giving way to an exciting new era of targeted and immunotherapy options with the potential for inclusion in upfront therapy in the future. This review critically evaluates the current evidence including ongoing studies for the frontline treatment of PCNSL.

Background: Ibrutinib compared with ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)., Patients and Methods: Measures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization., Results: With up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on ofatumumab (P < .0001). Higher rates of clinically meaningful improvement were demonstrated with ibrutinib versus ofatumumab for FACIT-F and EORTC global health. Greater improvement was observed in disease-related weight loss, fatigue, night sweats, and abdominal discomfort with ibrutinib versus ofatumumab. Hospitalizations in the first 30 days occurred less frequently with ibrutinib than ofatumumab (0.087 vs. 0.184 events/patient; P = .0198). New-onset diarrhea was infrequent with ibrutinib after the first 6 months (47% at ≤6 months vs. 5% at 12-18 months). With ibrutinib, grade ≥ 3 hypertension occurred in 6%, grade ≥ 3 atrial fibrillation in 4%, major hemorrhage in 2%, and tumor lysis syndrome in 1% of patients., Conclusion: Ibrutinib led to significant improvements in hematologic function and disease symptomatology versus ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The FOSL1/AP-1 transcription factor regulates gene expression, thereby controlling various pathophysiological processes. It is a major effector of RAS-ERK1/2 signaling and is activated in human lung epithelia by tumorigenic stimuli. Recent evidence shows an inverse correlation between FOSL1 expression and the survival of patients with lung cancer and adenocarcinomas; however, its role in lung tumorigenesis remains elusive. In this work, we sought to determine the role of FOSL1 in Kras-induced lung adenocarcinoma in vivo and its downstream effector mechanisms. We used mice expressing the Kras oncogene in the lung with concomitant Fosl1 deletion, Kras-activated murine alveolar epithelial cells (mAECs) with Fosl1 deletion, and KRAS mutant human lung adenocarcinoma (HLAC) cells with FOSL1 deficiency, and performed cell proliferation and gene expression analyses. Mutant Kras induced Fosl1 expression in vitro (mAECs) and in vivo (lung tissue), and mice with Fosl1 deletion showed reduced levels of mutant Kras-induced lung tumorigenesis and survived longer than Fosl1-sufficient mice. Studies with mutant Kras-activated mAECs and KRAS-mutant HLAC cells revealed that FOSL1 regulates mutant KRAS-induced gene expression, thereby controlling cell proliferation and survival. In contrast, FOSL1 depletion in non-KRAS-mutant HLAC cells and nonmalignant human lung epithelia had no effect. Our data support the notion that FOSL1-mediated expression of amphiregulin and apoptotic and antioxidative genes plays a role in regulating HLAC cell proliferation and survival. FOSL1 is a determinant of lung cancer in vivo and regulates HLAC cell proliferation and survival, largely in the context of KRAS mutations. Activation of FOSL1 in adenocarcinomas may be a prognostic marker and potential target for human lung cancer with KRAS mutations.