COVID-19 Outcomes in Patients with Hematologic Malignancies in the Era of COVID-19 Vaccination and the Omicron Variant.

A greater understanding of clinical trends in COVID-19 outcomes among patients with hematologic malignancies (HM) over the course of the pandemic, particularly the Omicron era, is needed. This ongoing, observational, and registry-based study with prospective data collection evaluated COVID-19 clinical severity and mortality in 1818 adult HM patients diagnosed with COVID-19 between 27 February 2020 and 1 October 2022, at 31 centers in the Madrid region of Spain. Of these, 1281 (70.5%) and 537 (29.5%) were reported in the pre-Omicron and Omicron periods, respectively. Overall, patients aged ≥70 years (odds ratio 2.16, 95% CI 1.64-2.87), with >1 comorbidity (2.44, 1.85-3.21), or with an underlying HM of chronic lymphocytic leukemia (1.64, 1.19-2.27), had greater odds of severe/critical COVID-19; odds were lower during the Omicron BA.1/BA.2 (0.28, 0.2-0.37) or BA.4/BA.5 (0.13, 0.08-0.19) periods and among patients vaccinated with one or two (0.51, 0.34-0.75) or three or four (0.22, 0.16-0.29) doses. The hospitalization rate (75.3% [963/1279], 35.7% [191/535]), rate of intensive care admission (30.0% [289/963], 14.7% [28/191]), and mortality rate overall (31.9% [409/1281], 9.9% [53/536]) and in hospitalized patients (41.3% [398/963], 22.0% [42/191]) decreased from the pre-Omicron to Omicron period. Age ≥70 years was the only factor associated with higher mortality risk in both the pre-Omicron (hazard ratio 2.57, 95% CI 2.03-3.25) and Omicron (3.19, 95% CI 1.59-6.42) periods. Receipt of prior stem cell transplantation, COVID-19 vaccination(s), and treatment with nirmatrelvir/ritonavir or remdesivir were associated with greater survival rates. In conclusion, COVID-19 mortality in HM patients has decreased considerably in the Omicron period; however, mortality in hospitalized HM patients remains high. Specific studies should be undertaken to test new treatments and preventive interventions in HM patients.

Impact of Interfractional Bladder and Trigone Displacement and Deformation on Radiation Exposure and Subsequent Acute Genitourinary Toxicity: A Post Hoc Analysis of Patients Treated with Magnetic Resonance Imaging-Guided Prostate Stereotactic Body Radiation Therapy in a Phase 3 Randomized Trial.

PURPOSE: Emerging data suggest that trigone dosimetry may be more associated with poststereotactic body radiation therapy (SBRT) urinary toxicity than whole bladder dosimetry. We quantify the dosimetric effect of interfractional displacement and deformation of the whole bladder and trigone during prostate SBRT using on-board, pretreatment 0.35T magnetic resonance images (MRI). METHODS AND MATERIALS: Seventy-seven patients treated with MRI-guided prostate SBRT (40 Gy/5 fractions) on the MRI arm of a phase 3 single-center randomized trial were included. Bladder and trigone structures were contoured on images obtained from a 0.35T simulation MRI and 5 on-board pretreatment MRIs. Dice similarity coefficient (DSC) scores and changes in volume between simulation and daily treatments were calculated. Dosimetric parameters including Dmax, D0.03 cc, Dmean, V40 Gy, V39 Gy, V38 Gy, and V20 Gy for the bladder and trigone for the simulation and daily treatments were collected. Both physician-scored (Common Terminology Criteria for Adverse Events, version 4.03 scale) as well as patient-reported (International Prostate Symptom Scores and the Expanded Prostate Cancer Index Composite-26 scores) acute genitourinary (GU) toxicity outcomes were collected and analyzed. RESULTS: The average treatment bladder volume was about 30% smaller than the simulation bladder volume; however, the trigone volume remained fairly consistent despite being positively correlated with total bladder volume. Overall, the trigone accounted for <2% of the bladder volume. Median DSC for the bladder was 0.79, whereas the median DSC of the trigone was only 0.33. No statistically significant associations between our selected bladder and trigonal dosimetric parameters and grade ≥2 GU toxicity were identified, although numerically, patients with GU toxicity (grade ≥2) had higher intermediate doses to the bladder (V20 Gy and Dmean) and larger volumes exposed to higher doses in the trigone (V40 Gy, V39 Gy, and V38 Gy). CONCLUSIONS: The trigone exhibits little volume change, but considerable interfractional displacement/deformation. As a result, the relative volume of the trigone receiving high doses during prostate SBRT varies substantially between fractions, which could influence GU toxicity and may not be predicted by radiation planning dosimetry.

Chondroid Tumors: Review of Salient Imaging Features and Update on the WHO Classification.

Chondrogenic tumors are typically well recognized on radiographs, but differentiation between benign and malignant cartilaginous lesions can be difficult both for the radiologist and for the pathologist. Diagnosis is based on a combination of clinical, radiological and histological findings. While treatment of benign lesions does not require surgery, the only curative treatment for chondrosarcoma is resection. This article (1) emphasizes the update of the WHO classification and its diagnostic and clinical effects; (2) describes the imaging features of the various types of cartilaginous tumors, highlighting findings that can help differentiate benign from malignant lesions; (3) presents differential diagnoses; and (4) provides pathologic correlation. We attempt to offer valuable clues in the approach to this vast entity.

Magnetic Resonance Imaging-Guided vs Computed Tomography-Guided Stereotactic Body Radiotherapy for Prostate Cancer: The MIRAGE Randomized Clinical Trial.

Importance: Magnetic resonance imaging (MRI) guidance offers multiple theoretical advantages in the context of stereotactic body radiotherapy (SBRT) for prostate cancer. However, to our knowledge, these advantages have yet to be demonstrated in a randomized clinical trial. Objective: To determine whether aggressive margin reduction with MRI guidance significantly reduces acute grade 2 or greater genitourinary (GU) toxic effects after prostate SBRT compared with computed tomography (CT) guidance. Design, Setting, and Participants: This phase 3 randomized clinical trial (MRI-Guided Stereotactic Body Radiotherapy for Prostate Cancer [MIRAGE]) enrolled men aged 18 years or older who were receiving SBRT for clinically localized prostate adenocarcinoma at a single center between May 5, 2020, and October 1, 2021. Data were analyzed from January 15, 2021, through May 15, 2022. All patients had 3 months or more of follow-up. Interventions: Patients were randomized 1:1 to SBRT with CT guidance (control arm) or MRI guidance. Planning margins of 4 mm (CT arm) and 2 mm (MRI arm) were used to deliver 40 Gy in 5 fractions. Main Outcomes and Measures: The primary end point was the incidence of acute (≤90 days after SBRT) grade 2 or greater GU toxic effects (using Common Terminology Criteria for Adverse Events, version 4.03 [CTCAE v4.03]). Secondary outcomes included CTCAE v4.03-based gastrointestinal toxic effects and International Prostate Symptom Score (IPSS)-based and Expanded Prostate Cancer Index Composite-26 (EPIC-26)-based outcomes. Results: Between May 2020 and October 2021, 156 patients were randomized: 77 to CT (median age, 71 years [IQR, 67-77 years]) and 79 to MRI (median age, 71 years [IQR, 68-75 years]). A prespecified interim futility analysis conducted after 100 patients reached 90 or more days after SBRT was performed October 1, 2021, with the sample size reestimated to 154 patients. Thus, the trial was closed to accrual early. The incidence of acute grade 2 or greater GU toxic effects was significantly lower with MRI vs CT guidance (24.4% [95% CI, 15.4%-35.4%] vs 43.4% [95% CI, 32.1%-55.3%]; P = .01), as was the incidence of acute grade 2 or greater gastrointestinal toxic effects (0.0% [95% CI, 0.0%-4.6%] vs 10.5% [95% CI, 4.7%-19.7%]; P = .003). Magnetic resonance imaging guidance was associated with a significantly smaller percentage of patients with a 15-point or greater increase in IPSS at 1 month (6.8% [5 of 72] vs 19.4% [14 of 74]; P = .01) and a significantly reduced percentage of patients with a clinically significant (≥12-point) decrease in EPIC-26 bowel scores (25.0% [17 of 68] vs 50.0% [34 of 68]; P = .001) at 1 month. Conclusions and Relevance: In this randomized clinical trial, compared with CT-guidance, MRI-guided SBRT significantly reduced both moderate acute physician-scored toxic effects and decrements in patient-reported quality of life. Longer-term follow-up will confirm whether these notable benefits persist. Trial Registration: ClinicalTrials.gov Identifier: NCT04384770.

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies.

Excess body weight is frequently associated with low-grade inflammation. Evidence indicates a relationship between obesity and cancer, as well as with other diseases, such as diabetes and non-alcoholic fatty liver disease, in which inflammation and the actions of various adipokines play a role in the pathological mechanisms involved in these disorders. Leptin is mainly produced by adipose tissue in proportion to fat stores, but it is also synthesized in other organs, where leptin receptors are expressed. This hormone performs numerous actions in the brain, mainly related to the control of energy homeostasis. It is also involved in neurogenesis and neuroprotection, and central leptin resistance is related to some neurological disorders, e.g., Parkinson's and Alzheimer's diseases. In peripheral tissues, leptin is implicated in the regulation of metabolism, as well as of bone density and muscle mass. All these actions can be affected by changes in leptin levels and the mechanisms associated with resistance to this hormone. This review will present recent advances in the molecular mechanisms of leptin action and their underlying roles in pathological situations, which may be of interest for revealing new approaches for the treatment of diseases where the actions of this adipokine might be compromised.

Daratumumab-based therapies in transplant-ineligible patients with untreated multiple myeloma and hepatic dysfunction: A systematic review of subgroup analyses.

INTRODUCTION: There is subgroup analysis suggesting a lack of benefit of daratumumab use in multiple myeloma (MM) and hepatic disease (HD). The objectives of this study were to conduct a systematic review and interpretation of daratumumab-based regimen efficacy in transplant-ineligible patients with untreated MM and HD. METHODS: A systematic search in Pubmed® database about randomized clinical trials (RCTs) with subgroup analysis regarding hepatic function for overall survival (OS) or progression-free survival (PFS) were developed. Two methodologies were applied. One of them considered statistical interaction, prespecification, biological support and consistency of subgroup results. Second methodology was two-part validated tool: preliminary questions to reject subset analysis without minimal relevance, and a checklist relating a recommendation for applicability in clinical practice. RESULTS: It was included three records. About first methodology, statistical interaction among subgroups was found for PFS in one RCT. Subsets were prespecified in all RCTs. Biological support of efficacy differences could be reasonable. Inconsistent results were found. Second methology directly rejected applicability of subset analysis in two records. Checklist recommended "null" application of results in the remaining RCT. CONCLUSIONS: No consistent heterogeneity for daratumumab-based regimen efficacy was observed among subgroups regarding hepatic function in transplant-ineligible patients with untreated MM. Patients with normal hepatic function and HD could benefit from these treatments.

Clinical impact of del Nido cardioplegia in adult cardiac surgery: A prospective randomized trial.

OBJECTIVE: The study objective was to assess the benefits of del Nido cardioplegia compared with cold blood cardioplegia solution in terms of myocardial protection during adult cardiac surgery. METHODS: A total of 474 adult patients undergoing coronary artery bypass grafting, heart valve surgery, thoracic aortic surgery, or combined procedures were randomized to the del Nido cardioplegia group (n = 234) or the cold blood cardioplegia solution group (n = 240) after provided informed consent. The primary end points assessed inotropic support requirements, severe cardiovascular events, and troponin trend within the first 48 hours of intensive care unit stay. Reperfusion arrhythmias, aortic crossclamp and cardiopulmonary bypass times, and other clinical perioperative variables were considered as secondary end points. RESULTS: No statistically significant differences were found regarding postoperative inotropic support requirements or the incidence of severe cardiovascular events. The del Nido cardioplegia group showed a higher return to spontaneous sinus rhythm (P< .001), a lower number of defibrillation attempts (P< .001), and an earlier peak troponin value in the postoperative period. Peak blood glucose levels and intravenous insulin requirements were significantly lower in the del Nido cardioplegia group. We found no significant differences regarding aortic crossclamp or cardiopulmonary bypass time. We did observe a lower incidence of postoperative stroke in the del Nido cardioplegia group (2.6% vs 6.7%; P= .035). CONCLUSIONS: del Nido cardioplegia can be used safely and with comparable outcomes compared with traditional cardioplegia solutions. Additional advantages over glycemic control, reperfusion arrhythmias, and its comfortable redosing interval make del Nido an interesting alternative for myocardial protection in adult cardiac surgery. A significant decrease in postoperative stroke will require further research to shed light on the results of this study. VIDEO ABSTRACT.

Long-lasting effect of belantamab mafodotin in heavily pretreated multiple myeloma.

Belantamab mafodotin (BLMF) is an interesting therapeutic alternative for multiple myeloma (MM) patients pretreated with immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. Scientific evidence on BLMF provides immature data about progression-free survival and overall survival by short follow-up of patients with poor prognoses. Cases with long follow-ups could provide additional information about BLMF. This case reports a patient with MM treated with BLMF who had received nine previous lines of therapy with a follow-up of 11 months. No complete response was obtained. However, no disease progression was observed and the patient was still alive at the end of this work. BLMF showed manageable adverse effects. Our patient presented advanced disease, good functional status at the beginning of BLMF treatment, and elevated levels of lactate dehydrogenase during BLMF therapy. The influence of these last two factors was not evaluated in clinical trials. This relationship should be assessed more deeply in future studies.

Belantamab mafodotin for relapsed or refractory multiple myeloma.

Objective: Refractory multiple myeloma (MM) presents poor responses to therapies. New drugs for highly pretreated MM are a hope for this clinical context with limited treatment options. We developed a comparative commentary on the evidence about the use of belantamab mafodotin in heavily pretreated relapsed or refractory MM with respect to other therapies. Data sources: Regimen data were extracted from pivotal clinical trials. Data summary: Response rates were the main efficacy outcomes reported in trials. Overall response was achieved by approximately 30% of patients trated with belantamab mafodotin. Response rates of different regimens must be supported by more relevant data, such as overall survival or progression-free survival. Subgroups of patients with extramedullary disease and revised International Staging System III should be thoroughly evaluated in phase III comparative clinical trials with larger sample sizes. Belantamab mafodotin presented specific adverse events (visual disturbances and kerathopathies). Grade 3-4 adverse events involved high percentages of patients treated with the different schemes. The budgetary impact of different treatments for heavily pretreated refractory MM would be very high. Literature suggested increased efficiency of belantamab mafodotin versus chimeric antigen receptor T-cell therapies. Conclusions: Belantamab mafodotin and other regimens are promising drugs for MM, especially for triple-class refractory patients. Comparative studies are necessary to perform a reliable therapeutic positioning.

Clinical and pharmacoeconomic impact of subgroup analysis in onco-hematological patients.

Subgroup analysis evaluates a health intervention in subpopulations according to a characteristic or factor. It can be useful for generating new hypotheses or conducting new studies. However, subgroup analysis presents several limitations and it should be considered cautiously. The development of new onco-hematological drugs is accelerating in recent years and the impact of subgroup analysis on clinical decision-making is increasing. The interpretation of subgroup analyses can be controversial in some cases, negatively affecting patients and healthcare systems. This work is a review of the clinical and pharmacoeconomic impact of subgroup analysis in onco-hematological patients. The study describes some illustrative examples of inadequate interpretations about subset analysis: combination of pembrolizumab plus chemotherapy in lung cancer, inhibitors of cyclin-dependent kinases in breast cancer, daratumumab-based regimens in newly diagnosed multiple myeloma, combination of nivolumab with ipilimumab in melanoma and docetaxel in prostate cancer. Subgroup analysis can have a significant impact on the data selection for the development of studies; efficacy, safety, and convenience of treatments in onco-hematological patients; efficiency of therapies in health systems; and therapeutic positioning of antineoplastic drugs. There is a strong need to establish homogeneous criteria for the assessment of subgroup analysis and to develop new tools for its consideration.

Dosimetric impact of interfraction prostate and seminal vesicle volume changes and rotation: A post-hoc analysis of a phase III randomized trial of MRI-guided versus CT-guided stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: Interfraction volumetric changes/rotations in the prostate and proximal seminal vesicles (SVs) might compromise target coverage when tight margins are used for prostate stereotactic body radiotherapy (SBRT). We investigated on-board MRI images from MRI-guided SBRT to better understand this. MATERIALS AND METHODS: Twenty consecutive patients treated with MRI-guided prostate SBRT (40 Gy/5 fractions) enrolled on the MRI arm of a phase III randomized trial were included. A 2 mm isotropic margin was used for prostate and proximal SVPTV. Target volume, prostate dimensions, angles of the proximal SV on axial (angle α) and sagittal view (angle θ) were measured on a 0.35 T simulation MRI and five on-board pre-treatment MRIs. Dice coefficient of the targets and target dosimetry were calculated. RESULTS: All patients experienced an isotropic increase in prostate volume during SBRT (p = 0.0016): 0.1%, 9.0%, 12.1%, 15.1%, and 14.2% (median) at fractions 1-5, respectively, regardless of baseline volume, which was significantly reduced with neoadjuvant ADT (p = 0.0042). There was minimal interfraction rotation of prostate, however, considerable variations in proximal SV angle α (median 21.5°) and angle θ (median 17.6°) were seen. Median V100% was 97.5% and 87.1% for prostate and proximal SV CTV, respectively. V95%≥95% was achieved in 94% of fractions for the prostate and in 59% for proximal SV. CONCLUSION: Prostate volume consistently increased during SBRT. Interfraction prostatic rotation was minimal while rotation of the proximal SV was considerable. Prostate dosimetry was favorable, but online adaptive therapy may be indicated occasionally to account for prostatic swelling and in particular proximal SV rotations.

Outcome of Liver Transplants Using Donors After Cardiac Death With Normothermic Regional Perfusion.

BACKGROUND AND AIMS: The incorporation of normothermic regional perfusion (NRP) to donors after cardiac death (DCD) allows the recovery of liver grafts without the deleterious effects on graft survival the super-rapid technique may cause. The aim of the present report is to determine if the use of NRP in Maastricht type III DCD donors achieves short- and medium-term results comparable to donors after brain death (DBD). PATIENTS AND METHODS: This is an observational cohort study including 117 liver transplants executed between November 2016 and April 2021, divided into NRP (n = 39) and DBD (n = 78). RESULTS: Donors were younger in the NRP group (NRP 52 vs DBD 59.4 years; P < .005). Liver recipients in each study group were of similar age and severity of liver disease, although the predominant transplant indication in the NRP group was hepatocellular carcinoma. No differences in ischemia times were found. The incidence of early allograft disfunction and primary nonfunction was balanced between NRP and DBD. Eight patients required retransplant, all of them in the DBD group. No differences were found in biliary complications (NRP 12% vs DBD 5%; P = .104). Ischemic cholangiopathy affected a single DBD patient. Graft survival's Kaplan Meier curve shows a better outcome in the NRP group, although the difference did not reach significance (P = .075). CONCLUSIONS: The incorporation of perfusion machines, and specifically the NPR in situ, converts suboptimal liver grafts such as DCD into organs comparable to DBDs.

El triaje de las vacunas / Triagem vacinal / Vaccine triage

El proceso de vacunación está generando problemas muy similares a los que se plantearon al inicio de la pandemia debido tanto a la escasez de vacunas como a la implacable letalidad del virus. La celeridad con que avanzan los contagios está obligando a establecer criterios de triaje, pero de una naturaleza diferente a la propiamente hospitalaria. En efecto, el número de factores se ha incrementado, ya que no solo hay que tener en cuenta los recursos sanitarios, sino variables geoestratégicas y de equilibriosde poder a escala internacional. En un contexto completamente mercantilizado, los planes de vacunación están tratando de conciliar los principios éticos con la eficacia, en un difícil equilibrio no siempre resuelto satisfactoriamente. En el presente artículo analizaremos el proceso de implementación de las vacunas en Europa, comenzando por las características específicas de las primeras vacunas aprobadas hasta descender a los criterios de ordenación de la población en España.

The vaccination process is creating problems very similar to those that arose at the beginning of the pandemic due to both the shortage of vaccines and the relentless lethality of the virus. The speed with which the infections are progressing is forcing triage criteria to be established, but of a different nature from the hospital itself. Indeed, the number of variables has increased, since it is not only necessary to take into account health resources, but also geostrategic variables and international power balances. In a completely mercantilist context, vaccination plans are trying to reconcile ethical principles with efficacy, in a difficult balance not always resolved. In this article, we will analyze the vaccine implementation process in Europe, starting with the specific characteristics of the first approved vaccines until descending to the criteria for ordering the population in Spain.

O processo de vacinação está a criar problemas muito semelhantes aos que surgiram no início da pandemia, devido quer à falta de vacinas, quer à letalidade implacável do vírus. A rapidez com que as infeções progridem está a obrigar ao estabelecimento de critérios de triagem, mas de natureza diferente do próprio contexto hospitalar. De facto, o número de variáveis tem aumentado, uma vez que não é apenas necessário levar em conta os recursos da saúde, mas também as variáveis ​​geoestratégicas e os equilíbrios de poder internacionais. Num contexto totalmente comercializado, os planos de vacinação procuram conciliar os princípios éticos com a eficácia, num equilíbrio difícil nem sempre resolvido de forma satisfatória. Neste artigo, iremos analisar o processo de implementação de vacinas na Europa, partindo das características específicas das primeiras vacinas aprovadas até aos critérios de ordenação da população em Espanha.

Differential effects of the second SARS-CoV-2 mRNA vaccine dose on T cell immunity in naive and COVID-19 recovered individuals.

The rapid development of mRNA-based vaccines against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) led to the design of accelerated vaccination schedules that have been extremely effective in naive individuals. While a two-dose immunization regimen with the BNT162b2 vaccine has been demonstrated to provide a 95% efficacy in naive individuals, the effects of the second vaccine dose in individuals who have previously recovered from natural SARS-CoV-2 infection has not been investigated in detail. In this study, we characterize SARS-CoV-2 spike-specific humoral and cellular immunity in naive and previously infected individuals during and after two doses of BNT162b2 vaccination. Our results demonstrate that, while the second dose increases both the humoral and cellular immunity in naive individuals, COVID-19 recovered individuals reach their peak of immunity after the first dose. These results suggests that a second dose, according to the current standard regimen of vaccination, may be not necessary in individuals previously infected with SARS-CoV-2.

Hormone-sensitive lipase deficiency affects the expression of SR-BI, LDLr, and ABCA1 receptors/transporters involved in cellular cholesterol uptake and efflux and disturbs fertility in mouse testis.

Hormone-sensitive lipase (HSL) hydrolyse acylglycerols, cholesteryl and retinyl esters. HSL is a key lipase in mice testis, as HSL deficiency results in male sterility. The present work study the effects of the deficiency and lack of HSL on the localization and expression of SR-BI, LDLr, and ABCA1 receptors/transporters involved in uptake and efflux of cholesterol in mice testis, to determine the impact of HSL gene dosage on testis morphology, lipid homeostasis and fertility. The results of this work show that the lack of HSL in mice alters testis morphology and spermatogenesis, decreasing sperm counts, sperm motility and increasing the amount of Leydig cells and lipid droplets. They also show that there are differences in the localization of HSL, SR-BI, LDLr and ABCA1 in HSL+/+, HSL+/- and HSL-/- mice. The deficiency or lack of HSL has effects on protein and mRNA expression of genes involved in lipid metabolisms in mouse testis. HSL-/- testis have augmented expression of SR-BI, LDLr, ABCA1 and LXRß, a critical sterol sensor that regulate multiple genes involved in lipid metabolism; whereas LDLr expression decreased in HSL+/- mice. Plin2, Abca1 and Ldlr mRNA levels increased; and LXRα (Nr1h3) and LXRß (Nr1h2) decreased in testis from HSL-/- compared with HSL+/+; with no differences in Scarb1. Together these data suggest that HSL deficiency or lack in mice testis induces lipid homeostasis alterations that affect the cellular localization and expression of key receptors/transporter involved in cellular cholesterol uptake and efflux (SR-BI, LDRr, ABCA1); alters normal cellular function and impact fertility.

The PI-3-Kinase P110α Catalytic Subunit of T Lymphocytes Modulates Collagen-Induced Arthritis.

The phosphatidylinositol 3-kinase (PI3K) family of enzymes plays a determinant role in inflammation and autoimmune responses. However, the implication of the different isoforms of catalytic subunits in these processes is not clear. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease that entails innate and adaptive immune response elements in which PI3K is a potential hub for immune modulation. In a mouse transgenic model with T-cell-specific deletion of p110α catalytic chain (p110α-/-ΔT), we show the modulation of collagen-induced arthritis (CIA) by this isoform of PI3K. In established arthritis, p110α-/-ΔT mice show decreased prevalence of illness than their control siblings, higher IgG1 titers and lower levels of IL-6 in serum, together with decreased ex vivo Collagen II (CII)-induced proliferation, IL-17A secretion and proportion of naive T cells in the lymph nodes. In a pre-arthritis phase, at 13 days post-Ag, T-cell-specific deletion of p110α chain induced an increased, less pathogenic IgG1/IgG2a antibodies ratio; changes in the fraction of naive and effector CD4+ subpopulations; and an increased number of CXCR5+ T cells in the draining lymph nodes of the p110α-/-ΔT mice. Strikingly, T-cell blasts in vitro obtained from non-immunized p110α-/-ΔT mice showed an increased expression of CXCR5, CD44 and ICOS surface markers and defective ICOS-induced signaling towards Akt phosphorylation. These results, plus the accumulation of cells in the lymph nodes in the early phase of the process, could explain the diminished illness incidence and prevalence in the p110α-/-ΔT mice and suggests a modulation of CIA by the p110α catalytic chain of PI3K, opening new avenues of intervention in T-cell-directed therapies to autoimmune diseases.

Magnetic resonance imaging-guided stereotactic body radiotherapy for prostate cancer (mirage): a phase iii randomized trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is becoming increasingly used in treating localized prostate cancer (PCa), with evidence showing similar toxicity and efficacy profiles when compared with longer courses of definitive radiation. Magnetic resonance imaging (MRI)-guided radiotherapy has multiple potential advantages over standard computed tomography (CT)-guided radiotherapy, including enhanced prostate visualization (abrogating the need for fiducials and MRI fusion), enhanced identification of the urethra, the ability to track the prostate in real-time, and the capacity to perform online adaptive planning. However, it is unknown whether these potential advantages translate into improved outcomes. This phase III randomized superiority trial is designed to prospectively evaluate whether toxicity is lower after MRI-guided versus CT-guided SBRT. METHODS: Three hundred men with localized PCa will be randomized in a 1:1 ratio to SBRT using CT or MRI guidance. Randomization will be stratified by baseline International Prostate Symptom Score (IPSS) (≤15 or > 15) and prostate gland volume (≤50 cc or > 50 cc). Five fractions of 8 Gy will be delivered to the prostate over the course of fourteen days, with or without hormonal therapy and elective nodal radiotherapy (to a dose of 5 Gy per fraction) as per the investigator's discretion. The primary endpoint is the incidence of physician-reported acute grade ≥ 2 genitourinary (GU) toxicity (during the first 90 days after SBRT), as assessed by the CTCAE version 4.03 scale. Secondary clinical endpoints include incidence of acute grade ≥ 2 gastrointestinal (GI) toxicity, 5-year cumulative incidences of physician-reported late grade ≥ 2 GU and GI toxicity, temporal changes in patient-reported quality of life (QOL) outcomes, 5-year biochemical recurrence-free survival and the proportion of fractions of MRI-guided SBRT in which online adaptive radiotherapy is used. DISCUSSION: The MIRAGE trial is the first randomized trial comparing MRI-guided with standard CT-guided SBRT for localized PCa. The primary hypothesis is that MRI-guided SBRT will lead to an improvement in the cumulative incidence of acute grade ≥ 2 GU toxicity when compared to CT-guided SBRT. The pragmatic superiority design focused on an acute toxicity endpoint will allow an early comparison of the two technologies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04384770. Date of registration: May 12, 2020. https://clinicaltrials.gov/ct2/show/NCT04384770 PROTOCOL VERSION: Version 2.1, Aug 28, 2020.

Role of endocytosis and trans-endocytosis in ICOS costimulator-induced downmodulation of the ICOS Ligand.

The interaction between the T-lymphocyte costimulatory molecule ICOS and its ligand (ICOS-L) is needed for efficient immune responses, but expression levels are tightly controlled, as altered expression of ICOS or ICOS-L may lead to immunodeficiency, or favor autoimmune diseases and tumor growth. Using cells of mouse B cell lymphoma (M12.C3) and melanoma (B16), or hamster CHO cells transfected with various forms of mouse ICOS-L, and ICOS+ T cell lines, we show that, within minutes, ICOS induces significant downmodulation of surface ICOS-L that is largely mediated by endocytosis and trans-endocytosis. So, after interaction with ICOS+ cells, ICOS-L was found inside permeabilized cells, or in cell lysates, with significant transfer of ICOS from ICOS+ T cells to ICOS-L-expressing cells, and simultaneous loss of surface ICOS by the T cells. Data from cells expressing ICOS-L mutants show that conserved, functionally important residues in the cytoplasmic domain of mouse ICOS-L (Arg300 , Ser307 and Tyr308 ), or removal of ICOS-L cytoplasmic tail have minor effect on its internalization. Internalization was dependent on temperature, and was partially dependent on actin polymerization, the GTPase dynamin, protein kinase C, or the integrity of lipid rafts. In fact, a fraction of ICOS-L was detected in lipid rafts. On the other hand, proteinase inhibitors had negligible effects on early modulation of ICOS-L from the cell surface. Our data add a new mechanism of control of ICOS-L expression to the regulation of ICOS-dependent responses.