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Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Abstract Aims Cardiac power is a measure of cardiac performance that incorporates both pressure and flow components. Prior studies have shown that cardiac power predicts outcomes in patients with reduced left ventricular (LV) ejection fraction (EF). We sought to evaluate the prognostic significance of peak exercise cardiac power and power reserve in patients with normal EF. Methods and results We performed a retrospective analysis in 24 885 patients (age 59 ± 13 years, 45% females) with EF ≥50% and no significant valve disease or right ventricular dysfunction, undergoing exercise stress echocardiography between 2004 and 2018. Cardiac power and power reserve (developed power with stress) were normalized to LV mass and expressed in W/100 g of LV myocardium. Endpoints at follow-up were all-cause mortality and diagnosis of heart failure (HF). Patients in the higher quartiles of power/mass (rest, peak stress, and power reserve) were younger and had higher peak blood pressure and heart rate, lower LV mass, and lower prevalence of comorbidities. During follow-up [median 3.9 (0.6–8.3) years], 929 patients died. After adjusting for age, sex, metabolic equivalents (METs) achieved, ischaemia/infarction on stress test results, medication, and comorbidities, peak stress power/mass was independently associated with mortality [adjusted hazard ratio (HR), highest vs. lowest quartile, 0.5, 95% confidence interval (CI) 0.4–0.6, P < 0.001] and HF at follow-up [adjusted HR, highest vs. lowest quartile, 0.4, 95% CI (0.3, 0.5), P < 0.001]. Power reserve showed similar results. Conclusion The assessment of cardiac power during exercise stress echocardiography in patients with normal EF provides valuable prognostic information, in addition to stress test findings on inducible myocardial ischaemia and exercise capacity.

Introduction: Among the most challenging complications of hemophilia A is inhibitor formation. A T-cell dependent B-cell response to exogenous factor VIII (FVIII), inhibitors result in a high burden of disease, with poorly controlled bleeding, twice the hospitalizations, 10-fold the cost, and 3.5-fold the mortality of non-inhibitor patients. Thus, a major goal of hemophilia management is to prevent and eradicate inhibitors. With the availability of novel therapies, including eloctate, a recombinant Fc-fusion protein (rFVIII-Fc) which induces regulatory T cells to promote FVIII tolerance, and emicizumab, a bispecific monoclonal FVIII mimetic, we designed the INHIBIT Clinical Trials Platform (X01HL143024), Fig.1. The platform is composed of two linked randomized phase III trials, the Inhibitor Prevention Trial (NCT04303559), comparing rFVIII-Fc vs emicizumab prophylaxis to prevent inhibitors, and the Inhibitor Eradication Trial (NCT04303572), comparing rFVIII-Fc immune tolerance induction (ITI) plus emicizumab vs rFVIII-Fc ITI alone to eradicate inhibitors. The platform uses adaptive design to incorporate historical data (Bayesian priors) on inhibitor formation to increase power and promote efficient use of rare data. Yet, there is equipoise regarding the optimal approach to inhibitor prevention and eradication, and, as clinical practice is changing, we aimed to test the feasibility of the INHIBIT trial design. Methods: To establish design feasibility, we conducted interviews with 30 hemophilia treatment center (HTC) physicians participating in the INHIBIT trials, to determine prophylaxis and tolerance regimens they prescribe and perceived barriers to the INHIBIT trials design. A 4-question survey was subsequently emailed to these physicians to ascertain the initial prophylaxis regimens they prescribe in previously untreated patients (PUPs) with severe hemophilia A, and the initial immune tolerance induction (ITI) they prescribe in high-responding inhibitor patients with severe hemophilia A; if new inhibitors had been observed during emicizumab prophylaxis, and willingness to participate in post-trial surveillance. Results: In interviews, HTC physicians indicated the issues that influenced choice of prophylaxis/ ITI regimen were patient preference, family history of inhibitors, infusion frequency, IV access, port requirement, and family fatigue. In the absence of clinical trials data in PUPs, there was general agreement that emicizumab prophylaxis, with it simpler subcutaneous (SQ) administration, might delay or potentially prevent inhibitors. Survey findings in Table 1 indicated 75% of physicians prescribe extended half-life (EHL) FVIII in a once-weekly prophylaxis regimen, as planned in the Prevention Trial, despite the persistent 27% inhibitor rate (ALong PUPs Trial, Königs et al, ISTH 2020) and potential risks with port use. There was support for the 1:3 preferential randomization to emicizumab in the Prevention Trial due to the simpler SQ route, despite concern it might delay rather than prevent inhibitor formation, although no inhibitors were reported by physician survey with emicizumab use alone. There was also concern that breakthrough bleeds requiring FVIII during emicizumab prophylaxis, might lead to immune activation and inhibitor formation. There was strong agreement, however, in 29 (97%) of physicians to participate in post-trial surveillance for long-term inhibitor outcomes. FVIII ITI was considered essential to eradicate inhibitors, despite the intensity of the infusion regimen. Notably, 60% prescribe emicizumab with FVIII ITI, as planned in the Eradicate Trial, although the every-other-day infusion was considered a potential barrier to participation. Omitting FVIII ITI was not favored due to the risk of inhibitor anamnesis if FVIII treatment was subsequently required for surgery or acute hemorrhages. Despite these concerns, there was agreement to participate in the trials. Discussion: Physician interviews and surveys confirm there is heterogeneity in current hemophilia clinical practice, specifically in initial prophylaxis regimens and in initial immune tolerance regimens, including agent choice and duration. However, there is physician consensus with the INHIBIT trial aims and with the proposed INHIBIT trial regimens to prevent and eradicate inhibitors. Disclosures Ragni: Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam/Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioMarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; ATHN: Research Funding; Sangamo: Research Funding. Seaman:Bayer: Consultancy; Genentech: Consultancy; Spark Therapeutics: Consultancy; Takeda: Consultancy. Acharya:Novonordisk: Membership on an entity's Board of Directors or advisory committees; BPL: Membership on an entity's Board of Directors or advisory committees; Bayer Pharma Inc.: Research Funding. Wheeler:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; UniQure: Membership on an entity's Board of Directors or advisory committees. Tarango:Takeda/Shire: Honoraria, Other; Bayer: Consultancy, Other; Sanofi: Honoraria, Other. Dunn:ATHN: Research Funding; Spire: Honoraria; Medscape: Honoraria; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; BioMarin: Research Funding; uniQure: Consultancy; Genentech, Inc.: Consultancy; Nationwide Children's Hospital: Current Employment. Kulkarni:Sanofi/ Bioverativ, Bayer, Biomarin, Shire/Takeda, Novo Nordisk, Freeline: Other: clinical trial research grants ; Bioverativ/Sanofi, BPL, Genentech, Kedrion, Novo Nordisk, Octapharma, Pfizer, Takeda, Catalyst Bioscience Bayer: Membership on an entity's Board of Directors or advisory committees. Ahuja:Genentech: Consultancy, Honoraria; Sanofi Genzyme: Consultancy, Honoraria; XaTek, Inc.: Consultancy, Patents & Royalties, Research Funding. Chitlur:Takeda: Honoraria; Biovertiv: Honoraria; Agios Pharmaceuticals: Research Funding; Pfizer: Honoraria; Novo Nordisk: Consultancy, Honoraria. Pipe:Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding; Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees. Malec:Sanofi Genzyme: Consultancy, Research Funding, Speakers Bureau; CSL: Consultancy; Takeda: Consultancy; Bayer: Consultancy; SOBI: Consultancy. Leissinger:Bayer: Consultancy; Kedrion: Consultancy; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; HEMA Biologics: Consultancy; Takeda: Consultancy; Uniqure: Consultancy; Spark: Consultancy. Carpenter:Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board; Kedrion: Honoraria; Novo Nordisk: Honoraria; Genentech, Inc.: Honoraria; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Shire: Research Funding. Knoll:NovoNordisk: Membership on an entity's Board of Directors or advisory committees. Wang:Bioverativ Inc: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria; Biomarin: Honoraria; Genentech: Honoraria; Takeda: Honoraria. Young:Genentech/Roche, Grifols, and Takeda: Research Funding; Bayer, CSL Behring, Freeline, UniQure: Consultancy; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria. Thornburg:Genentech: Speakers Bureau; Spark Therapeutics: Consultancy; Bluebird Bio: Consultancy; Ironwood Pharmaceuticals: Consultancy, Other: Data Safety Monitoring Board; American Thrombosis and Hemostasis Network: Research Funding; Sanofi Genzyme: Consultancy, Other: Data Safety Monitoring Board, Research Funding; NovoNordisk: Research Funding; Biomarin: Consultancy, Speakers Bureau; Bayer Pharmaceuticals: Research Funding; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lucas:CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hwang:Shire: Honoraria; Takeda: Honoraria.

SummaryAlthough new multiple myeloma (MM) therapies are effective in alleviating some disease‐associated symptoms (e.g. bone pain, fatigue, functional decline), they can result in additional toxicities, further impacting health‐related quality of life (HRQoL). Here, we compared HRQoL and safety of lenalidomide‐bortezomib‐dexamethasone [RVd (n = 445)], bortezomib‐melphalan‐prednisone [VMP (n = 77)] and Vd or VMP (n = 588) in patients with newly diagnosed MM (NDMM) from the Connect® MM Registry, a large, USA, multicentre, prospective observational cohort study. Functional Assessment of Cancer Therapy‐Multiple Myeloma subscale, EuroQol‐5D overall score and Bone Pain Inventory HRQoL scores were significantly improved with RVd versus Vd/VMP. Serious adverse event rates were similar in all groups. Treatment with RVd maintained HRQoL in this real‐world, largely community‐based population of patients with NDMM.

PolyQ ATXN3 is a pharmacodynamic marker for SCA3, and a SNP associated with the expanded allele may serve to specifically target mutant ATXN3 .

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression. Cyclin D1 is a major cell-cycle regulator and also regulates transcription, but the impact of cyclin D1–mediated transcriptional dysregulation on MCL pathogenesis remains poorly understood. The aim of this study was to define a cyclin D1–dependent gene expression program and analyze its prognostic value. Experimental Design: We integrated genome-wide expression analysis of cyclin D1–silenced and overexpressing cells with cyclin D1 chromatin-binding profiles to identify a cyclin D1–dependent transcriptional program in MCL cells. We analyzed this gene program in two MCL series of peripheral blood samples (n = 53) and lymphoid tissues (n = 106) to determine its biological and clinical relevance. We then obtained a simplified signature of this program and evaluated a third series of peripheral blood MCL samples (n = 81) by NanoString gene expression profiling to validate our findings. Results: We identified a cyclin D1–dependent transcriptional program composed of 295 genes that were mainly involved in cell-cycle control. The cyclin D1–dependent gene program was overexpressed in MCL tumors directly proportional to cyclin D1 levels. High expression of this program conferred an adverse prognosis with significant shorter overall survival of the patients. These observations were validated in an independent cohort of patients using a simplified 37-gene cyclin D1 signature. The cyclin D1–dependent transcriptional program was also present in multiple myeloma and breast tumors with cyclin D1 overexpression. Conclusions: We identified a cyclin D1–dependent transcriptional program that is overexpressed in MCL and predicts clinical outcome.

Abstract The authors have requested that this preprint be removed from Research Square.

Abstract Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B-cell receptor (BcR) immunoglobulins. Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR immunoglobulin stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR immunoglobulin stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. To address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29 856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed “satellites,” were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.

AbstractIntroductionThe situation generated in the health system by the COVID‐19 pandemic has provoked a crisis involving the necessity to cancel non‐urgent and oncologic activity in the operating room and in day‐to‐day practice. As the situation continues, the need to reinstate attention for patients with chronic pain grows. The restoration of this activity has to begin with on‐site appointments and possible surgical procedures. On‐site clinical activity has to guarantee the safety of patients and health workers.ObjectivesThe objective of this review was to evaluate how to manage activity in pain units, considering the scenario generated by the pandemic and the implications of chronic pain on the immune system and proposed pharmacological and interventional therapies.MethodsBesides the established general recommendations (physical distance, surgical masks, gloves, etc.), we established specific recommendations that will allow patient treatment and relieve the disruption of the immune response. It is important to highlight the use of opioids with the least influence in the immune system. Further, individualized corticoid use, risk assessment, reduced immune suppression, and dose adjustment should take patient needs into account. In this scenario, we highlight the use of radiofrequency and neuromodulation therapies, techniques that do not interfere with the immune response.ConclusionsWe describe procedures to implement these recommendations for individual clinical situations, the therapeutic possibilities and safety guidelines for each center, and government recommendations during the COVID‐19 pandemic.