Phase I/II Study of Bortezomib-BEAM and Autologous Hematopoietic Stem Cell Transplantation for Relapsed Indolent Non-Hodgkin Lymphoma, Transformed, or Mantle Cell Lymphoma

AbstractA phase I/II trial was designed to evaluate the safety and efficacy of adding bortezomib to standard BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous hematopoietic stem cell transplantation (ASCT). Eligible patients had relapsed/refractory indolent or transformed non-Hodgkin lymphoma or mantle cell lymphoma (MCL) that was relapsed/refractory or in first partial (PR) or complete remission (CR). Patients received bortezomib on days −11, −8, −5, and −2 before ASCT. Phase I had 4 dose cohorts (.8, 1, 1.3, and 1.5 mg/m2) and 3 patients were accrued to each. Any nonhematological ASCT-related toxicity >2 on the Bearman scale occurring between day −11 and engraftment defined the maximum tolerated dose (MTD). After the MTD has been reached, another 20 patients were enrolled at this dose to determine a preliminary overall response rate (ORR). Patients who were in CR or PR at day +100 were considered responders. The study enrolled 42 patients through August 14, 2009. The median age was 58 (range, 34 to 73) years, with 33 males and 9 females. The most common diagnoses were MCL (23 patients) and follicular lymphoma (7 patients). The median number of prior therapies was 1 (range, 0 to 6). The median follow-up was 4.88 (range, 1.07 to 6.98) years. Thirteen patients were treated in phase I and 29 patients were treated in phase II. The MTD was initially determined to be 1.5 mg/m2 but it was later decreased to 1 mg/m2 because of excessive gastrointestinal toxicity and peripheral neuropathy. The ORR was 95% at 100 days and 87% at 1 year. For all 38 evaluable patients at 1 year, responses were CR 84%, PR 1%, and progressive disease 13%. Progression-free survival (PFS) was 83% (95% CI, 68% to 92%) at 1 year, and 32% (15% to 51%) at 5 years. Overall survival (OS) was 91% (95% CI, 79% to 96%) at 1 year and 67% (50% to 79%) at 5 years. The most common National Cancer Institute grade 3 toxicities were neutropenic fever (59%), anorexia (21%), peripheral neuropathy (19%), orthostatic hypotension/vasovagal syncope (16%), and 1 patient failed to engraft. Compared with 26 MCL in CR1 historic controls treated with BEAM and ASCT, PFS was 85% and 43% for the BEAM group versus 87% and 57% for those who received bortezomib in addition to standard BEAM (V-BEAM) at 1 and 5 years, respectively (log-rank P = .37). OS was 88% and 50% for the BEAM group versus 96% and 72% for V-BEAM at 1 and 5 years, respectively (log-rank P = .78). In conclusion, V-BEAM and ASCT is feasible. The toxicities were manageable and we did not observe any treatment-related mortalities; however, we did observe an excess of autonomic dysfunction and ileus, which is concerning for overlapping toxicity with BEAM conditioning. Determining relative efficacy of V-BEAM compared to BEAM would require a randomized trial

Prevalence of Dysglycemia Among Coronary Artery Bypass Surgery Patients with No Previous Diabetic History

<p>Abstract</p> <p>Background</p> <p>Dysglycemia is a major risk factor for atherosclerosis. In many patient populations dysglycemia is under-diagnosed. Patients with severe coronary artery disease commonly have dysglycemia and there is growing evidence that dysglycemia, irrespective of underlying history of diabetes, is associated with adverse outcome in coronary artery bypass graft (CABG) surgery patients, including longer hospital stay, wound infections, and higher mortality. As HbA1c is an easy and reliable way of checking for dysglycemia we routinely screen all patients undergoing CABG for elevations in HbA1c. Our hypothesis was that a substantial number of patients with dysglycemia that could be identified at the time of cardiothoracic surgery despite having no apparent history of diabetes.</p> <p>Methods</p> <p>1045 consecutive patients undergoing CABG between 2007 and 2009 had HbA1c measured pre-operatively. The 2010 American Diabetes Association (ADA) diagnostic guidelines were used to categorize patients with no known history of diabetes as having diabetes (HbA1c ≥ 6.5%) or increased risk for diabetes (HbA1c 5.7-6.4%).</p> <p>Results</p> <p>Of the 1045 patients with pre-operative HbA1c measurements, 40% (n = 415) had a known history of diabetes and 60% (n = 630) had no known history of diabetes. For the 630 patients with no known diabetic history: 207 (32.9%) had a normal HbA1c (< 5.7%); 356 (56.5%) had an HbA1c falling in the increased risk for diabetes range (5.7-6.4%); and 67 (10.6%) had an HbA1c in the diabetes range (6.5% or higher). In this study the only conventional risk factor that was predictive of high HbA1c was BMI. We also found a high HbA1c irrespective of history of DM was associated with severe coronary artery disease as indicated by the number of vessels revascularized.</p> <p>Conclusion</p> <p>Among individuals undergoing CABG with no known history of diabetes, there is a substantial amount of undiagnosed dysglycemia. Even though labeling these patients as "diabetic" or "increased risk for diabetes" remains controversial in terms of perioperative management, pre-operative screening could lead to appropriate post-operative follow up to mitigate short-term adverse outcome and provide high priority medical referrals of this at risk population.</p

TCT-117 Impact of Proximal Cap Ambiguity on the Outcomes of Chronic Total Occlusion Intervention: Insights From the PROGRESS-CTO Registry

Background: The impact of proximal cap ambiguity on procedural techniques and outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has received limited study. Methods: We examined the clinical and angiographic characteristics and procedural outcomes of 11,169 CTO PCIs performed in 10,932 patients at 42 US and non-US centers between 2012 and 2022. Results: Proximal cap ambiguity was present in 35% of CTO lesions. Patients whose lesions had proximal cap ambiguity were more likely to have had prior PCI (65% vs 59%; P \u3c 0.01) and prior coronary artery bypass graft surgery (37% vs 24%; P \u3c 0.01). Lesions with proximal cap ambiguity were more complex with higher J-CTO score (3.1 ± 1.0 vs 2.0 ± 1.2; P \u3c 0.01) and lower technical (79% vs 90%; P \u3c 0.01) and procedural success (77% vs 89%; P \u3c 0.01) rates compared with non-ambiguous CTO lesions. The incidence of major adverse cardiovascular events (MACE) was higher in cases with proximal cap ambiguity (2.5% vs 1.7%; P \u3c 0.01). The retrograde approach was more commonly used among cases with ambiguous proximal cap (51% vs 21%; P \u3c 0.01) and was more likely to be the final successful crossing strategy (29% vs 13%; P \u3c 0.01). PCIs of CTOs with ambiguous proximal cap required longer procedure time (140 [95-195] vs 105 [70-150] min; P \u3c 0.01) and more contrast volume (225 [160-305] vs 200 [150-280] mL; P \u3c 0.01). Conclusion: Proximal cap ambiguity in CTO lesions is associated with higher utilization of the retrograde approach, lower technical and procedural success rates, and higher incidence of in-hospital MACE. Categories: CORONARY: Complex and Higher Risk Procedures for Indicated Patients (CHIP

TCT-171 Predicting the Risk of Perforation Requiring Pericardiocentesis in Chronic Total Occlusion Percutaneous Coronary Intervention: The PROGRESS-CTO Pericardiocentesis Score

Background: Estimating the risk for complications facilitates risk-benefit assessment and procedural planning in chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Methods: We analyzed the PROGRESS-CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention; NCT02061436) and created a risk score for pericardiocentesis. Patients with histories of coronary artery bypass graft surgery were excluded. Logistic regression prediction modeling was used to identify independently associated variables, and the model was internally validated with bootstrapping. Results: Of the 7,672 CTO PCI cases performed between 2012 and 2022 at 40 centers, 83 (1.1%) required pericardiocentesis. The final prediction model identified predictors of pericardiocentesis: age ≥ 65 years (OR: 2.10; 95% CI: 1.27-3.46), 1 point; female sex (OR: 2.25; 95% CI: 1.39-3.63), 1 point; moderate to severe calcification (OR: 3.28; 95% CI: 1.96-5.49), 1 point; antegrade dissection re-entry (OR: 2.83, 95% CI: 1.45-5.51), 1 point; and retrograde strategy (OR: 3.50; 95% CI: 2.08-5.87), 2 points; with a bootstrap corrected C statistic of 0.78 (95% CI: 0.72-0.83). The calculated risk percentages for pericardiocentesis on the basis of the PROGRESS-CTO mortality score ranged from 0.18% to 8.74% for pericardiocentesis, and 55% of patients had PROGRESS-CTO pericardiocentesis scores of 1 or 2, corresponding to a pericardiocentesis risk of 0.4% to 1.6%. Conclusions: The PROGRESS-CTO pericardiocentesis risk score can facilitate risk-benefit assessment and procedural planning in patients undergoing CTO PCI. Categories: CORONARY: Complex and Higher Risk Procedures for Indicated Patients (CHIP

TCT-113 Predicting the Risk of In-Hospital Major Adverse Cardiovascular Events in Chronic Total Occlusion Percutaneous Coronary Intervention: The PROGRESS-CTO MACE Score

Background: Estimating the risk of complications in chronic total occlusion (CTO) percutaneous coronary intervention (PCI) facilitates risk-benefit assessment and procedural planning. Methods: We analyzed the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS-CTO; NCT02061436) and created a risk score for in-hospital major adverse cardiovascular events (MACE). Logistic regression prediction modeling was used to identify independently associated variables and the model was internally validated with bootstrapping. Results: Of the 10,480 CTO PCI cases performed between 2012-2022 at 40 US and non-US centers, in-hospital MACE occurred in 215 (2.05%). The final prediction model identified 5 independent predictors of MACE: age ≥65 years, odds ratio (OR) 1.57, 95% confidence interval (CI) 1.10-2.26, 1 point; female sex, OR 2.46, 95% CI 1.72-3.53, 2 points; moderate to severe calcification, OR 1.71, 95% CI 1.20-2.44, 1 point; Blunt stump, OR 1.63, 95% CI 1.14-2.33, 1 point; and Antegrade dissection re-entry, OR 2.21, 95% CI 1.32-3.72, 1 point; and retrograde strategy, OR 2.86, 95% CI 1.94-4.22, 2 points; with a bootstrap corrected c-statistic of 0.72, 95% CI 0.68-0.76. The calculated risk percentages for MACE based on the PROGRESS-CTO MACE score ranged from 0.4% to 9.4% for MACE; 42% of patients had PROGRESS-CTO MACE score of 2-3, corresponding to a MACE risk of 1.1%-2.0%. Conclusion: The PROGRESS-CTO in-hospital MACE risk score can facilitate risk-benefit assessment and procedural planning in patients undergoing CTO PCI. Categories: CORONARY: Complex and Higher Risk Procedures for Indicated Patients (CHIP

Scoring System Prognostic of Outcome in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome

To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS)

Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic. Methods: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic. Findings: Global DALYs increased from 2·63 billion (95% UI 2·44–2·85) in 2010 to 2·88 billion (2·64–3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7–17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8–6·3) in 2020 and 7·2% (4·7–10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0–234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7–198·3]), neonatal disorders (186·3 million [162·3–214·9]), and stroke (160·4 million [148·0–171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3–51·7) and for diarrhoeal diseases decreased by 47·0% (39·9–52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54–1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5–9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0–19·8]), depressive disorders (16·4% [11·9–21·3]), and diabetes (14·0% [10·0–17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7–27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6–63·6) in 2010 to 62·2 years (59·4–64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6–2·9) between 2019 and 2021. Interpretation: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades. Funding: Bill &amp; Melinda Gates Foundation

Les droits disciplinaires des fonctions publiques : « unification », « harmonisation » ou « distanciation ». A propos de la loi du 26 avril 2016 relative à la déontologie et aux droits et obligations des fonctionnaires

The production of tt‾ , W+bb‾ and W+cc‾ is studied in the forward region of proton–proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98±0.02 fb−1 . The W bosons are reconstructed in the decays W→ℓν , where ℓ denotes muon or electron, while the b and c quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions.The production of $t\overline{t}$, $W+b\overline{b}$ and $W+c\overline{c}$ is studied in the forward region of proton-proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98 $\pm$ 0.02 \mbox{fb}^{-1}. The $W$ bosons are reconstructed in the decays $W\rightarrow\ell\nu$, where $\ell$ denotes muon or electron, while the $b$ and $c$ quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND: Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. METHODS: We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined. FINDINGS: Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer. INTERPRETATION: As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival