The emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence.

JOURNAL/nrgr/04.03/01300535-202504000-00030/figure1/v/2024-07-06T104127Z/r/image-tiff Our previous studies have reported that activation of the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain damage. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been shown to restore the neuroinflammatory response, along with myelin and synaptic structural alterations in the prefrontal cortex, and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent mice. Considering the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles, the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue, which inhibited the activation of the NLRP3 inflammasome, was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge drinking. We demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes (e.g., pyrin domain-containing 1, caspase recruitment domain-containing 4, and absent in melanoma 2, as well as the alterations in inflammatory genes (interleukin-1ß, interleukin-18, inducible nitric oxide synthase, nuclear factor-kappa B, monocyte chemoattractant protein-1, and C-X3-C motif chemokine ligand 1) and miRNAs (miR-21a-5p, miR-146a-5p, and miR-141-5p) induced by binge-like ethanol treatment in adolescent mice. Bioinformatic analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling pathways. Taken together, these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

Region-Specific Gene Expression Changes Associated with Oleoylethanolamide-Induced Attenuation of Alcohol Self-Administration.

Oleoylethanolamide (OEA) is a lipid with anti-inflammatory activity that modulates multiple reward-related behaviors. Previous studies have shown that OEA treatment reduces alcohol self-administration (SA) while inhibiting alcohol-induced inflammatory signaling. Nevertheless, the specific mechanisms that OEA targets to achieve these effects have not been widely explored. Here, we tested the effects of OEA treatment during alcohol SA, extinction or previous to cue-induced reinstatement of alcohol seeking. In addition, we measured gene expression changes in the striatum and hippocampus of relevant receptors for alcohol consumption (Drd1, Drd2, Cnr1, Oprm) as well as immune-related proteins (Il-6, Il-1ß, Tlr4) and the brain-derived neurotrophic factor (Bdnf). Our results confirmed that when administered contingently, systemic OEA administration reduced alcohol SA and attenuated cue-induced reinstatement. Interestingly, we also observed that OEA treatment reduced the number of sessions needed for the extinction of alcohol seeking. Biochemical analyses showed that OEA induced gene expression changes in dopamine and cannabinoid receptors in the striatum and hippocampus. In addition, OEA treatment modulated the long-term immune response and increased Bdnf expression. These results suggest that boosting OEA levels may be an effective strategy for reducing alcohol SA and preventing relapse.

Comparison of Three Graft-versus-Host Disease Prophylaxis Strategies after T Cell-Replete Haploidentical Hematopoietic Transplantation: Tacrolimus versus Calcineurin Inhibitors + Mycophenolate Mofetil versus Sirolimus + Mycophenolate Mofetil.

Since the introduction of post-transplantation cyclophosphamide (PTCy), haploidentical hematopoietic stem cell transplantation (haploSCT) has become a real alternative for patients who lack other eligible donors. The standard graft-versus-host disease (GVHD) prophylaxis after PTCy has been a calcineurin inhibitor (CNI) plus mycophenolate mofetil (MMF) (up to day +35), but promising results with sirolimus (with or without MMF) and single-agent tacrolimus have been published recently. This multicenter retrospective study compared the outcomes of 372 adult haploSCT recipients who received conditioning with thiotepa, busulfan, and fludarabine (TBF), PTCy, and additional GVHD prophylaxis with 1 of 3 strategies: cohort A, single-agent tacrolimus (n = 222); cohort B, CNI + MMF (n = 49); or cohort C, sirolimus + MMF (n = 101). No differences among the 3 cohorts were found in terms of grade II-IV acute GVHD (20% in cohort A, 25% in cohort B, and 30% in cohort C) or grade III-IV acute GVHD (9%, 6%, and 15%, respectively) at 100 days; however, cohort A had the lowest incidence of overall chronic GVHD (24%, 47%, and 52%, respectively; P = .001) and moderate-severe chronic GVHD (13%, 35%, and 33%, respectively; P = .001). There were no differences in 3-year overall survival, progression-free survival, nonrelapse mortality, or relapse among the 3 cohorts. Overall, our study suggests that single-agent tacrolimus, CNI + MMF, and sirolimus + MMF GVHD prophylaxis lead to similar outcomes following haploSCT with TBF and PTCy, with a low incidence of grade III-IV acute GVHD, although possible differences in chronic GVHD require further investigation.

PSMA PET/CT SUVmax as a prognostic biomarker in patients with metachronous metastatic hormone-sensitive prostate cancer (mHSPC).

BACKGROUND: Metastatic hormone-sensitive prostate cancer (mHSPC) is treatment-resistant and generally considered incurable. The development of prostate-specific membrane antigen positron emission-computed tomography (PSMA PET/CT) has generated immense expectations due to its diagnostic accuracy in prostate cancer (PCa). PSMA expression of the primary tumor, quantified by SUVmax, is a predictor of oncological outcomes. The role of PSMA-PET/CT SUVmax in metachronous mHSPC treated with ADT plus second-generation antiandrogens (ARSI) is unknown. The main aim of this study was to evaluate 68Ga-PSMA-11expression (SUVmax) as a potential prognostic biomarker in patients with metachronous mHSPC treated with ADT and first or second-generation antiandrogens. A second aim was to determine the association between PSMA SUVmax and PSA response to hormone therapy. MATERIAL AND METHODS: Patients diagnosed with metachronous mHSPC between July 2017 and February 2023 who developed biochemical recurrence following radical surgery (with or without salvage radiotherapy and/or ADT) or external radiation therapy (with or without ADT) were included. All patients underwent 68 Ga-PSMA-11 PET/CT imaging and the SUVmax value was determined for all measurable locations. The SUVmax value was used for the semiquantitative analysis. The Wilcoxon method was used to compare responders (PSA reduction ≥ 50%) to non-responders (PSA reduction < 50%). The SUVmax value and hormone therapy were evaluated as independent variables relative to the PSA response rate or PSA reduction using the linear regression method. A mixed-effects model (ANOVA) was used for the comparisons. RESULTS: A total of 82 patients were included. Median follow-up was 11.7 months. On the linear regression analysis, patients with a high SUVmax treated with ADT + ARSI showed a greater PSA response (p = 0.034) than those treated with ADT + first-generation antiandrogens. In the mixed-effects model, SUVmax was significant (p = 0.041). On the univariate analysis, PSA at recurrence (HR, 3.2; 95% CI: 1.07-13.6; p = 0.078) and the number of metastases (HR, 4.77; 95% CI 1.1-26.1: p = 0.002) were associated with the type of hormone therapy administered. CONCLUSIONS: PSMA-PET/CT SUVmax is a prognostic biomarker that can be used to predict a PSA response to ADT + ARSI in patients with metachronous mHSPC. However, these findings need to be confirmed in larger prospective studies.

Let's talk about sex: consensus guidelines of the GINECOR working group of the Spanish Society of Radiation Oncology: clinical recommendations after pelvic radiotherapy.

PURPOSE: The present consensus statement was developed by the GINECOR working group on behalf of the Spanish Society of Radiation Oncology (SEOR). This document addresses sexual health management in patients with gynaecological cancer after pelvic radiotherapy. METHODS: A modified two-round online Delphi study was conducted, where GINECOR members were surveyed on the diagnosis, treatment, and follow-up of sexual health problems. An expert panel of radiation oncologists, nurses and a gynaecologist participated in the Delphi study to reach a consensus, applying GRADE criteria to establish the level of agreement. RESULTS: The consensus recommendations cover both diagnosis and treatment, with an emphasis on patient-reported outcome measures (PROMs). They highlight recommendations such as the systematic assessment of genitourinary, gastrointestinal, and sexual symptoms, and the use of several treatments after radiotherapy. Recommendations include pharmacological options like vaginal lubricants and hormone therapy, and mechanical interventions such as vaginal dilators and vibrators. These suggestions stem from both scientific evidence and clinical expertise. CONCLUSION: This consensus statement describes a comprehensive, multidisciplinary approach developed to address the sexual needs and enhance the quality of life of patients with gynaecological tumours after pelvic radiotherapy. It offers specific recommendations for managing sexual issues, emphasizing the importance of specialized care and regular assessment. The document underscores the significance of proactive, patient-centered sexual health management in gynaecological cancer patients.

Evaluation of CHROMagar™ B. cepacia agar for the detection of Burkholderia cepacia complex species from sputum samples of patients with cystic fibrosis.

INTRODUCTION: Burkholderia cepacia complex (BCC) are non-fermenting Gram-negative bacteria that can chronically colonize the lungs of people with cystic fibrosis (pwCF), causing a severe and progressive respiratory failure, post-transplant complications and epidemic outbreaks. Therefore, rapid and accurate identification of these bacteria is relevant for pwCF, in order to facilitate early eradication and prevent chronic colonization. However, BCCs are often quite difficult to detect on culture media as they have a slow growth rate and can be hidden by other fast-growing microorganisms, including Pseudomonas aeruginosa and filamentous fungi. MATERIAL AND METHODS: We evaluated the sensitivity of CHROMagar™ B. cepacia agar using 11 isolates from a well-characterized BCC collection, using BCA agar (Oxoid, UK) as a gold standard. We also studied 180 clinical sputum samples to calculate positive (PPV) and negative (NPV) predictive values. Furthermore, we used three of the well-characterized BCC isolates to determine the limit of detection (LOD). RESULTS: Eleven isolates grew on CHROMagar™ B. cepacia at 37ºC after 48 h. The NPV and PPV of CHROMagar™ B. cepacia were 100% and 87.5%, respectively. The LOD of CHROMagar™ B. cepacia was around 1 × 103 CFU/ml, requiring a ten-fold dilution lower bacterial load than BCA for BCC detection. CONCLUSION: CHROMagar™ B. cepacia agar proved to have a very good sensitivity and specificity for the detection of clinical BCCs. Moreover, the chromogenic nature of the medium allowed us to clearly differentiate BCC from other Gram-negative species, filamentous fungi and yeasts, thereby facilitating the identification of contaminants.

Novel insight into the lipid network of plasma extracellular vesicles reveal sex-based differences in the lipidomic profile of alcohol use disorder patients.

BACKGROUND: Alcohol use disorder (AUD) is one of the most common psychiatric disorders, with the consumption of alcohol considered a leading cause of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes; however, we know little about the role of lipids in extracellular vesicles (EVs) as regulatory molecules and disease biomarkers. METHODS: We employed a sensitive lipidomic strategy to characterize lipid species from the plasma EVs of AUD patients to evaluate functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism after alcohol consumption. We analyzed plasma EV lipids from AUD females and males and healthy individuals to highlight lipids with differential abundance and biologically interpreted lipidomics data using LINEX2, which evaluates enzymatic dysregulation using an enrichment algorithm. RESULTS: Our results show, for the first time, that AUD females exhibited more significant substrate-product changes in lysophosphatidylcholine/phosphatidylcholine lipids and phospholipase/acyltransferase activity, which are potentially linked to cancer progression and neuroinflammation. Conversely, AUD males suffer from dysregulated ceramide and sphingomyelin lipids involving sphingomyelinase, sphingomyelin phosphodiesterase, and sphingomyelin synthase activity, which relates to hepatotoxicity. Notably, the analysis of plasma EVs from AUD females and males demonstrates enrichment of lipid ontology terms associated with "negative intrinsic curvature" and "positive intrinsic curvature", respectively. CONCLUSIONS: Our methodological developments support an improved understanding of lipid metabolism and regulatory mechanisms, which contribute to the identification of novel lipid targets and the discovery of sex-specific clinical biomarkers in AUD.

Alcohol use disorder (AUD) is one of the most common psychiatric disorders, with the consumption of alcohol considered a leading cause of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes; however, we know little about the role of lipids in extracellular vesicles (EVs) as regulatory molecules and disease biomarkers. We employed a sensitive lipidomic strategy to characterize lipid species from the plasma EVs of AUD patients to evaluate functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism after alcohol consumption. We analyzed plasma EV lipids from AUD females and males and healthy individuals to highlight lipids with differential abundance and biologically interpreted lipidomics data using LINEX², which evaluates enzymatic dysregulation using an enrichment algorithm. Our results show, for the first time, that AUD females exhibited more significant substrate-product changes in lysophosphatidylcholine/phosphatidylcholine lipids and phospholipase/acyltransferase activity, which are potentially linked to cancer progression and neuroinflammation. Conversely, AUD males suffer from dysregulated ceramide and sphingomyelin lipids involving sphingomyelinase, sphingomyelin phosphodiesterase, and sphingomyelin synthase activity, which relates to hepatotoxicity. Notably, the analysis of plasma EVs from AUD females and males demonstrates enrichment of lipid ontology terms associated with "negative intrinsic curvature" and "positive intrinsic curvature", respectively. Our methodological developments support an improved understanding of lipid metabolism and regulatory mechanisms, which contribute to the identification of novel lipid targets and the discovery of sex-specific clinical biomarkers in AUD.

Upper and/or Lower Respiratory Tract Infection Caused by Human Metapneumovirus After Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly investigated area. METHODS: This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT. RESULTS: We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases. CONCLUSIONS: These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases.

Unveiling tetrahydroquinolines as promising BVDV entry inhibitors: Targeting the envelope protein.

Bovine viral diarrhea virus (BVDV) is known to cause financial losses and decreased productivity in the cattle industry worldwide. Currently, there are no available antiviral treatments for effectively controlling BVDV infections in laboratories or farms. The BVDV envelope protein (E2) mediates receptor recognition on the cell surface and is required for fusion of virus and cell membranes after the endocytic uptake of the virus during the entry process. Therefore, E2 is an attractive target for the development of antiviral strategies. To identify BVDV antivirals targeting E2 function, we defined a binding site in silico located in domain IIIc at the interface between monomers in the disulfide linked dimer of E2. Employing a de novo design methodology to identify compounds with the potential to inhibit the E2 function, compound 9 emerged as a promising candidate with remarkable antiviral activity and minimal toxicity. In line with targeting of E2 function, compound 9 was found to block the virus entry into host cells. Furthermore, we demonstrated that compound 9 selectively binds to recombinant E2 in vitro. Molecular dynamics simulations (MD) allowed describing a possible interaction pattern between compound 9 and E2 and indicated that the S enantiomer of compound 9 may be responsible for the antiviral activity. Future research endeavors will focus on synthesizing enantiomerically pure compounds to further support these findings. These results highlight the usefulness of de novo design strategies to identify a novel class of BVDV inhibitors that block E2 function inhibiting virus entry into the host cell.

Treatment of metastatic squamous cell carcinoma arising in sacrococcygeal pilonidal sinus: a case report series.

Background: Squamous cell carcinoma (SCC) arising in a sacrococcygeal pilonidal sinus is rare, with cases of metastatic disease being even rarer. Among published cases, almost none have reported on systemic treatment. Objective: This disease has a poorer prognosis than other forms of cutaneous SCC; therefore, our objective is to shed some light on the treatment of metastatic disease. Methods: We present a series of nine cases treated at a single center, four of whom received systemic treatment. Additionally, other previously reported cases of metastatic disease are included in an attempt to draw stronger conclusions. Results: Four patients were treated under several treatment regimens, with a median progression-free survival of only 2 months and two instances of partial response (18%). The best result was achieved with cemiplimab. Across all the cases, there was a trend toward a benefit of the use of systemic treatment (HR 0.41, 95% CI 0.15-1.12, p = 0.083; median overall survival 13 vs. 8 months). Limitations: Limitations include the significant lack of information on previously published cases and the extremely heterogeneous nature of the existing information. Conclusion: The initial systemic treatment should be an anti-PD-1, as with other SCCs. After progression on anti-PD-1, there is no strong evidence to support the recommendation of a specific treatment or sequence: options include cetuximab and/or chemotherapy (platinum, paclitaxel, 5-fluorouracyl).

Presence of Adenomyosis Impairs Clinical Outcomes in Women Undergoing Frozen Embryo Transfer: A Retrospective Cohort Study.

(1) Background: The presence of adenomyosis among pregnant patients has been associated with a higher incidence of miscarriage and pregnancy complications. Although the role of adenomyosis in women undergoing in vitro fertilization (IVF) was investigated in several studies and demonstrated a potentially detrimental effect on live birth rates following IVF, most of them were small studies in which the adenomyosis diagnosis was not confirmed based on solid ultrasonographic criteria. (2) Methods: 3503 patients undergoing their first blastocyst frozen transfer through a hormonal replacement (HRT) FET cycle. Among them, 140 women had a confirmed diagnosis of adenomyosis based on the MUSA criteria. (3) Results: Adenomyosis patients were more likely to proceed with deferred FET compared with no-adenomyosis women (p = 0.002) and were significantly more likely to be treated with GnRH agonist pre-treatment (2 months) (p < 0.001). The presence of adenomyosis significantly decreased the clinical pregnancy rates (aOR 0.62, 95% CI: 0.39-0.98, p = 0.040) and live birth rates (aOR 0.46, 95% CI: 0.27-0.75, p = 0.003) and significantly increased the miscarriage rates (aOR 2.13, 95% CI: 0.98-4.37, p = 0.045). Multivariable logistic regression adjusting for age, autologous or donor oocytes, PGT-A, deferred FET, serum progesterone levels the day before FET, GnRH agonist pre-treatment, number of embryos transferred, and adenomyosis demonstrated that the use of the GnRH agonist protocol did not decrease or increase the miscarriage rate, clinical pregnancy rate, or live birth rate. (4) Conclusions: The presence of adenomyosis had a significant negative impact on the clinical outcomes of patients undergoing FET and was associated with higher miscarriage, lower clinical pregnancy, and live birth rates. GnRH agonist pre-treatment does not appear to improve clinical outcomes.

Therapeutic role of mesenchymal stem cell-derived extracellular vesicles in neuroinflammation and cognitive dysfunctions induced by binge-like ethanol treatment in adolescent mice.

BACKGROUND: Extracellular vesicles (EVs) are heterogeneous membrane vesicles secreted by cells in extracellular spaces that play an important role in intercellular communication under both normal and pathological conditions. Mesenchymal stem cells (MSC) are anti-inflammatory and immunoregulatory cells capable of secreting EVs, which are considered promising molecules for treating immune, inflammatory, and degenerative diseases. Our previous studies demonstrate that, by activating innate immune receptors TLR4 (Toll-like receptor 4), binge-like ethanol exposure in adolescence causes neuroinflammation and neural damage. AIMS: To evaluate whether the intravenous administration of MSC-derived EVs is capable of reducing neuroinflammation, myelin and synaptic alterations, and the cognitive dysfunction induced by binge-like ethanol treatment in adolescent mice. MATERIALS & METHODS: MSC-derived EVs obtained from adipose tissue were administered in the tail vein (50 microg/dose, one weekly dose) to female WT adolescent mice treated intermittently with ethanol (3.0 g/kg) during two weeks. RESULTS: MSC-derived EVs from adipose tissue ameliorate ethanol-induced up-regulation of inflammatory genes (e.g., COX-2, iNOS, MIP-1α, NF-κB, CX3CL1, and MCP-1) in the prefrontal cortex of adolescent mice. Notably, MSC-derived EVs also restore the myelin and synaptic derangements, and the memory and learning impairments, induced by ethanol treatment. Using cortical astroglial cells in culture, our results further confirm that MSC-derived EVs decrease inflammatory genes in ethanol-treated astroglial cells. This, in turn, confirms in vivo findings. CONCLUSION: Taken together, these results provide the first evidence for the therapeutic potential of the MSC-derived EVs in the neuroimmune response and cognitive dysfunction induced by binge alcohol drinking in adolescence.

Oleoylethanolamide attenuates cocaine-primed reinstatement and alters dopaminergic gene expression in the striatum.

The lipid oleoylethanolamide (OEA) has been shown to affect reward-related behavior. However, there is limited experimental evidence about the specific neurotransmission systems OEA may be affecting to exert this modulatory effect. The aim of this study was to evaluate the effects of OEA on the rewarding properties of cocaine and relapse-related gene expression in the striatum and hippocampus. For this purpose, we evaluated male OF1 mice on a cocaine-induced CPP procedure (10 mg/kg) and after the corresponding extinction sessions, we tested drug-induced reinstatement. The effects of OEA (10 mg/kg, i.p.) were evaluated at three different timepoints: (1) Before each cocaine conditioning session (OEA-C), (2) Before extinction sessions (OEA-EXT) and (3) Before the reinstatement test (OEA-REINST). Furthermore, gene expression changes in dopamine receptor D1 gene, dopamine receptor D2 gene, opioid receptor µ, cannabinoid receptor 1, in the striatum and hippocampus were analyzed by qRT-PCR. The results obtained in the study showed that OEA administration did not affect cocaine CPP acquisition. However, mice receiving different OEA treatment schedules (OEA-C, OEA-EXT and OEA-REINST) failed to display drug-induced reinstatement. Interestingly, the administration of OEA blocked the increase of dopamine receptor gene D1 in the striatum and hippocampus caused by cocaine exposure. In addition, OEA-treated mice exhibited reduced striatal dopamine receptor gene D2 and cannabinoid receptor 1. Together, these findings suggest that OEA may be a promising pharmacological agent in the treatment of cocaine use disorder.

Impact of cytomegalovirus immunodominant HLA-I donor-recipient matching on the incidence and features of virus DNAemia and virus-specific T-cell immune reconstitution in unmanipulated haploidentical hematopoietic stem cell transplantation.

BACKGROUND: We investigated whether donor-recipient mismatch involving one or more cytomegalovirus (CMV) immunodominant (ID) human leukocyte antigen (HLA)-I alleles may impact on the degree of CMV pp65/immediate-early 1 (IE-1) T-cell reconstitution and the incidence of CMV DNAemia in patients undergoing unmanipulated haploidentical hematopoietic stem cell transplantation with high-dose posttransplant cyclophosphamide (PT/Cy-haplo). METHODS: Multicenter observational study including 106 consecutive adult PT/Cy-haplo patients (34 CMV ID HLA-I matched and 72 mismatched). A real-time PCR was used for plasma CMV DNA load monitoring. Enumeration of CMV-specific (pp65/IE-1) interferon (IFN)-γ-producing T cells from several patients was performed by flow cytometry by days +30, +60, +90 and +180 after transplantation. RESULTS: The cumulative incidence of CMV DNAemia, clinically significant CMV DNAemia episodes (cs-CMVi), and recurrent CMV DNAemia was comparable across CMV ID HLA-I matched and mismatched patients (71.8% vs. 80.9%, p = .95; 40.7% vs. 44.2%, p = .85; 16.4% vs. 28.1%; p = .43, respectively). The percentage of patients exhibiting detectable CMV-specific IFN-γ-producing T-cell responses (either CD8+ or CD4+ ) was similar across groups; nevertheless, significantly higher CMV-specific CD8+ T-cell counts were enumerated in the CMV ID HLA-I matched compared to mismatched patients by day +60 (p = .04) and +180 (p = .016) after transplantation. CONCLUSION: CMV ID HLA-I matching may impact on the magnitude of CMV-pp65/IE-1-specific CD8+ T-cell reconstitution; yet, this effect seemed not to have an impact on the incidence of initial, recurrent CMV DNAemia, or cs-CMVi.

SARS-CoV-2-reactive antibody waning, booster effect and breakthrough SARS-CoV-2 infection in hematopoietic stem cell transplant and cell therapy recipients at one year after vaccination.

The kinetics of SARS-CoV-2 reactive IgG antibodies after full vaccination and booster in allogeneic and autologous stem cell transplantation (allo-HSCT, ASCT) and chimeric antigen receptor T-cell therapy (CAR-T) are of utmost importance for estimating risk of infection. A prospective multicenter registry-based cohort study, conducted from December 2020 to July 2022 was used to analyze antibody waning over time, booster effect and the relationship of antibody response and breakthrough infection in 572 recipients (429 allo-HSCT, 121 ASCT and 22 CAR-T cell therapy). A significant decline in antibody titers was observed at 3 and 6 months after full vaccination in recipients without pre-vaccine SARS-CoV-2 infection, whereas recipients infected prior to vaccination showed higher and stable antibody titers over time. In poor responders, a booster dose was able to increase antibody titers in 83% of allo-HSCT and 58% of ASCT recipients but not in CART-T cell recipients [0%] (p < 0.01). One-year cumulative incidence of breakthrough infection was 15%, similar among cell therapy procedures. Immunosuppressive drugs at the time of vaccination [hazard ratio (HR) 1.81, p = 0.0028] and reduced intensity conditioning (HR 0.49, p = 0.011) were identified as the only conditions associated with different risk of breakthrough infection in allo-HSCT recipients. Antibody titers were associated with breakthrough infection and disease severity. No death was observed among the 72 breakthrough infections. Antibody level decay after the first two vaccine doses was common except in recipients with pre-vaccination SARS-CoV-2 infection. Poorly responding allo-HSCT recipients showed a response advantage with the booster as compared to ASCT and, especially, the null response found in CAR-T cell recipients. Antibody titers were positively correlated with the risk of breakthrough SARS-CoV-2 infection which was mainly driven by the immunosuppression status.

Role of allogeneic hematopoietic cell transplant for relapsed/refractory aggressive B-cell lymphomas in the CART era.

Anti-CD19 chimeric antigen receptor T cells (CART) has rapidly been adopted as the standard third-line therapy to treat aggressive B-cell lymphomas (ABCL) after failure of second-line therapy despite the lack of direct comparisons with allogeneic hematopoietic cell transplantation (alloHCT)-based strategies. Using the Grupo Español de Trasplante y Terapia Celular (GETH-TC) registry, we selected patients with the following characteristics: CART or alloHCT performed between 2016 and 2021; ≥18 years old; ABCL diagnosis; ≥2 lines of therapy; and either anti-CD19 CART or alloHCT as therapy at relapse. The analysis included a total of 316 (CART = 215, alloHCT = 101) patients. Median follow-up was 15 and 36 months for the CART and alloHCT cohorts, respectively. In the multivariate analysis, CART was confirmed to be similar to alloHCT for the primary study endpoint (progression-free survival) (hazard ratio [HR] 0.92, CI95%:0.56-1.51, p = 0.75). Furthermore, when the analysis was limited to only patients with chemo-sensitive diseases (complete and partial response) at infusion (CART = 26, alloHCT=93), no differences were reported (progression-free survival at month +18: 65% versus 55%, p = 0.59). However, CART had lower non-relapse mortality (HR 0.34, 95% CI: 0.13-0.85, p = 0.02). Given the lower toxicity and similar survival outcomes, these results suggest the use of CART before alloHCT.

O-RADS Classification for Ultrasound Assessment of Adnexal Masses: Agreement between IOTA Lexicon and ADNEX Model for Assigning Risk Group.

BACKGROUND: The O-RADS system is a new proposal for establishing the risk of malignancy of adnexal masses using ultrasound. The objective of this study is to assess the agreement and diagnostic performance of O-RADS when using the IOTA lexicon or ADNEX model for assigning the O-RADS risk group. METHODS: Retrospective analysis of prospectively collected data. All women diagnosed as having an adnexal mass underwent transvaginal/transabdominal ultrasound. Adnexal masses were classified according to the O-RADS classification, using the criterion of the IOTA lexicon and according to the risk of malignancy determined by the ADNEX model. The agreement between both methods for assigning the O-RADS group was estimated using weighted Kappa and the percentage of agreement. The sensitivity and specificity of both approaches were calculated. RESULTS: 454 adnexal masses in 412 women were evaluated during the study period. There were 64 malignant masses. The agreement between the two approaches was moderate (Kappa: 0.47), and the percentage of agreement was 46%. Most disagreements occurred for the groups O-RADS 2 and 3 and for groups O-RADS 3 and 4. The sensitivity and specificity for O-RADS using the IOTA lexicon and O-RADS using the ADNEX model were 92.2% and 86.1%, and 85.9% and 87.4%, respectively. CONCLUSION: The diagnostic performance of O-RADS classification using the IOTA lexicon as opposed to the IOTA ADNEX model is similar. However, O-RADS group assignment varies significantly, depending on the use of the IOTA lexicon or the risk estimation using the ADNEX model. This fact might be clinically relevant and deserves further research.

AI: Can It Make a Difference to the Predictive Value of Ultrasound Breast Biopsy?

(1) Background: This study aims to compare the ground truth (pathology results) against the BI-RADS classification of images acquired while performing breast ultrasound diagnostic examinations that led to a biopsy and against the result of processing the same images through the AI algorithm KOIOS DS TM (KOIOS). (2) Methods: All results of biopsies performed with ultrasound guidance during 2019 were recovered from the pathology department. Readers selected the image which better represented the BI-RADS classification, confirmed correlation to the biopsied image, and submitted it to the KOIOS AI software. The results of the BI-RADS classification of the diagnostic study performed at our institution were set against the KOIOS classification and both were compared to the pathology reports. (3) Results: 403 cases were included in this study. Pathology rendered 197 malignant and 206 benign reports. Four biopsies on BI-RADS 0 and two images are included. Of fifty BI-RADS 3 cases biopsied, only seven rendered cancers. All but one had a positive or suspicious cytology; all were classified as suspicious by KOIOS. Using KOIOS, 17 B3 biopsies could have been avoided. Of 347 BI-RADS 4, 5, and 6 cases, 190 were malignant (54.7%). Because only KOIOS suspicious and probably malignant categories should be biopsied, 312 biopsies would have resulted in 187 malignant lesions (60%), but 10 cancers would have been missed. (4) Conclusions: KOIOS had a higher ratio of positive biopsies in this selected case study vis-à-vis the BI-RADS 4, 5 and 6 categories. A large number of biopsies in the BI-RADS 3 category could have been avoided.

Learning Curve for Ultrasound Assessment of Myometrial Infiltration in Endometrial Cancer Visualizing Videoclips: Potential Implications for Training.

BACKGROUND: Diagnostic accuracy for estimating myometrial infiltration by ultrasound in endometrial cancer requires experience. The objective of this study is to determine the learning curve (LC) for assessing myometrial infiltration in cases of endometrial cancer using transvaginal ultrasound (TVS). METHODS: Five trainees (one staff radiologist and four fourth-year OB/GYN residents) participated in this study. All trainees had experience in performing TVS, but none of them had specific training on the assessment of myometrial infiltration. Trainees were given one specific lecture about the topic, and then they observed videoclips from 10 cases explained by the trainer. After this, all trainees visualized 45 videoclips of uterine ultrasound scans of endometrial cancer cases. The assessment of myometrial infiltration was based on the subjective impression. Definitive histology was used as a reference standard. Trainees stated whether myometrial infiltration was ≥50% or <50%. LC-CUSUM and standard CUSUM graphics were plotted to determine how many cases were needed to reach competence, allowing a mistake rate of 15%. RESULTS: All trainees completed the study. LC-CUSUM graphics showed that three trainees reached competence at the 33rd, 35th and 36th case, respectively. All three of them kept the process under control after reaching competence. One trainee reached competence but did not maintain it in the cumulative analysis. One trainee did not reach competence. CONCLUSION: Our study suggests that 30-40 cases would be needed to be trained for assessing myometrial infiltration by TVS by visual interpretation of videoclips by most trainees.