Citations

Introduction: Preclinical studies have suggested synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a master transcriptional factor that regulates myeloma cell survival. Single agent oral IBR combined with dexamethasone proved well tolerated and active in advanced, steroid refractory relapsed MM as part of a large Phase1/2 study in 60 patients, with durable stabilization and minimal response seen in most evaluable patients (Richardson PG et al, BJH 2018). LEN is considered a standard of care in newly diagnosed MM, as maintenance and in relapsed disease, and a backbone of oral therapy in the MM treatment paradigm (Laubach JP et al, Leukemia 2016). Methods: We therefore conducted a 3+3 phase I trial to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least 2 prior lines of therapy. Three dose levels (DL) were planned. Cycle length was 28 days. IBR was administered orally daily at 560mg on DL1-2 and 840mg on DL3, LEN orally days 1-21 at 15mg on DL1 and 25mg on DL2-3, and DEX orally days 1, 8, 15, and 22 at 40 mg if age < 75 or 20 mg if ≥75 for DL1-3. Patients with GFR ≥ 30 and < 60 were treated according to manufacturer's instructions with lenalidomide dosed at 10mg/d. Dose limiting toxicities (DLT) included grade 4 thrombocytopenia; grade 4 neutropenia lasting more than 5 days or febrile neutropenia; grade 4 nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; grade 3-4 hyperglycemia or thrombotic/embolic event, treatment delays ≥ 21 days for toxicity; and treatment related death. Due to changes in standard of care during the study, eligibility was modified to allow the enrollment of patients with RRMM who had at least 1 prior line of therapy. Response was assessed using IMWG/Uniform Criteria. Results: Fourteen patients (DL1-6 pts; DL2-3 pts; DL3-5 pts) registered to the study from March 2019 to May 2023, prior to its closure due to slow accrual. One patient on DL3 cancelled participation prior to start of treatment due to disease progression (PD). The remaining 13 patients are included in summary of toxicities and response but 2 patients on DL3 are excluded from determination of MTD due to discontinuing cycle 1 treatment due to COVID and receiving 280 mg/day of IBR instead of assigned 840 mg/day dose during cycle 1, respectfully. Twelve patients were evaluable for response. The median number of prior lines of therapy was 3 (range: 2-9), reflecting a heavily pretreated relapsed and refractory population. One of the 6 patient on DL1 developed a DLT, grade 3 non-viral hepatitis. None of the 3 patients on DL2 or the 2 patients on DL3 had a DLT. One patient on DL1 remains on treatment with stable disease for 42+ cycles. The median number of cycles administered was 3 (range: 1-42+). Severe toxicities reported included grade 3 lymphocytopenia (3), anemia (2), alanine aminotransferase increase (1), aspartate aminotransferase increase (1), blood bilirubin increase (1), hypocalcemia (1), hypokalemia (1) hypophosphatemia (1), febrile neutropenia (1), chronic kidney disease (1), non-viral hepatitis (1), soft tissue infection (1), and fatigue (1); grade 4 lymphocytopenia (1), and grade 5 sepsis (1). End of treatment reasons included: PD (7), toxicity (2), death [soft tissue infection that turned into sepsis considered to be likely related to DEX] (1), and concomitant conditions (2). Stable disease (SD) or better was achieved in 10 of 12 evaluable patients (83%), including one patient who achieved disease control for over 3.5 years. One patient (8%) on DL3 had a complete response (CR) but stopped treatment after 2 cycles due to reversible toxicity and comorbid conditions, based upon physician advice and patient choice. Conclusions: The combination of lenalidomide with Ibrutinib as an all-oral approach in RR MM proved feasible and generally tolerable, with the majority of discontinuation seen in this Phase I study due to disease progression. No COVID related - mortality was seen. SD or better was achieved in 83% of patients, including one CR. Potential future directions include combination approaches with next generation IMids such as pomalidomide, as well as other orally bioavailable novel agents with potent immune activating properties, such as CelMoDs. Support: AFT; Pharmacyclics; Clinicaltrials.gov Identifier: NCT03702725

Abstract The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the gene-drug interaction of CYP2C9 and HLA-B with phenytoin, HLA-A and HLA-B with carbamazepine and HLA-B with oxcarbazepine and lamotrigine. A systematic review was performed and pharmacotherapeutic recommendations were developed. For CYP2C9 intermediate and poor metabolisers, the DPWG recommends lowering the daily dose of phenytoin and adjust based on effect and serum concentration after 7–10 days. For HLA-B*15:02 carriers, the risk of severe cutaneous adverse events associated with phenytoin, carbamazepine, oxcarbazepine and lamotrigine is strongly increased. For carbamazepine, this risk is also increased in HLA-B*15:11 and HLA-A*31:01 carriers. For HLA-B*15:02, HLA-B*15:11 and HLA-A*31:01 positive patients, the DPWG recommends choosing an alternative anti-epileptic drug. If not possible, it is recommended to advise the patient to report any rash while using carbamazepine, lamotrigine, oxcarbazepine or phenytoin immediately. Carbamazepine should not be used in an HLA-B*15:02 positive patient. DPWG considers CYP2C9 genotyping before the start of phenytoin “essential” for toxicity prevention. For patients with an ancestry in which the abovementioned HLA-alleles are prevalent, the DPWG considers HLA-B*15:02 genotyping before the start of carbamazepine, phenytoin, oxcarbazepine and lamotrigine “beneficial”, as well as genotyping for HLA-B*15:11 and HLA-A*31:01 before initiating carbamazepine.

Importance Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. Objective To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. Design, Setting, and Participants NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR ( NCT01737398 ; March 2013–November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo (“placebo”) group. Interventions Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Main Outcomes and Measures Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, –22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, –4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Results Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was −81.7% with eplontersen and −11.2% with placebo (difference, −70.4% [95% CI, −75.2% to −65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, −24.8 [95% CI, −31.0 to −18.6; P < .001) and for Norfolk QoL-DN (−5.5 vs 14.2; difference, −19.7 [95% CI, −25.6 to −13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. Conclusions and Relevance In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. Trial Registration ClinicalTrials.gov Identifier: NCT04136184 ; EU Clinical Trials Register: EudraCT 2019-001698-10

AbstractLiver transplant patients require a multidisciplinary and personalized approach to optimize outcomes. Posttransplant complications can be devastating for the patient and can jeopardize graft survival. Therefore, a careful evaluation and stepwise decision-making process is necessary to determine the best strategy, whether it is surgical, interventional, or a combination of both. While access to liver transplant interventions in Latin America can be more limited compared with other parts of the world, many countries in the region have made significant progress in developing their liver transplant programs and improving the management of posttransplant complications. For example, in Brazil, specialized transplant centers and multidisciplinary teams have been established to reduce morbidity and improve graft survival rates. The article also explores the latest advancements in interventional radiology techniques, such as angioplasty, stent placement, and embolization, and how they can be used to successfully treat these complications. Overall, this article highlights the importance of a comprehensive approach to managing complications in liver transplant patients and emphasizes how individualized treatment plans can lead to improved outcomes, even in settings with limited resources.

Abstract Objectives To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations and malignancy, between adults with anti-synthetase syndrome (ASyS) and DM. Methods Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1γ/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron’s papules/sign, violaceous rash, shawl sign, V-sign, erythroderma, and/or periorbital rash). Results In total 1054 patients were included (DM, n = 405; ASyS, n = 649). In the ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic’s hands, Raynaud’s phenomenon, arthritis, interstitial lung disease and cardiac involvement differentiated ASyS-DMskin from DM (all P < 0.001), whereas higher frequency of any of four DM-type rashes—heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V-sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%)—differentiated DM from ASyS-DMskin (all P < 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both P < 0.001). Conclusion DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.

Background: The normal limits of nerve conduction studies are commonly determined by testing healthy subjects. However, in comprehensive real-life nerve conduction electrodiagnostic (EDX) evaluations, multiple nerves are tested, including normal nerves, for purposes of comparison with abnormal ones. Objective: This study aims to evaluate the average values of normal nerve conduction studies in a large population and examined the influence of age and sex. Methods: EDX parameters were extracted from an electronic database of studies performed from May 2016 to February 2022. Established normal values were used to determine the classification of a nerve study as normal. Results: We identified 10,648 EDX reports with 5077 normally interpreted nerve conduction studies (47.6%) of which 57% ( n = 2890) were for females. The median age of studies with no abnormalities was 45.1 years (range < 1 to 92) overall and 42.5 years (range: 0.16 –89.5 years) for males and 47.5 years (range:<1 –91.7) for females. Correlations between age and amplitude, latency, and velocity ( p < 0.001) were observed in most nerves. Amplitude correlated negatively with age in adults in all nerves with a mean of –0.44 (range: –0.24 to –0.62). However, in the pediatric population (age < 18 years), amplitude as well as velocity increased significantly with age. In the adult cohort, sex differences were noted, where females had higher mean sensory nerve action potentials in ulnar, median, and radial evaluations ( p < 0.001). In older patients (aged > 70 years) with normally interpreted EDX studies (845 records of 528 patients), sural responses were present in 97%. Conclusions: This real-life study confirms that advanced aging is associated with decreased nerve conduction amplitudes, increased latency, and the slowing of conduction velocity. The findings also indicate higher sensory amplitudes and conduction velocities in females. Sural nerve responses were identified in most adults over age 70.

OBJETIVO: Estimar a prevalência de gestação não planejada (GNP) em oito hospitais públicos universitários, distribuídos nas cinco regiões que compõem o Brasil. MÉTODOS: Análise secundária de um estudo transversal multicêntrico nacional, realizado em oito hospitais universitários públicos, entre 1º de junho e 31 de agosto de 2020, no Brasil. Amostra por conveniência incluindo mulheres que deram à luz em período de sessenta dias consecutivos e atenderam aos seguintes critérios: maiores de 18 anos; idade gestacional acima de 36 semanas no parto; com recém-nascido único e vivo, sem malformações. RESULTADOS: Amostra composta por 1.120 puérperas, das quais 756 (67,5%) declararam que a gravidez não tinha sido programada. A mediana da prevalência de GNP foi de 59,7%. Observou-se diferença significativa na prevalência de GNP entre os hospitais: Campinas (54,8%), Porto Alegre (58,2%), Florianópolis (59%), Teresina (61,2%), Brasília (64,3%), São Paulo (64,6%), Campo Grande (73,9%) e Manaus (95,3%) (p < 0,001). Foram fatores significativamente associados a GNP a idade materna, cor negra, menor renda familiar, maior número de filhos, maior número de pessoas convivendo em casa e não ter parceiro. CONCLUSÃO: na amostra estudada, cerca de dois terços das gestações foram declaradas como não programadas. A prevalência de gestação não planejada teve relação com fatores sociais e demográficos e variou significativamente entre os hospitais universitários avaliados.

Aberrant activation of the Hedgehog (Hh) signaling pathway, through which the GLI family of transcription factors (TF) is stimulated, is commonly observed in cancer cells. One well-established mechanism of this increased activity is through the inactivation of Suppressor of Fused (SUFU), a negative regulator of the Hh pathway. Relief from negative regulation by SUFU facilitates GLI activity and induction of target gene expression. Here, we demonstrate a novel role for SUFU as a promoter of GLI activity in pancreatic ductal adenocarcinoma (PDAC). In non-ciliated PDAC cells unresponsive to Smoothened agonism, SUFU overexpression increases GLI transcriptional activity. Conversely, knockdown (KD) of SUFU reduces the activity of GLI in PDAC cells. Through array PCR analysis of GLI target genes, we identified B-cell lymphoma 2 (BCL2) among the top candidates down-regulated by SUFU KD. We demonstrate that SUFU KD results in reduced PDAC cell viability, and overexpression of BCL2 partially rescues the effect of reduced cell viability by SUFU KD. Further analysis using as a model GLI1, a major TF activator of the GLI family in PDAC cells, shows the interaction of SUFU and GLI1 in the nucleus through previously characterized domains. Chromatin immunoprecipitation (ChIP) assay shows the binding of both SUFU and GLI1 at the promoter of BCL2 in PDAC cells. Finally, we demonstrate that SUFU promotes GLI1 activity without affecting its protein stability. Through our findings, we propose a novel role of SUFU as a positive regulator of GLI1 in PDAC, adding a new mechanism of Hh/GLI signaling pathway regulation in cancer cells.

Abstract Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.