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Despite the concurrent use of haploidentical cord (HCT) and dual cord (DCT) stem cell transplant approaches for over a decade, there have been few comparisons of their outcomes. Our objective in this study is to assess for differences in the outcomes and adverse effects associated with HCTs versus DCTs. Here we report a retrospective analysis of HCTs and DCTs at our institution. From October 2012 to October 2022, 70 HCT and 133 DCT transplants were performed following 50 mg/kg of IV cyclophosphamide, 150 mg/m 2 of IV fludarabine, 10 mg/kg of IV thiotepa, and 4 Gy total body irradiation conditioning. With a median follow-up of 3.6 years among survivors, there was no difference in overall survival (OS) (3 years OS 65% DCT versus 63% HCT, P = 1) or relapse-free survival (3 years RFS 62% DCT versus 64% HCT, P = .97) for all patients. Time to neutrophil recovery was faster in HCT recipients (median 17 versus 22 days, P = .021), with no difference in platelet recovery to 20,000/μL (P = .12). Median hospitalization for HCT recipients was 20 days versus 24 days for DCT recipients (P < .0001). Engraftment syndrome treated with steroids occurred in 47/133 (35%) DCT recipients versus 42/70 (60%) HCT recipients (odds ratios 0.37, P value=.001). There was a significant increase in grade 3 to 4 acute graft-versus-host disease (aGVHD) in haplo-cord recipients (P = .007), but no difference in grade 2 to 4 aGVHD (P = .11), all chronic GVHD (cGVHD) (P = .9), or moderate-severe cGVHD (P = .3). Our outcomes demonstrate faster engraftment and shorter hospitalization in HCTs relative to DCTs, but more engraftment syndrome and higher grade 3 to 4 aGVHD. When both are options, these factors should guide the choice between HCTs and DCTs., (Copyright © 2024. Published by Elsevier Inc.)

Predictors for response to intensive therapy in AML have focused on baseline factors: percent leukemic blasts in marrow, cytogenetic/molecular genetic abnormalities, and presence of secondary AML. Non-baseline dynamic factors, occurring after induction but before response, may be useful for decisions related to salvage chemotherapy. We hypothesized white blood cell (WBC) count nadir after induction may be a real time indicator of treatment efficacy. We also examined whether time to stem cell transplant (SCT) or baseline molecular genetic abnormalities are associated with a low nadir. Data showed WBC nadir = 0 was a negative predictor for response to intensive induction and was correlated with reduced overall survival and progression free survival. Patients with WBC nadir = 0 did not have a significantly longer time to SCT, and none of the mutations increased the likelihood of reaching WBC nadir = 0. WBC nadir may be a useful real-time monitor in AML patients receiving intensive induction chemotherapy.

Venetoclax with azacitidine (ven/aza) is a lower-intensity therapeutic regimen that has been shown to improve outcomes in elderly patients with acute myeloid leukemia (AML). Measurable residual disease (MRD) using flow cytometry is a valuable tool for the prediction of relapse in AML using conventional therapies and ven/aza; however, the prognostic value for broadscale molecular MRD after ven/aza treatment is less clear. We aimed to determine the utility of retrospective assessment using multi-gene molecular MRD by droplet digital polymerase chain reaction (ddPCR). We found this approach correlates with outcomes in a cohort of patients receiving frontline ven/aza for AML. The predictive value of ddPCR MRD persisted when NPM1 mutations were removed from analysis, as well as after adjustment for the impact of stem cell transplant on outcomes. Late achievement of MRD negativity, including after SCT, was still associated with superior outcomes compared to persistently detectable MRD. We further explored the impact of ven/aza on the burden of different classes of mutations, and identified the persistence of splicing factor mutations, commonly associated with MDS, as a consistent finding after ven/aza treatment. These data add to our understanding of the effects of ven/aza on AML disease biology and provide details on molecular depth of remission that can guide prospective trials in the future.

Monoclonal antibodies targeting CD38 are important for treatment of both newly diagnosed and relapsed multiple myeloma (MM). Daratumumab and isatuximab are anti-CD38 antibodies with the US Food and Drugs Administration approval in multiple different combinations. Despite good initial efficacy, patients inevitably develop drug resistance. Whether patients can be effectively re-treated with these antibodies in subsequent lines of therapy is unclear. Thus far, studies have mostly been limited to clinical retrospectives with short washout periods. To answer whether patients regain sensitivity after longer washouts, we used ex vivo sensitivity testing to isolate the anti-CD38 antibody-specific cytotoxicity in samples obtained from patients who had been exposed to and then off daratumumab for up to 53 months. MM cells from patients who had been off daratumumab for >1 year showed greater sensitivity than those with <1 year, although they still were less sensitive than those who were daratumumab naïve. CD38 expression on MM cells gradually recovered, although, again, not to the level of anti-CD38 antibody-naïve patients. Interestingly, low MM CD38 explained only 45% of cases identified to have daratumumab resistance. With clinical follow-up, we found ex vivo sensitivity predicted subsequent clinical response but CD38 overexpression did not. Patients clinically re-treated with anti-CD38 antibodies had <6 months of clinical benefit, but 1 patient who was daratumumab exposed but not refractory achieved complete response lasting 13 months. We conclude that transient efficacy can be achieved by waiting 1 year before CD38 antibody rechallenge, but this approach may be best used as a bridge to, or after, chimeric antigen receptor T-cell therapy., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Atopic dermatitis (AD) is a common inflammatory disease caused by a type 2 T helper cell-mediated immune response to environmental antigens. Approximately 1 in 5 patients with AD presents with moderate to severe disease, and treatments approved by the Food and Drug Administration include emollients, topical glucocorticoids, and calcineurin inhibitors. Dupilumab, a fully human monoclonal antibody, improves AD via inhibition of interleukin-4 and interleukin-13., Objective: Our aim was to characterize the prescribing patterns of dupilumab for AD in adults at a large university-affiliated health system., Methods: A retrospective, observational cohort study was conducted using electronic data from the Observational Health Data Sciences and Informatics database, assessing data from the University of Colorado Medical Campus and its affiliates. The outcome measured was the prevalence of dupilumab prescribed for adults with AD (n=6421), between March 28, 2013, and March 28, 2021. We assessed whether the characteristics of patients who received dupilumab were different from those who did not. Each patient characteristic was assessed using a univariate logistic regression with the binary outcome of receiving or not receiving dupilumab., Results: We found a population prevalence of 5.6% (6421/114,476) for AD. In our cohort, Black patients with AD were more than twice as likely to have received dupilumab compared to White patients (odds ratio 2.352, 95% CI 1.58-3.39). Patients with a diagnosis of atopic neurodermatitis were approximately twice as likely to have received dupilumab compared to those with other diagnostic variants of AD (odds ratio 1.87, 95% CI 1.01-3.22)., Conclusions: Our results demonstrate that both patient racial characteristics and specific AD diagnoses were associated with variations in dupilumab prescription patterns., (©Torunn E Sivesind, Ani Oganesyan, Grace Bosma, Camille Hochheimer, Lisa M Schilling, Robert Dellavalle. Originally published in JMIR Dermatology (http://derma.jmir.org), 30.08.2023.)

Background: Guidelines established by the American Academy of Dermatology recommend oral antibiotics as first-line therapy for mild, moderate, and severe acne. However, it is recommended to minimize the duration of oral antibiotic use, and there is increasing support for other systemic agents for acne., Objective: We sought to characterize the use of oral antibiotics and isotretinoin for the treatment of acne in the pediatric and young adult population aged 10 through 20 years and the adult population aged 21 to 45 years from 2011 to 2019., Methods: We conducted a retrospective, observational cohort study using electronic data from the enterprise data warehouse of the University of Colorado Anschutz Medical Campus and its affiliates, with data in the format of the Observational Health Data Sciences and Informatics (OHDSI) Observational Medical Outcomes Partnership (OMOP) common data model. Categorical values (sex, race, and ethnicity) were compared using chi-square tests, and continuous variables (age) were compared using 2-tailed t tests., Results: Our cohort of 15,704 patients was composed of mostly White (12,776/15,704, 81.4%), non-Hispanic or Latino (13,307/15,704, 84.7%), and female (11,093/15,704, 70.6%) patients. Among the 4605 male patients in the eligible cohort, 1810 (39%) received an oral antibiotic treatment, in comparison to 3109 (28%) of the 11,093 eligible women (P<.001). Among the 4605 men who were eligible for treatment with isotretinoin in this population, 988 (21.5%) received a course of isotretinoin, compared to only 10.4% (1159/11,093) eligible women (P<.001). Male patients were 1.67 times more likely to have received an antibiotic prescription (odds ratio [OR] 1.67, 95% CI 1.55-1.79) and over twice as likely to have received an isotretinoin prescription (OR 2.34, 95% CI 2.13-2.57) than female patients., Conclusions: Minocycline was the most frequently prescribed antibiotic for the treatment of acne in this study cohort. From 2015 to 2019, there was no significant change in the number of antibiotic prescriptions over time. Men were significantly more likely to receive both oral antibiotics and isotretinoin than female patients. Multiple factors could be contributing to this discrepancy, including the burden of iPLEDGE, additional systemic treatment options for female patients, and the difference in acne severity across sexes. We could not determine the difference in severity of acne between male and female patients in our cohort, and further research is needed to ascertain the variation across sexes., (©Madeline J Adelman, Torunn E Sivesind, Isaac Weber, Grace Bosma, Camille Hochheimer, Chante Karimkhani, Lisa M Schilling, John S Barbieri, Robert P Dellavalle. Originally published in JMIR Dermatology (http://derma.jmir.org), 21.08.2023.)

Relapse is the most common cause of mortality in acute myeloid leukemia (AML) patients after allogeneic stem cell transplant (SCT). Post-SCT maintenance strategies that prevent relapse are desirable but must be well tolerated and convenient to administer. We hypothesized single agent venetoclax (ven) may be an effective maintenance therapy among high relapse risk patients. Between February 2019 and December 2021, we administered post-SCT ven maintenance to 49 AML patients at high-risk for relapse as a prospectively defined off-label practice at our institution. Ven was planned to be administered until 1-year post-SCT. While temporary interruptions were common (67.3% of all patients), of those with >1 year follow up, 22/25 (88%) completed the full year of planned therapy. Cytopenias (40.8%) and gastrointestinal adverse events (34.7%) were the most common toxicities. At 1-year post-SCT, overall survival (OS) and relapse-free survival (RFS) were 70% and 67% respectively. Our experience demonstrates single agent ven is a safe, tolerable, and feasible maintenance therapy that may improve RFS and OS in high relapse risk post-SCT patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Allogeneic hematopoietic stem cell transplantation (SCT) after a patient with acute myeloid leukemia (AML) achieves a remission from intensive chemotherapy (IC) is given with curative intent. Recently, venetoclax-based regimens have become the standard of care for patients with newly diagnosed AML who are unfit for IC. If these patients achieve remission, they may also be considered for potentially curative consolidation with SCT. There are limited data comparing outcomes after SCT with these different induction strategies. The purpose of the current study was to evaluate depth of remission before SCT and outcomes after SCT in adults with nonrelapsed/refractory AML receiving pre-SCT therapy with either venetoclax/azacitidine (ven/aza) or IC. This was a retrospective, single-institution analysis of 169 patients receiving SCT in first remission after IC or ven/aza. Patient demographics and AML risk features were collected, as well as pre-SCT measurable residual disease (MRD) assessed by flow cytometry and molecular methods. Relapse, transplantation-related mortality, incidence of acute and chronic graft-versus-host-disease (GVHD), and death from any cause were also recorded. Descriptive and survival statistics were applied to these data to compare IC and ven/aza groups. Cox proportional hazard models were used for univariate and multivariate analyses. We demonstrate that despite differences in baseline factors between these groups, outcomes were similar. Relapse-free and overall survival, as well as cumulative incidences of transplantation-related mortality, relapse, and acute and chronic GVHD were comparable between groups. Exploring survival in younger (<65 years) versus older (≥65 years) patients by treatment group did not alter these results. Finally, although pre-SCT MRD by flow cytometry was significantly predictive of post-SCT relapse and survival in the IC + SCT patients, it was not significantly predictive of relapse and survival in the ven/aza + SCT patients. Although these findings require prospective validation in a larger cohort of patients, they suggest that ven/aza followed by SCT is a reasonable management strategy for transplantation candidates at any age., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: To analyze how the MRI reporting of rectal cancer has evolved (following guideline updates) in The Netherlands., Methods: Retrospective analysis of 712 patients (2011-2018) from 8 teaching hospitals in The Netherlands with available original radiological staging reports that were re-evaluated by a dedicated MR expert using updated guideline criteria. Original reports were classified as "free-text," "semi-structured," or "template" and completeness of reporting was documented. Patients were categorized as low versus high risk, first based on the original reports (high risk = cT3-4, cN+, and/or cMRF+) and then based on the expert re-evaluations (high risk = cT3cd-4, cN+, MRF+, and/or EMVI+). Evolutions over time were studied by splitting the inclusion period in 3 equal time periods., Results: A significant increase in template reporting was observed (from 1.6 to 17.6-29.6%; p < 0.001), along with a significant increase in the reporting of cT-substage, number of N+ and extramesorectal nodes, MRF invasion and tumor-MRF distance, EMVI, anal sphincter involvement, and tumor morphology and circumference. Expert re-evaluation changed the risk classification from high to low risk in 18.0% of cases and from low to high risk in 1.7% (total 19.7%). In the majority (17.9%) of these cases, the changed risk classification was likely (at least in part) related to use of updated guideline criteria, which mainly led to a reduction in high-risk cT-stage and nodal downstaging., Conclusion: Updated concepts of risk stratification have increasingly been adopted, accompanied by an increase in template reporting and improved completeness of reporting. Use of updated guideline criteria resulted in considerable downstaging (of mainly high-risk cT-stage and nodal stage)., (© 2021. The Author(s).)

Purpose: A new inferior vena cava filter was evaluated in vivo to determine the percutaneous retrievability after an implantation period of up to 18 days., Materials and Methods: The inferior venae cavae of six goats were percutaneously implanted with three filters, and one animal received two filters. To assess filter stability, a plain radiograph was obtained after 7-9 days and on the day of retrieval. After cavography, filter retrieval with an endovascular snare and retrieval catheter was performed in three animals after 12 days and in three others after 14 days. In one animal, retrieval of one filter was performed after 18 days, and one filter was intended to be permanent. Twenty-eight days after filter retrieval, cavography was performed before inferior vena cava removal for gross and histologic examination., Results: All filters (N = 20) were implanted without complications. There was no migration during the implantation period. Preretrieval cavography demonstrated all filters to be patent and centered. Filters intended for retrieval (n = 19) were all successfully extracted at 12 (nine filters), 14 (nine filters), and 18 days (one filter). For the animal with the filter extracted at 18 days, one filter remained in situ intentionally. Postretrieval cavography showed no visible signs of vessel wall anomalies. There were no complications during the 28 days of follow-up after retrieval. Presacrifice cavography showed no evidence of caval wall abnormalities. In all animals, gross examination of the inner wall of the explanted vena cava showed only minimal macroscopic changes. The struts of the filter in situ for 46 days (18 days with 28 days of follow-up) were overgrown with neointima. Histological study of the 19 filter retrieval sites revealed no to moderate intima proliferation, minimal residual signs of hemorrhages, and no or only occasional slight inflammatory reaction., Conclusions: In this animal model, the new vena cava filter demonstrated event-free retrieval, without postretrieval complications, up to 18 days postimplantation. After implantation of 46 days, the filter showed neointima overgrowth of the struts.

We report a single step procedure to prepare monodisperse colloidal poly(methyl)methacrylate (PMMA) particles where fluorescent dyes are incorporated into the polymer network. The particles are sterically stabilized against flocculation by poly(12-hydroxystearic acid). The fluorescent dyes are RITC (rhodamine isothiocyanate)-aminostyrene (RAS) and 4-methylaminoethylmethacrylate-7-nitrobenzo-2-oxa-1,3-diazol (NBD-MAEM), which are prepared from (commercially available) RITC and 4-chloro-7-nitrobenzo-2-oxa-1,3-diazol (NBD-Cl), respectively, as starting materials. The particles can be grown larger with nonfluorescent PMMA. Examples of the usefulness of these model particles in colloid science are given.

In severe combined immunodeficient (scid) mice, V(D)J recombination is severely impaired due to a recessive mutation (scid). Thus, we were surprised to find in this study that Vlambda1-Jlambda1 rearrangement is routinely detectable in scid fetal liver, adult bone marrow, and spleen in the apparent absence of completed VH-DJH and Vkappa-Jkappa rearrangements. Particularly surprising, we found the level of Vlambda1-Jlambda1 rearrangement in scid fetal liver to be comparable to that in fetal liver of wild-type mice. The majority of scid Vlambda1-Jlambda1 rearrangements contained abnormal deletions at the VJ junction, consistent with the known effect of scid. However, approximately 15% of Vlambda1-Jlambda1 rearrangements lacked abnormal deletions. Productive lambda1 transcripts resulting from in-frame rearrangements were readily detectable in scid adult bone marrow and spleen, consistent with our ability to detect lambda1-expressing cells by flow cytometry in the spleens of bcl-2-transgenic scid mice. Strikingly, lambda1 transcripts from individual scid mice often showed VJ junctional sequences with the same recurring palindromic (P) additions of three, four, or five nucleotides. To account for these findings, we suggest that (a) nonhomologous end joining of Vlambda1 and Jlambda1 coding ends in fetal B lineage cells may not be (severely) impaired by scid; (b) recurring P additions in scid lambda1 transcripts may reflect certain molecular constraints imposed by scid on the resolution of Vlambda1 and Jlambda1 hairpin coding ends; and (c), scid lymphocytes with productively rearranged Vlambda1 and Jlambda1 elements may differentiate into recombinase-inactive cells and emigrate from bone marrow to spleen.

Progression of pro-B lymphocytes to the pre-B stage depends on the expression of a pre-B cell receptor (pre-BCR), consisting of an Ig mu H chain, Ig surrogate light chain, and associated signal transducing chains. Mice that are unable to express a pre-BCR show an arrest of B cell development at the pro-B stage. Such is the case for severe combined immune deficient (SCID) mice in which mu chains are not made because of a defect in V(D)J recombination. When mu chains are made, as in SCID mice bearing a functional mu transgene, then B cell differentiation can proceed to the pre-B stage. However, as reported here, a mu transgene (M54) that promotes development of SCID pre-B cells in adult bone marrow fails to do so in fetal liver. We suggest that a pre-BCR containing the M54 mu chain cannot signal progression of pro-B cells to the pre-B stage in the fetal liver microenvironment.