Matching-Adjusted Indirect Comparison of Risankizumab Versus Deucravacitinib in Patients with Moderate-to-Severe Plaque Psoriasis.

INTRODUCTION: Despite advancements in the treatment of psoriasis (PsO), there are few head-to-head studies assessing comparative effectiveness of the newest therapies approved to treat PsO. Our objective was to assess the comparative clinical effectiveness of risankizumab and deucravacitinib in patients with moderate-to-severe PsO. METHODS: This placebo-anchored matching-adjusted indirect comparison (MAIC) analysis utilized data from UltIMMa-1/2 risankizumab and POETYK PSO-1/2 deucravacitinib trials. Individual patient data from UltiMMA-1/2 were weighted via propensity score to match POETYK PSO-1/2 published summary data. Rate differences between risankizumab and deucravacitinib were assessed for Psoriasis Area and Severity Index (PASI) 75/90/100, the Static Physician Global Assessment (sPGA = 0 or 0/1), and the Dermatology Life Quality Index (DLQI) 0/1. RESULTS: At 16 weeks, risankizumab-treated patients demonstrated statistically significantly higher rates of skin clearance and greater improvement in quality of life (QoL) compared to those treated with deucravacitinib. Across all outcomes, risankizumab demonstrated a lower number needed to treat compared to deucravacitinib. Limitations are potential bias due to unobserved/unmeasurable differences and limited generalizability of the results. CONCLUSIONS: This indirect comparison demonstrates that risankizumab has higher rates of skin clearance and greater improvements in QoL than deucravacitinib. This study will help inform healthcare providers in their treatment and management strategy of PsO.

Improving Patient Understanding and Outcomes in Lung Cancer Using an Animated Patient's Guide with Visual Formats of Learning.

Lung cancer patient education resources that address barriers to health literacy, improve understanding, and demonstrate improved patient outcomes are limited. Our study aim was to evaluate and report on learner knowledge improvement and intent to implement behavior change, and validate the benefits of the You and Lung Cancer website and YouTube resources. Our study occurred from November 2017 to December 2023. We evaluated audience reach (visit sessions, unique visitors, country origins, page views) and calculated top views by media type (animations, expert videos, patient videos). We assessed the impact and commitment to change through learner surveys (areas of interest, intention to modify behaviors, and intention to discuss disease management with providers) and tested the knowledge of learners pre- and post-reviewing of website content. Our program reached 794,203 views globally; 467,546 were unique visitors; and 243,124 (51%) were unique visitors from the USA. Of US visitors, 46% identified as lung cancer patients. These were patients in treatment (38%), survivors (8%), family members or caregivers (21%), and healthcare providers (14%) with other audiences unspecified (19%). Three areas of highest learner importance were the animations "Understanding Non-Small Cell Lung Cancer" (180,591), "Staging of Lung Cancer" (144,238), and "Treatment and Management of Small Cell Lung Cancer" (49,244). Our study confirmed areas of importance to lung cancer patients and suggests that visual formats of learning, such as animations, can mitigate health literacy barriers and help improve patient understanding and outcomes. Exporting this format of learning to other cancers has the potential to benefit patients and improve health outcomes.

Pirtobrutinib monotherapy in Bruton tyrosine kinase inhibitor-intolerant patients with B-cell malignancies: results of the phase I/II BRUIN trial.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Minimum information for reporting on the TEER (trans-epithelial/endothelial electrical resistance) assay (MIRTA).

Standard information reporting helps to ensure that assay conditions and data are consistently reported and to facilitate inter-laboratory comparisons. Here, we present recommendations on minimum information for reporting on the TEER (trans-epithelial/endothelial electrical resistance) assay (MIRTA). The TEER assay is extensively used to evaluate the health of an epithelial/endothelial cell culture model and as an indicator of the potential toxicity of a test substance. This publication is the result of an international collaboration─called the RespTox (Respiratory Toxicity) Collaborative─through which twelve laboratories shared their protocols for assessing the barrier function of respiratory epithelial cells using the TEER assay following exposure to substances. The protocols from each laboratory were reviewed to identify general steps for performing the TEER assay, interlaboratory differences between steps, the rationale for differences, whether these differences impact results or cross-laboratory comparisons between TEER measurements. While the MIRTA recommendations are focused on respiratory epithelial cell systems, these recommendations can be adapted for other cell systems that form barriers. The use of these recommendations will support data transparency and reproducibility, reduce challenges in data interpretation, enable cross-laboratory comparisons, help assess study quality, and facilitate the incorporation of the TEER assay into national and international testing guidance.

Accuracy of MRI in detecting seminal vesicle invasion in prostate cancer: a systematic review and meta-analysis.

OBJECTIVE: To determine the diagnostic test accuracy of multiparametric magnetic resonance imaging (mpMRI) in detecting seminal vesicle invasion (SVI). METHODS: The Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed, the Excerpta Medica dataBASE (EMBASE) and Cochrane databases were search up to May 2023. We included studies that investigated the accuracy of mpMRI in detecting SVI when compared to radical prostatectomy specimens as the reference standard. Data extraction was performed by two independent reviewers to construct 2 × 2 tables, as well as patient and study characteristics. The methodological quality of the included studies was assessed with the Quality of Assessment of Diagnostic Accuracy Studies-2 tool. Sensitivity and specificity were pooled and presented graphically with summary receiver operator characteristic (SROC) plots. RESULTS: A total of 27 articles with 4862 patients were included for analysis. The summary sensitivity and specificity were 0.57 (95% confidence interval [CI] 0.45-0.68) and 0.95 (95% CI 0.92-0.99), respectively. Meta-regression indicated that there was no evidence that coil strength (P = 0.079), coil type (P = 0.589), year of publication (P = 0.503) or use of the Prostate Imaging-Reporting and Data System (P = 0.873) significantly influenced these results. The summary diagnostic odds ratio was 28.3 (95% CI 15.0-48.8) and the area under the curve for the SROC curve was 0.87. The I2 statistic was a modest 11.9%. In general, methodological quality was good. CONCLUSION: The use of mpMRI in detecting SVI has excellent specificity but poor sensitivity. Both endorectal coils and magnetic field strength do not significantly impact the accuracy of MRI. These findings suggest that mpMRI cannot reliably rule out SVI in patients with prostate cancer.

Estimated incidence of disruptions to event-free survival from non-metastatic cancers in New South Wales, Australia - a population-wide epidemiological study of linked cancer registry and treatment data.

Introduction: Population cancer registries record primary cancer incidence, mortality and survival for whole populations, but not more timely outcomes such as cancer recurrence, secondary cancers or other complications that disrupt event-free survival. Nonetheless, indirect evidence may be inferred from treatment data to provide indicators of recurrence and like events, which can facilitate earlier assessment of care outcomes. The present study aims to infer such evidence by applying algorithms to linked cancer registry and treatment data obtained from hospitals and universal health insurance claims applicable to the New South Wales (NSW) population of Australia. Materials and methods: Primary invasive cancers from the NSW Cancer Registry (NSWCR), diagnosed in 2001-2018 with localized or regionalized summary stage, were linked to treatment data for five common Australian cancers: breast, colon/rectum, lung, prostate, and skin (melanomas). Clinicians specializing in each cancer type provided guidance on expected treatment pathways and departures to indicate remission and subsequent recurrence or other disruptive events. A sample survey of patients and clinicians served to test initial population-wide results. Following consequent refinement of the algorithms, estimates of recurrence and like events were generated. Their plausibility was assessed by their correspondence with expected outcomes by tumor type and summary stage at diagnosis and by their associations with cancer survival. Results: Kaplan-Meier product limit estimates indicated that 5-year cumulative probabilities of recurrence and other disruptive events were lower, and median times to these events longer, for those staged as localized rather than regionalized. For localized and regionalized cancers respectively, these were: breast - 7% (866 days) and 34% (570 days); colon/rectum - 15% (732 days) and 25% (641 days); lung - 46% (552 days) and 66% (404 days); melanoma - 11% (893 days) and 38% (611 days); and prostate - 14% (742 days) and 39% (478 days). Cases with markers for these events had poorer longer-term survival. Conclusions: These population-wide estimates of recurrence and like events are approximations only. Absent more direct measures, they nonetheless may inform service planning by indicating population or treatment sub-groups at increased risk of recurrence and like events sooner than waiting for deaths to occur.

Ayurvedic management of systemic sclerosis - A case report.

Scleroderma, an autoimmune connective tissue disorder, leads to skin and tissue thickening. In this autoimmune disease condition, the defense mechanism works against the body itself and mistakenly attacks normal cells. Ayurveda links it to vatarakta, initially affecting tvak, rakta, and mamsa. Vata is primarily involved, but as the disease progresses, all doshas and dhatu get involved. A 45-year-old woman presented with skin hardening, skin depigmentation all over her body, limb stiffness, weakness, arthralgia, anorexia, constipation and burning in the chest region for the last three years. She was diagnosed with diffuse systemic sclerosis (SSc) but as per Ayurveda we can correlate with aamvata and vatarakta based on her lakshanas(symptoms). Ayurvedic treatment commenced with vardhamana pippali(Piper longum)rasayan, svedana karma, and virechan karma, followed by basti(enema) chikitsa (pathyadi kvath niruh basti) and oral ayurvedic medication viz., Manjisthadi kvatha, kaishora guggulu, Jatamansi(Nardostachys Jatamansi) churna, mishreya(Foeniculum vulgare) arka, dashang churna with water for local application and daily shamanarth panchtikta ghrit. After 8 weeks, depigmentation was reduced, new hair growth emerged, mild skin softening occured, chest burning, anorexia, sleeplessness was decreased and enhanced mental well-being. The treatment aimed to balance vitiated doshas and dhatu while alleviating symptoms, and enhancing overall well-being, demonstrating the efficacy of the holistic approach in managing scleroderma through Ayurveda. Auto-immune disorder, scleroderma, chronic complications, skin tightness, salt pepper depigmentation, sclerodactyly.

Pathological Assessment of Men with Grade Group 2 Prostate Cancer.

PURPOSE: A variety of treatment options are now available for men with localized prostate cancer (PC); however, there is still debate in determining how and when to intervene for Grade Group (GG) 2 disease. Our study aims to formulate strategies to identify men at risk of upgrading and having adverse pathological outcomes. MATERIALS AND METHODS: This retrospective study includes 243 patients with GG2 PC that were treated with radical prostatectomy between 2015 and 2021. Patients on active surveillance, previous history of prostate biopsy, hormonal and/or radiation therapy prior to surgery were excluded from this study. A retrospective analysis was conducted using clinicopathological data obtained from medical records. RESULTS: Prostate-specific antigen (PSA) and Prostate Imaging Reporting and Data System (PI-RADS) score were statistically significant variables for risk of upgrading. In men who had presence of composite poor outcomes, PSA, PI-RADS score, presence of extraprostatic extension and seminal vesical invasion on MRI, number of positive cores, percentage of high grade (pattern 4/5) on prostate biopsy and Gleason pattern 4 volume on biopsy were all statistically significant variables. Strategy 8 (PI-RADS 5 lesion or percentage high grade [Gleason pattern 4] on prostate biopsy grade >10% or >3 cores positive on prostate biopsy) had significant association to identifying the highest number of men with upgrading and composite poor outcomes. CONCLUSIONS: Our study supports the use of strategy 8 in treatment decision making of men with GG2 PC. Further validation of the use of this strategy is warranted.

Risk of developing inflammatory arthritis in patients with psoriasis initiating treatment with biologics: A population-based analysis.

BACKGROUND: The relationship between biologic treatments for psoriasis (PsO) and the development of inflammatory arthritis in patients is not fully understood. OBJECTIVE: The objective of this study was to analyze the effects of biologic treatment on the development of inflammatory arthritis in patients with PsO. METHODS: This retrospective study assessed patients with PsO identified in the Optum Clinformatics Data Mart database from Jan 2007 to Mar 2023 with no baseline diagnosis of inflammatory arthritis. Patients were stratified based on the class of initial biologic treatment (interleukin [IL] 23, IL-12/23, IL-17, or tumor necrosis factor [TNF] inhibitor) and followed for up to 3 years or development of inflammatory arthritis. Risk of developing inflammatory arthritis was assessed using a multivariate Cox proportional hazard model using IL-23 inhibitors as reference. RESULTS: Incidence rates of developing inflammatory arthritis expressed as events/100 person-years were 4.99, 7.29, 6.06, and 9.39 for IL-23, IL-17, IL-12/23, and TNF inhibitors, respectively. Adjusted hazard ratios were significantly higher for patients receiving IL-17 (1.44; P = .0294) and TNF (1.90; P < .0001) inhibitors when compared with patients receiving IL-23 inhibitors. LIMITATIONS: Limitations include those associated with medical coding errors and the potential for protopathic bias. CONCLUSION: Patients receiving IL-23 inhibitors are at lower risk of developing inflammatory arthritis or psoriatic arthritis than those receiving IL-17 and TNF inhibitors.

ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Nab-Paclitaxel in Patients with Advanced Solid Tumors.

PURPOSE: In preclinical models, glucocorticoid receptor (GR) signaling drives resistance to taxane chemotherapy in multiple solid tumors via upregulation of antiapoptotic pathways. ORIC-101 is a potent and selective GR antagonist that was investigated in combination with taxane chemotherapy as an anticancer regimen preclinically and in a phase 1 clinical trial. PATIENTS AND METHODS: The ability of ORIC-101 to reverse taxane resistance was assessed in cell lines and xenograft models, and a phase 1 study (NCT03928314) was conducted in patients with advanced solid tumors to determine the dose, safety, and antitumor activity of ORIC-101 with nab-paclitaxel. RESULTS: ORIC-101 reversed chemoprotection induced by glucocorticoids in vitro and achieved tumor regressions when combined with paclitaxel in both taxane-naïve and -resistant xenograft models. In the phase 1 study, 21 patients were treated in dose escalation and 62 patients were treated in dose expansion. All patients in dose expansion had previously progressed on a taxane-based regimen. In dose escalation, five objective responses were observed. A preplanned futility analysis in dose expansion showed a 3.2% (95% confidence interval, 0.4-11.2) objective response rate with a median progression-free survival of 2 months (95% confidence interval, 1.8-2.8) across all four cohorts, leading to study termination. Pharmacodynamic analysis of tissue and plasma showed GR pathway downregulation in most patients in cycle 1. CONCLUSIONS: ORIC-101 with nab-paclitaxel showed limited clinical activity in taxane-resistant solid tumors. Despite clear inhibition of GR pathway signaling, the insufficient clinical signal underscores the challenges of targeting a single resistance pathway when multiple mechanisms of resistance may be in play. SIGNIFICANCE: Glucocorticoid receptor (GR) upregulation is a mechanism of resistance to taxane chemotherapy in preclinical cancer models. ORIC-101 is a small molecule GR inhibitor. In this phase 1 study, ORIC-101 plus nab-paclitaxel did not show meaningful clinical benefit in patients who previously progressed on taxanes despite successful GR pathway downregulation.

T Cell Responses to Individualized Neoantigen Therapy mRNA-4157 (V940) Alone or in Combination With Pembrolizumab in the Phase 1 KEYNOTE-603 Study.

mRNA-4157 (V940) is an individualized neoantigen therapy (INT) targeting up to 34 patient-specific tumor neoantigens to induce T cell responses and potentiate anti-tumor activity. We report mechanistic insights into the immunogenicity of mRNA-4157 via characterization of T cell responses to neoantigens from the first-in-human phase 1, KEYNOTE-603 study (NCT03313778) in patients with resected non-small cell lung cancer (Part A: 1mg mRNA-4157, n = 4) or resected cutaneous melanoma (Part D: 1mg mRNA-4157 + 200mg pembrolizumab, n = 12). Safety, tolerability, and immunogenicity were assessed. All patients experienced ≥1 treatment-emergent adverse event (AE); there were no grade 4/5 AEs or dose-limiting toxicities. mRNA-4157 alone induced consistent de novo, and strengthened pre-existing, T cell responses to targeted neoantigens. Following combination therapy, sustained mRNA-4157-induced neoantigen-specific T cell responses and expansion of cytotoxic CD8 and CD4 T cells were observed. These findings show the potential of a novel mRNA INT approach in oncology.

Evaluating the Efficacy of ChatGPT as a Patient Education Tool in Prostate Cancer: Multimetric Assessment.

BACKGROUND: Artificial intelligence (AI) chatbots, such as ChatGPT, have made significant progress. These chatbots, particularly popular among health care professionals and patients, are transforming patient education and disease experience with personalized information. Accurate, timely patient education is crucial for informed decision-making, especially regarding prostate-specific antigen screening and treatment options. However, the accuracy and reliability of AI chatbots' medical information must be rigorously evaluated. Studies testing ChatGPT's knowledge of prostate cancer are emerging, but there is a need for ongoing evaluation to ensure the quality and safety of information provided to patients. OBJECTIVE: This study aims to evaluate the quality, accuracy, and readability of ChatGPT-4's responses to common prostate cancer questions posed by patients. METHODS: Overall, 8 questions were formulated with an inductive approach based on information topics in peer-reviewed literature and Google Trends data. Adapted versions of the Patient Education Materials Assessment Tool for AI (PEMAT-AI), Global Quality Score, and DISCERN-AI tools were used by 4 independent reviewers to assess the quality of the AI responses. The 8 AI outputs were judged by 7 expert urologists, using an assessment framework developed to assess accuracy, safety, appropriateness, actionability, and effectiveness. The AI responses' readability was assessed using established algorithms (Flesch Reading Ease score, Gunning Fog Index, Flesch-Kincaid Grade Level, The Coleman-Liau Index, and Simple Measure of Gobbledygook [SMOG] Index). A brief tool (Reference Assessment AI [REF-AI]) was developed to analyze the references provided by AI outputs, assessing for reference hallucination, relevance, and quality of references. RESULTS: The PEMAT-AI understandability score was very good (mean 79.44%, SD 10.44%), the DISCERN-AI rating was scored as "good" quality (mean 13.88, SD 0.93), and the Global Quality Score was high (mean 4.46/5, SD 0.50). Natural Language Assessment Tool for AI had pooled mean accuracy of 3.96 (SD 0.91), safety of 4.32 (SD 0.86), appropriateness of 4.45 (SD 0.81), actionability of 4.05 (SD 1.15), and effectiveness of 4.09 (SD 0.98). The readability algorithm consensus was "difficult to read" (Flesch Reading Ease score mean 45.97, SD 8.69; Gunning Fog Index mean 14.55, SD 4.79), averaging an 11th-grade reading level, equivalent to 15- to 17-year-olds (Flesch-Kincaid Grade Level mean 12.12, SD 4.34; The Coleman-Liau Index mean 12.75, SD 1.98; SMOG Index mean 11.06, SD 3.20). REF-AI identified 2 reference hallucinations, while the majority (28/30, 93%) of references appropriately supplemented the text. Most references (26/30, 86%) were from reputable government organizations, while a handful were direct citations from scientific literature. CONCLUSIONS: Our analysis found that ChatGPT-4 provides generally good responses to common prostate cancer queries, making it a potentially valuable tool for patient education in prostate cancer care. Objective quality assessment tools indicated that the natural language processing outputs were generally reliable and appropriate, but there is room for improvement.

Associations of demographic and tobacco use characteristics with young adults' self-reported clinical encounters: Implications for cessation efforts.

Introduction: Accelerating smoking cessation, particularly among young adults, is a national priority for decreasing tobacco-related disease. Healthcare providers play a critical role in delivering tobacco treatment interventions to this population. This study examined associations of demographic and tobacco use characteristics with young adults' self-reported past-year clinical encounters to identify opportunities to facilitate cessation. Methods: We conducted cross-sectional, secondary analyses on a sample of 831 young adults aged 18-34 participating in the first wave of the National Young Adult Health Survey (NYAHS 2018-2019). Demographic and tobacco use characteristics were participants' sex, age, race, current cigarette use, and current other tobacco use. Clinical encounter outcomes were past-year self-report of (1) seeing a clinician, (2) being asked about tobacco use, and among those currently smoking, (3) being advised to quit smoking. Results: After adjustment for covariates, women (vs. men) had 2.16 times greater odds of reporting seeing a clinician, while Non-White (vs. White) young adults and those currently (vs. never) smoking had 69% and 47% lower odds. Women and those currently smoking had 2.98 and 2.66 times greater odds, respectively, of being asked about tobacco use. Among those who currently smoked, being not confident (vs. confident) about quitting smoking was associated with 69% lower odds of being advised to quit; those who reported moderate (vs. low) nicotine dependence had 3.11 times higher odds of being advised to quit. Conclusions: Sex, racial, and smoking status differences in young adults' clinical encounter outcomes suggest multiple opportunities for future smoking prevention and cessation intervention efforts.

Pre-Op Hydronephrosis Predicts Outcomes in Patients Receiving Robot-Assisted Radical Cystectomy.

INTRODUCTION: Robot-assisted radical cystectomy (RARC) has gained momentum in the management of muscle invasive bladder cancer (MIBC). Predictors of RARC outcomes are not thoroughly studied. We aim to investigate the implications of preoperative hydronephrosis on oncological outcomes. PATIENTS AND METHODS: This study analysed data from the Asian RARC consortium, a multicentre registry involving nine Asian centres. Cases were divided into two groups according to the presence or absence of pre-operative hydronephrosis. Background characteristics, operative details, perioperative outcomes, and oncological results were reviewed. Outcomes were (1) survival outcomes, including 10-year disease-free survival (DFS) and overall survival (OS), and (2) perioperative and pathological results. Multivariate regression analyses were performed on survival outcomes. RESULTS: From 2007 to 2020, 536 non-metastatic MIBC patients receiving RARC were analysed. 429 had no hydronephrosis (80.0%), and 107 (20.0%) had hydronephrosis. Hydronephrosis was found to be predictive of inferior DFS (HR = 1.701, p = 0.003, 95% CI = 1.196-2.418) and OS (HR = 1.834, p = 0.008, 95% CI = 1.173-2.866). Subgroup analysis demonstrated differences in the T2-or-above subgroup (HR = 1.65; p = 0.004 in DFS and HR = 1.888; p = 0.008 in OS) and the T3-or-above subgroup (HR = 1.757; p = 0.017 in DFS and HR = 1.807; p = 0.034 in OS). CONCLUSIONS: The presence of preoperative hydronephrosis among MIBC patients carries additional prognostic implications on top of tumour staging. Its importance in case selection needs to be highlighted.

Exploring the versatility of miRNA-128: a comprehensive review on its role as a biomarker and therapeutic target in clinical pathways.

MicroRNAs (miRNAs/ miRs) are short, noncoding RNAs, usually consisting of 18 to 24 nucleotides, that control gene expression after the process of transcription and have crucial roles in several clinical processes. This article seeks to provide an in-depth review and evaluation of the many activities of miR-128, accentuating its potential as a versatile biomarker and target for therapy; The circulating miR-128 has garnered interest because of its substantial influence on gene regulation and its simplicity in extraction. Several miRNAs, such as miR-128, have been extracted from circulating blood cells, cerebrospinal fluid, and plasma/serum. The miR-128 molecule can specifically target a diverse range of genes, enabling it to have intricate physiological impacts by concurrently regulating many interrelated pathways. It has a vital function in several biological processes, such as modulating the immune system, regulating brain plasticity, organizing the cytoskeleton, and inducing neuronal death. In addition, miR-128 modulates genes associated with cell proliferation, the cell cycle, apoptosis, plasma LDL levels, and gene expression regulation in cardiac development. The dysregulation of miR-128 expression and activity is associated with the development of immunological responses, changes in neural plasticity, programmed cell death, cholesterol metabolism, and heightened vulnerability to autoimmune illnesses, neuroimmune disorders, cancer, and cardiac problems; The paper highlights the importance of studying the consequences of miR-128 dysregulation in these specific locations. By examining the implications of miRNA-128 dysregulation in these areas, the article underscores its significance in diagnosis and treatment, providing a foundation for research and clinical applications.

Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study.

BACKGROUND: Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study. METHODS: This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0-2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with ClinicalTrials.gov and is closed to enrolment (NCT03740529). FINDINGS: Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59-72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7-61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths. INTERPRETATION: Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor. FUNDING: Loxo Oncology.

Fixed-duration pirtobrutinib plus venetoclax with or without rituximab in relapsed/refractory CLL: the phase 1b BRUIN trial.

ABSTRACT: Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial. Prior covalent BTKi therapy was allowed, but not prior treatment with venetoclax. Patients were assigned to receive PV (n = 15) or PVR (n = 10) for 25 cycles. Most patients (68%) had received prior covalent BTKi therapy. At the data cutoff date, the median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% confidence interval [CI], 68.1-99.8) for PV and 100% (95% CI, 69.2-100.0) for PVR, with 10 complete responses (PV: 7; PVR: 3). After 12 cycles of treatment, 85.7% (95% CI, 57.2-98.2) of PV and 90.0% (95% CI, 55.5-99.7) of PVR patients achieved undetectable minimal residual disease (<10-4) in peripheral blood. Progression-free survival at 18 months was 92.9% (95% CI, 59.1-99.0) for PV patients and 80.0% (95% CI, 40.9-94.6) for PVR patients. No dose-limiting toxicities were observed during the 5-week assessment period. The most common grade ≥3 adverse events (AEs) for all patients included neutropenia (52%) and anemia (16%). AEs led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi. This trial was registered at www.clinicaltrials.gov as #NCT03740529.