Citations

Abstract Background: Haploidentical allogeneic hematopoietic cell transplantation (haplo) has expanded applicability of the procedure to patients for whom a suitable HLA compatible donor was not available in the past. A small multicenter retrospective study of 185 patients with hematologic malignancies who received a nonmyeloablative preparative regimen followed by infusion of bone marrow (BM) hematopoietic cells from haploidentical donors showed no significant association between the number of HLA mismatches (HLA-A, -B, -C, and -DRB1 combined) and risk of acute grade 2-4 graft-versus-host disease (GVHD) (hazard ratio [HR]=0.89; P=0.68 for 3-4 mismatches vs fewer antigen mismatches). This haploidentical transplant platform has certainly evolved. Nowadays, G-CSF mobilized peripheral blood stem cells (PBSC) are commonly used owing to its increased convenience vis-à-vis performing a BM harvest. Study population: Here, we evaluate post transplant outcomes when using haploidentical donors with T-replete PBSC and PTCy in AML in CR1. A total of 494 patients (4/8 HLA mismatch (group 1)=360, 2-3/8 HLA mismatch (group 2)=134) underwent the procedure at an EBMT participating center. The primary endpoints were cumulative incidences of grade 2-4 acute GVHD and chronic (all grades) GVHD. Secondary endpoints included cumulative incidence of relapse (RI), non-relapse mortality (NRM), leukemia-free (LFS) and overall survival (OS) and GVHD-free relapse-free survival (GRFS). Results: Group 1 and group 2 were not statistically different in regards to median age at allografting (54.1 vs. 56.1 years, p=0.51), median year of haplo transplantation (2018 vs. 2018, p=0.36), incidence of de novo AML (86.4% vs. 88.1%, p=0.63), Karnofsky equal or more than 90 (77.5% vs. 79.1%, p=0.70), and use of myeloablative conditioning (MAC) (44.7% vs. 48.5%, p=0.45). Patients in group 1 had a longer time from diagnosis to haplo-transplantation (5.3 vs. 4.9 months, p=0.03). In multivariate analysis, group 1 and group 2 did not differ in cumulative incidence of grade 2-4 acute GVHD (Hazard ratio (HR)=0.89 (95%CI=0.62-1.26), p=0.51) but group 1 had a significantly higher incidence of chronic (all grades) GVHD (HR=1.49 (95%CI=1.02-2.16), p=0.04). There was no difference in RI (HR=0.73 (95%CI=0.47-1.14), p=0.17), NRM (HR=1.25 (95%CI=0.78-2.02), p=0.36), LFS (HR=0.95 (95%CI=0.69-1.31), p=0.76), OS (HR=1.09 (95%CI=0.76-1.55), p=0.64) and GRFS (HR=1.07 (95%CI=0.81-1.42), p=0.64) between the groups. Presence of adverse cytogenetics was independently associated with higher RI (HR=1.90 (95%CI=1.20-2.99), p=0.006), inferior LFS (HR=1.59 (95%CI=1.15-2.19), p=0.005), inferior OS (HR=1.48 (95%CI=1.05-2.08), p=0.03), and worse GRFS (HR=1.54 (95%CI=1.17-2.04), p=0.002). Conclusion: Results show that patients undergoing haplo-transplantation with 4/8 (vs. 2-3/8) HLA mismatches have a higher incidence of chronic GVHD (all grades) without adversely affecting acute grade 2-4 GVHD, RI, LFS, OS and GRFS. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria. McDonald: BioCryst Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Forcade: Novartis: Other: travel grant. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Mohty: Takeda: Honoraria; Astellas: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Jazz: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria.

Carotid plaque vulnerability features beyond the degree of stenosis may play a key role in the pathogenesis and recurrence of ischemic cerebrovascular events. This study sought to compare intraplaque hemorrhage (IPH) as a marker of plaque vulnerability in symptomatic patients with mild (<50%), moderate (50%–69%), and severe (≥70%) carotid artery stenosis. We included patients who experienced ischemic cerebrovascular events with no other identifiable sources and underwent carotid endarterectomy for mild (n=32), moderate (n=47), and severe (n=58) carotid artery stenosis. The degree of stenosis and imaging hallmarks were assessed by computed tomography angiography or magnetic resonance angiography. Plaque specimens were stained with hematoxylin and eosin and Movat pentachrome staining. Carotid plaques of patients with mild stenosis had a higher extent of IPH (%) on tissue analysis compared with patients with moderate (mild, 15.7% [interquartile range, 7.8%–26.7%]; moderate, 3.9% [0.0%–9.2%]; P <0.001) and severe carotid artery stenosis (mild, 15.7% [interquartile range, 7.8%–26.7%]; severe, 2.5% [interquartile range, 0.0%–11.2%]; P <0.001). When considering the degree of carotid artery stenosis as a continuous variable, a lower lumen narrowing was associated with higher extent of IPH ( P <0.001; R, −0.329). Our major finding is the association of IPH with mild carotid artery stenosis based on histological analysis. The current study may suggest that IPH potentially plays a role in the mechanism of stroke in patients with nonobstructive carotid stenosis.

The role of calcium in atherosclerosis is controversial and the relationship between vascular calcification and plaque vulnerability is not fully understood. Although calcifications are present in ≈50% to 60% of carotid plaques, their association with cerebrovascular ischemic events remains unclear. In this review, we summarize current understanding of carotid plaque calcification. We outline the role of calcium in atherosclerotic carotid disease by analyzing laboratory studies and histopathologic studies, as well as imaging findings to understand clinical implications of carotid artery calcifications. Differences in mechanism of calcium deposition express themselves into a wide range of calcification phenotypes in carotid plaques. Some patterns, such as rim calcification, are suggestive of plaques with inflammatory activity with leakage of the vasa vasourm and intraplaque hemorrhage. Other patterns such as dense, nodular calcifications may confer greater mechanical stability to the plaque and reduce the risk of embolization for a given degree of plaque size and luminal stenosis. Various distributions and patterns of carotid plaque calcification, often influenced by the underlying systemic pathological condition, have a different role in affecting plaque stability. Modern imaging techniques afford multiple approaches to assess geometry, pattern of distribution, size, and composition of carotid artery calcifications. Future investigations with these novel technologies will further improve our understanding of carotid artery calcification and will play an important role in understanding and minimizing stroke risk in patients with carotid plaques.

AbstractAimThe existing literature was updated, assessing the use of surgery in patients with ulcerative colitis in more recent years.MethodsThis was a retrospective observational study identifying all patients with ulcerative colitis within the National Inpatient Sample, years 2009–2018. All patients with International Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification diagnostic codes for ulcerative colitis were included. The primary outcome was the trend in total number of total abdominal colectomy, proctocolectomy and simultaneous versus delayed pouch construction.ResultsA total of 1 184 711 ulcerative‐colitis‐related admissions were identified. An increase of 18.6% in the number of patients was observed, while the number of surgeries decreased. A total of 40 499 patients underwent total colectomy, annually decreasing from 5241 to 3185. The number of proctocolectomies without pouch decreased from 1191 to 530, while the number of patients undergoing pouch construction decreased from 2225 to 1284. The proportion of patients undergoing initial pouch at time of proctocolectomy decreased from 995 (45%) to 265 (21%), while the proportion of patients undergoing delayed pouch construction in 2018 was 79% (n = 1120).ConclusionSurgery use in ulcerative colitis has decreased in the last decade despite increasing numbers of hospital admissions in patients with this condition. While the overall proportion of patients undergoing pouch construction remained stable, the majority of patients were initially treated with total colectomy and their ileal pouches werre constructed in a delayed fashion.

Abstract Rationale Lung biopsy (LBx) has a relevant role in the prediction of prognosis of interstitial lung diseases (ILDs), but its impact on the clinical management of patients remains unexplored. Objectives This study evaluates whether LBx may change the therapeutic strategy and assesses the effect of diagnostic reclassification after LBx on long-term prognosis. Methods We evaluated the LBx of 426 consecutive patients with ILDs, without a definite usual interstitial pneumonia pattern on high-resolution computed tomographic imaging. A total of 266 patients underwent transbronchial lung cryobiopsy (TBLC), and 160 patients underwent surgical lung biopsy (SLB). The multidisciplinary team (MDT) determined a diagnosis with high or low confidence, and a management strategy, both before and after the LBx data. Results Final MDT diagnoses were 189 idiopathic pulmonary fibrosis (IPF), 143 non-IPF fibrotic ILDs, and 94 nonfibrotic ILDs. LBx data changed the management strategy in 145 cases (34%), with similar results for TBLC and SLB (the treatment strategy changed in 31.5% of TBLC cases, 84/266, P &lt; 0.001, and in 38% of SLB, 61/160, P &lt; 0.001). After LBx, the MDT was less inclined to “wait and see” (from 15% to 4% of cases, P &lt; 0.001) or to prescribe steroids only (from 54% to 37%, P &lt; 0.001) and was more confident to treat with antifibrotics (from 23% to 44%, P &lt; 0.001) or immunosuppressive drugs (from 7% to 14%, P &lt; 0.001). The therapeutic strategy changed in 70% of reclassified cases (60/85) and in 59% of cases in which LBx increased the MDT confidence (84/142). Reclassification significantly impacted the outcome. The cases classified as non-IPF by clinician and radiologist and then reclassified to be IPF after LBx showed a significantly worse survival compared with non-IPF confirmed cases (adjusted hazard ratio [HR], 3.8; 95% confidence interval [CI], 1.75–8.3); P = 0.001. Cases initially classified as IPF and then reclassified as non-IPF after LBx showed a better prognosis compared with IPF confirmed cases (HR, 0.41; 95% CI, 0.18–0.94; P = 0.03). Conclusions Reclassification of cases with LBx data increased diagnostic confidence and changed the therapeutic strategy in one-third of cases. Pathologic reclassification of cases refined prognosis prediction. Patients classified as non-IPF by clinician and radiologist and then reclassified IPF after LBx had worse prognosis compared with the non-IPF confirmed cases.

Background: For COVID-19 lung severity, segmentation of lungs on computed tomography (CT) is the first crucial step. Current deep learning (DL)-based Artificial Intelligence (AI) models have a bias in the training stage of segmentation because only one set of ground truth (GT) annotations are evaluated. We propose a robust and stable inter-variability analysis of CT lung segmentation in COVID-19 to avoid the effect of bias. Methodology: The proposed inter-variability study consists of two GT tracers for lung segmentation on chest CT. Three AI models, PSP Net, VGG-SegNet, and ResNet-SegNet, were trained using GT annotations. We hypothesized that if AI models are trained on the GT tracings from multiple experience levels, and if the AI performance on the test data between these AI models is within the 5% range, one can consider such an AI model robust and unbiased. The K5 protocol (training to testing: 80%:20%) was adapted. Ten kinds of metrics were used for performance evaluation. Results: The database consisted of 5000 CT chest images from 72 COVID-19-infected patients. By computing the coefficient of correlations (CC) between the output of the two AI models trained corresponding to the two GT tracers, computing their differences in their CC, and repeating the process for all three AI-models, we show the differences as 0%, 0.51%, and 2.04% (all < 5%), thereby validating the hypothesis. The performance was comparable; however, it had the following order: ResNet-SegNet > PSP Net > VGG-SegNet. Conclusions: The AI models were clinically robust and stable during the inter-variability analysis on the CT lung segmentation on COVID-19 patients.

Abstract Video-polysomnography (v-PSG) is essential for diagnosing rapid eye movement (REM) sleep behavior disorder (RBD). Although there are current American Academy of Sleep Medicine standards to diagnose RBD, several aspects need to be addressed to achieve harmonization across sleep centers. Prodromal RBD is a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria for RBD. However, the boundary between prodromal and definite RBD is still unclear. As a common effort of the Neurophysiology Working Group of the International RBD Study Group, this manuscript addresses the need for comprehensive and unambiguous v-PSG recommendations to diagnose RBD and identify prodromal RBD. These include: (1) standardized v-PSG technical settings; (2) specific considerations for REM sleep scoring; (3) harmonized methods for scoring REM sleep without atonia; (4) consistent methods to analyze video and audio recorded during v-PSGs and to classify movements and vocalizations; (5) clear v-PSG guidelines to diagnose RBD and identify prodromal RBD. Each section follows a common template: The current recommendations and methods are presented, their limitations are outlined, and new recommendations are described. Finally, future directions are presented. These v-PSG recommendations are intended for both practicing clinicians and researchers. Classification and quantification of motor events, RBD episodes, and vocalizations are however intended for research purposes only. These v-PSG guidelines will allow collection of homogeneous data, providing objective v-PSG measures and making future harmonized multicentric studies and clinical trials possible.

Abstract Background Stress echocardiography (SE) was recently upgraded to the ABCDE protocol: step A, regional wall motion abnormalities; step B, B-lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in left anterior descending coronary artery; and step E, EKG-based heart rate reserve. Aim: to assess the prognostic value of ABCDE-SE in a prospective, large scale, multicenter, international, effectiveness study. Methods From July 2016 to November 2020, we enrolled 3,574 all-comers (age 65±11 years, 2,070 males, 58%; ejection fraction 60±10%) with known or suspected chronic coronary syndromes referred from 13 certified laboratories. All patients underwent ABCDE-SE. The employed stress modality was exercise (n=952, with semi-supine bike, n=887, or treadmill, n=65 with adenosine for step D) or pharmacological stress (n=2,622, with vasodilator, n=2,151; or dobutamine, n=471). SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). All-cause death was the only end-point. Results Rate of abnormal results was 16% for A, 30% for B, 36% for C, 28% for D and 37% for E step. During a median follow-up of 21 months, 73 deaths occurred. At univariable analysis, predictors of all-cause mortality were step B (hazard ratio, HR: 2.621, 95% Confidence Intervals, CI: 1.654–4.152, p&lt;0.001), step D (HR: 2.578, 95% CI: 1.624–4.093, p&lt;0.001), and step E (HR: 2.955, 95% CI: 1.848–4.725, p&lt;0.001), but not step A (HR: 1.333, 95% CI: 0.731–2.430, p=0.349) and step C (HR1.581, 95% CI: 0.997–2.506, p=0.051). At multivariable analysis, ABCDE-SE was an independent predictor of mortality with score 3 (HR: 3.472, 95% CI: 1.483–8.135, p=0.004), 4 (HR: 4.045, 95% CI: 1.595–10.259, p=0.003) and 5 (HR: 5.678, 95% CI: 2.106–15.313, p=0.001) (Figure). Annual mortality rate ranged from 0.4% person/year for score 0 up to 2.4% person/year for score 5. Conclusion ABCDE-SE allows an effective risk stratification of patient global vulnerability. Funding Acknowledgement Type of funding sources: None. Survival curves based on ABCDE score

Background Immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer. Methods We collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI. Results ICPi-AKI occurred at a median of 16 weeks (IQR 8–32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3–10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI. Conclusions Patients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

Objective: The ISGPS aimed to develop a universally accepted definition for PPAP for standardized reporting and outcome comparison. Background: : PPAP is an increasingly recognized complication after partial pancreatic resections, but its incidence and clinical impact, and even its existence are variable because an internationally accepted consensus definition and grading system are lacking. Methods: The ISGPS developed a consensus definition and grading of PPAP with its members after an evidence review and after a series of discussions and multiple revisions from April 2020 to May 2021. Results: We defined PPAP as an acute inflammatory condition of the pancreatic remnant beginning within the first 3 postoperative days after a partial pancreatic resection. The diagnosis requires (1) a sustained postoperative serum hyperamylasemia (POH) greater than the institutional upper limit of normal for at least the first 48 hours postoperatively, (2) associated with clinically relevant features, and (3) radiologic alterations consistent with PPAP. Three different PPAP grades were defined based on the clinical impact: (1) grade postoperative hyperamylasemia, biochemical changes only; (2) grade B, mild or moderate complications; and (3) grade C, severe life-threatening complications. Discussions: The present definition and grading scale of PPAP, based on biochemical, radiologic, and clinical criteria, are instrumental for a better understanding of PPAP and the spectrum of postoperative complications related to this emerging entity. The current terminology will serve as a reference point for standard assessment and lend itself to developing specific treatments and prevention strategies.