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Nivolumab in sorafenib-naive and sorafenib-experienced patients with advanced hepatocellular carcinoma: 5-year follow-up from CheckMate 040.
El-Khoueiry, AB, Trojan, J, Meyer, T, Yau, T, Melero, I, Kudo, M, Hsu, C, Kim, TY, Choo, SP, Kang, YK, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2024;(4):381-391
Abstract
BACKGROUND Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced groups of CheckMate 040 is presented here. PATIENTS AND METHODS Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator as per RECIST version 1.1 (dose expansion). RESULTS Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR as per BICR was 20% [95% confidence interval (CI) 12% to 30%] and 14% (95% CI 9% to 21%) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death-ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6 months) and 15.1 months (95% CI 13.0-18.2 months) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced groups; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% of patients in the sorafenib-naive and sorafenib-experienced groups, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year. CONCLUSION With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC.
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In-depth analysis of data from the RAS-ALS study reveals new insights in rasagiline treatment for amyotrophic lateral sclerosis.
Schuster, J, Dreyhaupt, J, Mönkemöller, K, Dupuis, L, Dieterlé, S, Weishaupt, JH, Kassubek, J, Petri, S, Meyer, T, Grosskreutz, J, et al
European journal of neurology. 2024;(4):e16204
Abstract
BACKGROUND AND PURPOSE In 2016, we concluded a randomized controlled trial testing 1 mg rasagiline per day add-on to standard therapy in 252 amyotrophic lateral sclerosis (ALS) patients. This article aims at better characterizing ALS patients who could possibly benefit from rasagiline by reporting new subgroup analysis and genetic data. METHODS We performed further exploratory in-depth analyses of the study population and investigated the relevance of single nucleotide polymorphisms (SNPs) related to the dopaminergic system. RESULTS Placebo-treated patients with very slow disease progression (loss of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R] per month before randomization of ≤0.328 points) showed a per se survival probability after 24 months of 0.85 (95% confidence interval = 0.65-0.94). The large group of intermediate to fast progressing ALS patients showed a prolonged survival in the rasagiline group compared to placebo after 6 and 12 months (p = 0.02, p = 0.04), and a reduced decline of ALSFRS-R after 18 months (p = 0.049). SNP genotypes in the MAOB gene and DRD2 gene did not show clear associations with rasagiline treatment effects. CONCLUSIONS These results underline the need to consider individual disease progression at baseline in future ALS studies. Very slow disease progressors compromise the statistical power of studies with treatment durations of 12-18 months using clinical endpoints. Analysis of MAOB and DRD2 SNPs revealed no clear relationship to any outcome parameter. More insights are expected from future studies elucidating whether patients with DRD2CC genotype (Rs2283265) show a pronounced benefit from treatment with rasagiline, pointing to the opportunities precision medicine could open up for ALS patients in the future.
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Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial.
Qin, S, Kudo, M, Meyer, T, Bai, Y, Guo, Y, Meng, Z, Satoh, T, Marino, D, Assenat, E, Li, S, et al
JAMA oncology. 2023;(12):1651-1659
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Abstract
IMPORTANCE Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and additional first-line treatments are needed. The programmed cell death protein 1 inhibitor tislelizumab demonstrated efficacy and a tolerable safety profile as second-line HCC treatment. OBJECTIVE To investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC. DESIGN, SETTING, AND PARTICIPANTS The open-label, global, multiregional phase 3 RATIONALE-301 randomized clinical trial enrolled systemic therapy-naive adults with histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, disease progression following (or patient was not amenable to) locoregional therapy, Eastern Cooperative Oncology Group performance status of 1 or less, and Child-Pugh class A, between December 27, 2017, and October 2, 2019. Data cutoff was July 11, 2022. INTERVENTION Patients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily. MAIN OUTCOMES AND MEASURES The primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety. RESULTS A total of 674 patients were included in the analysis (570 men [84.6%]; median age, 61 years [range, 23-86 years]). As of July 11, 2022, minimum study follow-up was 33 months. The primary end point of OS noninferiority of tislelizumab vs sorafenib was met in the intention-to-treat population (n = 674); median overall survival was 15.9 (95% CI, 13.2-19.7) months vs 14.1 (95% CI, 12.6-17.4) months, respectively (hazard ratio [HR], 0.85 [95.003% CI, 0.71-1.02]), and superiority of tislelizumab vs sorafenib was not met. The objective response rate was 14.3% (n = 49) for tislelizumab vs 5.4% (n = 18) for sorafenib, and median duration of response was 36.1 (95% CI, 16.8 to not evaluable) months vs 11.0 (95% CI, 6.2-14.7) months, respectively. Median progression-free survival was 2.1 (95% CI, 2.1-3.5) months vs 3.4 (95% CI, 2.2-4.1) months with tislelizumab vs sorafenib (HR, 1.11 [95% CI, 0.92-1.33]). The incidence of treatment-emergent adverse events (AEs) was 96.2% (325 of 338 patients) for tislelizumab and 100% (n = 324) for sorafenib. Grade 3 or greater treatment-related AEs were reported in 75 patients (22.2%) receiving tislelizumab and 173 (53.4%) receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation (21 [6.2%] vs 33 [10.2%]) and drug modification (68 [20.1%] vs 187 [57.7%]) with tislelizumab vs sorafenib. CONCLUSIONS AND RELEVANCE In RATIONALE-301, tislelizumab demonstrated OS benefit that was noninferior vs sorafenib, with a higher objective response rate and more durable responses, while median progression-free survival was longer with sorafenib. Tislelizumab demonstrated a favorable safety profile vs sorafenib. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03412773.
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Conserved E1B-55K SUMOylation in Different Human Adenovirus Species Is a Potent Regulator of Intracellular Localization.
Kolbe, V, Ip, WH, Kieweg-Thompson, L, Lang, J, Gruhne, J, Meyer, T, Wilkens, B, Schie, M, Thünauer, R, Schreiner, S, et al
Journal of virology. 2022;(3):e0083821
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Abstract
Over the past decades, studies on the biology of human adenoviruses (HAdVs) mainly focused on the HAdV prototype species C type 5 (HAdV-C5) and revealed fundamental molecular insights into mechanisms of viral replication and viral cell transformation. Recently, other HAdV species are gaining more and more attention in the field. Reports on large E1B proteins (E1B-55K) from different HAdV species showed that these multifactorial proteins possess strikingly different features along with highly conserved functions. In this work, we identified potential SUMO-conjugation motifs (SCMs) in E1B-55K proteins from HAdV species A to F. Mutational inactivation of these SCMs demonstrated that HAdV E1B-55K proteins are SUMOylated at a single lysine residue that is highly conserved among HAdV species B to E. Moreover, we provide evidence that E1B-55K SUMOylation is a potent regulator of intracellular localization and p53-mediated transcription in most HAdV species. We also identified a lysine residue at position 101 (K101), which is unique to HAdV-C5 E1B-55K and specifically regulates its SUMOylation and nucleo-cytoplasmic shuttling. Our findings reveal important new aspects on HAdV E1B-55K proteins and suggest that different E1B-55K species possess conserved SCMs while their SUMOylation has divergent cellular effects during infection. IMPORTANCE E1B-55K is a multifunctional adenoviral protein and its functions are highly regulated by SUMOylation. Although functional consequences of SUMOylated HAdV-C5 E1B-55K are well studied, we lack information on the effects of SUMOylation on homologous E1B-55K proteins from other HAdV species. Here, we show that SUMOylation is a conserved posttranslational modification in most of the E1B-55K proteins, similar to what we know about HAdV-C5 E1B-55K. Moreover, we identify subcellular localization and regulation of p53-dependent transcription as highly conserved SUMOylation-regulated E1B-55K functions. Thus, our results highlight how HAdV proteins might have evolved in different HAdV species with conserved domains involved in virus replication and differing alternative functions and interactions with the host cell machinery. Future research will link these differences and similarities to the diverse pathogenicity and organ tropism of the different HAdV species.
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[Amyotrophic lateral sclerosis (ALS) - diagnosis, course of disease and treatment options].
Meyer, T
Deutsche medizinische Wochenschrift (1946). 2021;(24-25):1613-1618
Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disorder which is characterized by progressive motor symptoms, such as muscle weakness, muscle atrophy and spasticity. In Germany, 6000-8000 people are affected by ALS. Between 1200 and 1600 newly diagnosed patients are expected each year. Protein deposits in the cytoplasm of motor neurons are a molecular feature of ALS. The most common protein aggregates result from excessive deposition of TDP-43. Familial ALS is present in 5 to 10 % of all ALS patients. Common causal genes include C9orf72, SOD1, FUS, and TARDBP. Genetic factors may be involved even without a family history of ALS and may be underestimated. The disease course and progression are highly variable. Symptom severity and rate of progression are determined by the ALS Functional Scale (ALSFRS-R). Beyond clinical symptoms and the patient's perception of disease burden, measurement of slow vital capacity (SVC), peak cough flow (PCF), and body mass index (BMI) are used to underscore the indications for ventilatory and nutritional interventions, as well as palliative care. The validity of the biomarker neurofilament light chain (NF-L) for estimating prognosis is currently being investigated. ALS is not curable - however, various individual treatment options have to be considered for improving survival, symptom control and social participation. The care in specialized ALS centers is recommended to ensure optimal treatment regarding symptomatic medication, assistive devices, nutrition support and ventilation therapy. Optimal care is achieved by interdisciplinary collaboration of general practitioners, specialized physicians, neurologists and ALS experts being integrated in multiprofessional care networks.
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Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment.
Freigang, M, Wurster, CD, Hagenacker, T, Stolte, B, Weiler, M, Kamm, C, Schreiber-Katz, O, Osmanovic, A, Petri, S, Kowski, A, et al
Annals of clinical and translational neurology. 2021;(5):1049-1063
Abstract
OBJECTIVE To determine whether serum creatine kinase activity (CK) and serum creatinine concentration (Crn) are prognostic and predictive biomarkers for disease severity, disease progression, and nusinersen treatment effects in adult patients with 5q-associated spinal muscular atrophy (SMA). METHODS Within this retrospective, multicenter observational study in 206 adult patients with SMA, we determined clinical subtypes (SMA types, ambulatory ability) and repeatedly measured CK and Crn and examined disease severity scores (Hammersmith Functional Motor Scale Expanded, Revised Upper Limb Module, and revised Amyotrophic Lateral Sclerosis Functional Rating Scale). Patients were followed under nusinersen treatment for 18 months. RESULTS CK and Crn differed between clinical subtypes and correlated strongly with disease severity scores (e.g., for Hammersmith Functional Motor Scale Expanded: (CK) ρ = 0.786/ (Crn) ρ = 0.558). During the 18 months of nusinersen treatment, CK decreased (∆CK = -17.56%, p < 0.0001), whereas Crn slightly increased (∆Crn = +4.75%, p < 0.05). INTERPRETATION Serum creatine kinase activity and serum creatinine concentration reflect disease severity of spinal muscular atrophy and are promising biomarkers to assess patients with spinal muscular atrophy during disease course and to predict treatment response. The decrease of creatine kinase activity, combined with the tendency of creatinine concentration to increase during nusinersen treatment, suggests reduced muscle mass wasting with improved muscle energy metabolism.
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A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia.
Fields, T, Patterson, M, Bremova-Ertl, T, Belcher, G, Billington, I, Churchill, GC, Davis, W, Evans, W, Flint, S, Galione, A, et al
Trials. 2021;(1):84
Abstract
BACKGROUND The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations and thereby expedite the approval of promising treatments to address patients' high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-L-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 gangliosidoses (Tay-Sachs and Sandhoff disease; "GM2"), and ataxia telangiectasia (A-T). METHODS/DESIGN The innovative IB1001 master protocol and novel CI-CS primary endpoints were developed through a close collaboration between the Industry Sponsor, Key Opinion Leaders, representatives of the Patient Communities, and National Regulatory Authorities. As a result, the open-label, rater-blinded study design is considerate of the practical limitations of recruitment and retention of subjects in these ultra-orphan populations. The novel primary endpoint, the Clinical Impression of Change in Severity© (CI-CS), accommodates the heterogenous clinical presentation of NPC, GM2, and A-T: at screening, the principal investigator appoints for each patient a primary anchor test (either the 8-m walk test (8MWT) or 9-hole peg test of the dominant hand (9HPT-D)) based on his/her unique clinical symptoms. The anchor tests are videoed in a standardized manner at each visit to capture all aspects related to the patient's functional performance. The CI-CS assessment is ultimately performed by independent, blinded raters who compare videos of the primary anchor test from three periods: baseline, the end of treatment, and the end of a post-treatment washout. Blinded to the time point of each video, the raters make an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient's neurological signs and symptoms from video A to video B. To investigate both the symptomatic and disease-modifying effects of treatment, N-acetyl-L-leucine is assessed during two treatment sequences: a 6-week parent study and 1-year extension phase. DISCUSSION The novel CI-CS assessment, developed through a collaboration of all stakeholders, is advantageous in that it better ensures the primary endpoint is functionally relevant for each patient, is able to capture small but meaningful clinical changes critical to the patients' quality of life (fine-motor skills; gait), and blinds the primary outcome assessment. The results of these three trials will inform whether N-acetyl-L-leucine is an effective treatment for NPC, GM2, and A-T and can also serve as a new therapeutic paradigm for the development of future treatments for other orphan diseases. TRIAL REGISTRATION The three trials (IB1001-201 for Niemann-Pick disease type C (NPC), IB1001-202 for GM2 gangliosidoses (Tay-Sachs and Sandhoff), IB1001-203 for ataxia telangiectasia (A-T)) have been registered at www.clinicaltrials.gov (NCT03759639; NCT03759665; NCT03759678), www.clinicaltrialsregister.eu (EudraCT: 2018-004331-71; 2018-004406-25; 2018-004407-39), and https://www.germanctr.de (DR KS-ID: DRKS00016567; DRKS00017539; DRKS00020511).
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A Real-World Observational Cohort of Patients with Hepatocellular Carcinoma: Design and Rationale for TARGET-HCC.
Cabrera, R, Singal, AG, Colombo, M, Kelley, RK, Lee, H, Mospan, AR, Meyer, T, Newell, P, Parikh, ND, Sangro, B, et al
Hepatology communications. 2021;(3):538-547
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This study describes the design of the TARGET-hepatocellular carcinoma (HCC) cohort and descriptive characteristics of the patient population at diagnosis among those who were enrolled in the cohort across academic and community clinical centers. TARGET-HCC is a 5-year, longitudinal, observational cohort of patients with HCC receiving care in usual clinical practice. Redacted clinical information, obtained from medical records, captures the natural history and management of the disease, including the safety and efficacy of treatment interventions used in usual clinical practice. Patients can complete patient-reported outcome measures and provide biological specimens for future translational studies. The TARGET-HCC study includes adults with histologic, cytologic, or radiologic diagnosis of HCC from academic and community centers in both the United States and Europe. A total of 1,841 participants were enrolled between January 9, 2017, and July 23, 2019, at 67 sites in the United States and Europe. To date, the most common liver disease etiology in the cohort continues to be hepatitis C, although nearly half had a nonviral etiology, including alcohol-related liver disease or nonalcoholic steatohepatitis. Most included patients were diagnosed at an early stage (Barcelona Clinic Liver Cancer Stage [BCLC] 0/A), but only approximately one third underwent curative treatment. Systemic therapy has been used in 7.3% of enrolled patients, including 45.7% of those with BCLC stage C tumors. Conclusion: Overall, the TARGET-HCC cohort allows for the assessment of patient characteristics and investigation of new treatment paradigms and sequencing with existing agents as well as novel regimens for HCC.
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Repeatability of the Individual Response to the Use of Active Recovery the Day After High-Intensity Interval Training: A Double-Crossover Trial.
Wiewelhove, T, Thase, C, Glahn, M, Hessel, A, Schneider, C, Hottenrott, L, Meyer, T, Kellmann, M, Pfeiffer, M, Ferrauti, A
International journal of sports physiology and performance. 2021;(8):1160–1168
Abstract
PURPOSE To identify whether the use of active recovery (ACT) the day after high-intensity interval training (HIIT) benefits recovery and to assess whether individual responses to ACT are repeatable. METHODS Eleven well-trained, male intermittent-sport athletes (age: 25.5 ± 1.8 y) completed 4 HIIT sessions, each separated by a 2-week washout period. Of the 4 sessions, 2 were followed by passive recovery (PAS) and 2 by 60 minutes of moderate biking (ACT) 24 hours postexercise in the following sequences: ACT→PAS→ACT→PAS or PAS→ACT→PAS→ACT. Before and after HIIT and after 24 and 48 hours of recovery, maximal voluntary isometric strength (MVIC), countermovement jump height (CMJ), tensiomyographic markers of muscle fatigue (TMG), serum concentration of creatine kinase (CK), muscle soreness (MS), and perceived stress state (PS) were determined. RESULTS A 3-way repeated-measure analysis of variance with a triple-nested random effects model revealed a significant (P < .05) fatigue-related time effect of HIIT on markers of fatigue (MVIC↓; CMJ↓; TMG↑; CK↑; MS↑; PS↑). No significant (P > .05) main effect of recovery strategy was detected. In 9 subjects, the individual results revealed inconsistent and nonrepeatable responses to ACT, while a consistent and repeatable positive or negative response to ACT was found in 2 individuals. CONCLUSIONS The repeated failure of ACT to limit the severity of fatigue was found both at the group level and with most individuals. However, a small percentage of athletes may be more likely to benefit repeatedly from either ACT or PAS. Therefore, the use of ACT should be individualized.
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Assessing the impact of COVID-19 on liver cancer management (CERO-19).
Muñoz-Martínez, S, Sapena, V, Forner, A, Nault, JC, Sapisochin, G, Rimassa, L, Sangro, B, Bruix, J, Sanduzzi-Zamparelli, M, Hołówko, W, et al
JHEP reports : innovation in hepatology. 2021;(3):100260
Abstract
BACKGROUND & AIMS The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). Herein, we evaluated whether the schedule of LC screening or procedures has been interrupted or delayed because of the COVID-19 pandemic. METHODS An international survey evaluated the impact of the COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international, and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave. RESULTS Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia, and Africa (73.7%, 17.1%, 5.3%, 2.6%, and 1.3% per continent, respectively). Eighty-seven percent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening programme, 50% cancelled curative and/or palliative treatments for LC, and 41.7% modified the liver transplantation programme. Forty-five out of 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service before the COVID-19 pandemic (n = 19/37). CONCLUSIONS The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with liver cancer. Modifications in screening, diagnostic, and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision-making. LAY SUMMARY The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems globally. Herein, we assessed the impact of the first wave pandemic on patients with liver cancer and found that routine care for these patients has been majorly disrupted, which could have a significant impact on outcomes.