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

Systematic review of studies investigating ventilator associated pneumonia diagnostics in intensive care

Abstract Background Ventilator-associated pneumonia (VAP) is an important diagnosis in critical care. VAP research is complicated by the lack of agreed diagnostic criteria and reference standard test criteria. Our aim was to review which reference standard tests are used to evaluate novel index tests for suspected VAP. Methods We conducted a comprehensive search using electronic databases and hand reference checks. The Cochrane Library, MEDLINE, CINHAL, EMBASE, and web of science were searched from 2008 until November 2018. All terms related to VAP diagnostics in the intensive treatment unit were used to conduct the search. We adopted a checklist from the critical appraisal skills programme checklist for diagnostic studies to assess the quality of the included studies. Results We identified 2441 records, of which 178 were selected for full-text review. Following methodological examination and quality assessment, 44 studies were included in narrative data synthesis. Thirty-two (72.7%) studies utilised a sole microbiological reference standard; the remaining 12 studies utilised a composite reference standard, nine of which included a mandatory microbiological criterion. Histopathological criteria were optional in four studies but mandatory in none. Conclusions Nearly all reference standards for VAP used in diagnostic test research required some microbiological confirmation of infection, with BAL culture being the most common reference standard used

Efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of acute pain after orthopedic trauma: a practice management guideline from the Eastern Association for the Surgery of Trauma and the Orthopedic Trauma Association

OBJECTIVES: Fracture is a common injury after a traumatic event. The efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) to treat acute pain related to fractures is not well established. METHODS: Clinically relevant questions were determined regarding NSAID use in the setting of trauma-induced fractures with clearly defined patient populations, interventions, comparisons and appropriately selected outcomes (PICO). These questions centered around efficacy (pain control, reduction in opioid use) and safety (non-union, kidney injury). A systematic review including literature search and meta-analysis was performed, and the quality of evidence was graded per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. The working group reached consensus on the final evidence-based recommendations. RESULTS: A total of 19 studies were identified for analysis. Not all outcomes identified as critically important were reported in all studies, and the outcome of pain control was too heterogenous to perform a meta-analysis. Nine studies reported on non-union (three randomized control trials), six of which reported no association with NSAIDs. The overall incidence of non-union in patients receiving NSAIDs compared with patients not receiving NSAIDs was 2.99% and 2.19% (p=0.04), respectively. Of studies reporting on pain control and reduction of opioids, the use of NSAIDs reduced pain and the need for opioids after traumatic fracture. One study reported on the outcome of acute kidney injury and found no association with NSAID use. CONCLUSIONS: In patients with traumatic fractures, NSAIDs appear to reduce post-trauma pain, reduce the need for opioids and have a small effect on non-union. We conditionally recommend the use of NSAIDs in patients suffering from traumatic fractures as the benefit appears to outweigh the small potential risks

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

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

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)

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

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