Treg-targeted IL-2/anti-IL-2 complex controls graft-versus-host disease and supports anti-tumor effect in allogeneic hematopoietic stem cell transplantation.

Modulating an immune response in opposite directions represents the holy grail in allogeneic hematopoietic stem cell transplantation (allo-HSCT) to avoid insufficient reactivity of donor T cells and hematologic malignancy relapse while controlling the potential development of graft-versus-host disease (GVHD), in which donor T cells attack the recipient's tissues. IL-2/anti-IL-2 complexes (IL-2Cx) represent a therapeutic option to selectively accentuate or dampen the immune response. In dedicated experimental models of allo-HSCT, including also human cells injected in immunodeficient NSG mice, we evaluated side-by-side the therapeutic effect of two IL-2Cx designed either to boost regulatory T cells (Treg) or alternatively to activate effector T cells (Teff), on GVHD occurrence and tumor relapse. We also evaluated the effect of the complexes on the phenotype and function of immune cells in vivo. Unexpectedly, both pro-Treg and pro-Teff IL-2Cx prevented GVHD development. They both induced Treg expansion and reduced CD8+ T-cell numbers, compared to untreated mice. However, only mice treated with the pro-Treg IL-2Cx, showed a dramatic reduction of exhausted CD8+ T cells, consistent with a potent anti-tumor effect. When evaluated on human cells, pro-Treg IL-2Cx also preferentially induced Treg expansion in vitro and in vivo, while allowing the development of a potent anti-tumor effect in NSG mice. Our results demonstrate the clinical relevance of using a pro-Treg, but not a pro-Teff IL2Cx to modulate alloreactivity after HSCT, while promoting a graft-versus-leukemia effect.

Viral genomic, metagenomic and human transcriptomic characterization and prediction of the clinical forms of COVID-19.

COVID-19 is characterized by respiratory symptoms of various severities, ranging from mild upper respiratory signs to acute respiratory failure/acute respiratory distress syndrome associated with a high mortality rate. However, the pathophysiology of the disease is largely unknown. Shotgun metagenomics from nasopharyngeal swabs were used to characterize the genomic, metagenomic and transcriptomic features of patients from the first pandemic wave with various forms of COVID-19, including outpatients, patients hospitalized not requiring intensive care, and patients in the intensive care unit, to identify viral and/or host factors associated with the most severe forms of the disease. Neither the genetic characteristics of SARS-CoV-2, nor the detection of bacteria, viruses, fungi or parasites were associated with the severity of pulmonary disease. Severe pneumonia was associated with overexpression of cytokine transcripts activating the CXCR2 pathway, whereas patients with benign disease presented with a T helper "Th1-Th17" profile. The latter profile was associated with female gender and a lower mortality rate. Our findings indicate that the most severe cases of COVID-19 are characterized by the presence of overactive immune cells resulting in neutrophil pulmonary infiltration which, in turn, could enhance the inflammatory response and prolong tissue damage. These findings make CXCR2 antagonists, in particular IL-8 antagonists, promising candidates for the treatment of patients with severe COVID-19.

Effect of lethal total body irradiation on bone marrow chimerism, acute graft-versus-host disease, and tumor engraftment in mouse models: impact of different radiation techniques using low- and high-energy X-rays.

PURPOSE: Effects of X­ray energy levels used for myeloablative lethal total body irradiation (TBI) delivery prior to bone marrow transplantation (BMT) in preclinical mouse models were examined. MATERIALS AND METHODS: In mouse models, single-fraction myeloablative TBI at a lethal dose was delivered using two different X­ray devices, either low (160 kV cabinet irradiator) or high energy (6 MV linear accelerator), before semi-allogeneic hematopoietic stem-cell transplantation (HSCT) to ensure bone marrow (BM) chimerism, graft-versus-host disease (GVHD), and tumor engraftment. Recipient mice were clinically followed for 80 days after bone marrow transplantation (BMT). Flow cytometry was performed to assess donor chimerism and tumor engraftment in recipient mice. RESULTS: Both X­ray irradiation techniques delivered a 10 Gy single fraction of TBI, presented a lethal effect, and could allow near-complete early donor chimerism on day 13. However, low-energy irradiation increased T cells' alloreactivity compared to high-energy irradiation, leading to clinical consequences for GVHD and tumor engraftment outcomes. The alloreactive effect differences might be attributed to the distinction in inflammatory status of irradiated recipients at donor cell infusion (D0). Delaying donor cell administration (D1 after lethal TBI) attenuated T cells' alloreactivity and clinical outcomes in GVHD mouse models. CONCLUSION: Different X­ray irradiation modalities condition T cell alloreactivity in experimental semi-allogeneic BMT. Low-energy X­ray irradiator induces a post-TBI inflammatory burst and exacerbates alloreactive reactions. This technical and biological information should be considered in interpreting GVHD/ graft-versus-leukemia effect results in mice experimental models of BMT.

[GLIOBLASTOMA MULTIFORME AFTER STEREOTACTIC RADIOSURGERY TREATMENT FOR ARTERIO-VENOUS MALFORMATION].

INTRODUCTION: Stereotactic radiosurgery (SRS) is a minimally invasive option commissioned in the treatment of intracranial arteriovenous malformations (AVMs). As long-term follow-up data became available, some late adverse effects have been reported, including SRS-induced neoplasia. However, the exact incidence of this adverse effect is unknown. In this article we present and discuss the topic with an unusual case of a young patient who was treated with SRS for AVM and developed a malignant brain tumor.

Radiation therapy for triple-negative breast cancer: emerging role of microRNAs as biomarkers and radiosensitivity modifiers. A systematic review.

PURPOSE: Radiation therapy (RT) for triple-negative breast cancer (TNBC) treatment is currently delivered in the adjuvant setting and is under investigation as a booster of neoadjuvant treatments. However, TNBC radioresistance remains an obstacle, so new biomarkers are needed to select patients for any integration of RT in the TNBC therapy sequence. MicroRNAs (miRs) are important regulators of gene expression, involved in cancer response to ionizing radiation (IR) and assessable by tumor tissue or liquid biopsy. This systematic review aimed to evaluate the relationships between miRs and response to radiation in TNBC, as well as their potential predictive and prognostic values. METHODS: A thorough review of studies related to miRs and RT in TNBC was performed on PubMed, EMBASE, and Web of Science. We searched for original English articles that involved dysregulation of miRs in response to IR on TNBC-related preclinical and clinical studies. After a rigorous selection, 44 studies were chosen for further analysis. RESULTS: Thirty-five miRs were identified to be TNBC related, out of which 21 were downregulated, 13 upregulated, and 2 had a double-side expression in this cancer. Expression modulation of many of these miRs is radiosensitizing, among which miR-7, -27a, -34a, -122, and let-7 are most studied, still only in experimental models. The miRs reported as most influencing/reflecting TNBC response to IR are miR-7, -27a, -155, -205, -211, and -221, whereas miR-21, -33a, -139-5p, and -210 are associated with TNBC patient outcome after RT. CONCLUSION: miRs are emerging biomarkers and radiosensitizers in TNBC, worth further investigation. Dynamic assessment of circulating miRs could improve monitoring and TNBC RT efficacy, which are of particular interest in the neoadjuvant and the high-risk patients' settings.

Solid vs. cystic predominance in posterior fossa hemangioblastomas: implications for cerebrovascular risks and patient outcome.

BACKGROUND: Hemangioblastomas (HGBs) are highly vascular benign tumors, commonly located in the posterior fossa, and 80% of them are sporadic. Patients usually present with features of raised intracranial pressure and cerebellar symptoms. HGB can be classified as either mostly cystic or solids. Although the solid component is highly vascularized, aneurysm or hemorrhagic presentation is rarely described, having catastrophic results. METHODS: We identified 32 consecutive patients with posterior fossa HBG who underwent surgery from 2008 through 2020 at our medical center. Tumors were classified as predominantly cystic or solid according to radiological features. Resection was defined as gross total (GTR) or subtotal (STR). RESULTS: During the study period, 32 posterior fossa HGBs were resected. There were 26 cerebellar lesions and 4 medullar lesions, and in 2 patients, both structures were affected. Predominant cystic tumors were seen in 15 patients and solids in 17. Preoperative digital subtraction angiography (DSA) was performed in 8 patients with solid tumors, and 4 showed tumor-related aneurysms. Embolization of the tumors was performed in 6 patients, including the four tumor-related aneurysms. GTR was achieved in 29 tumors (91%), and subtotal resection in 3 (9%). Three patients had postoperative lower cranial nerve palsy. Functional status was stable in 5 patients (16%), improved in 24 (75%), and 3 patients (9%) deteriorated. One patient died 2 months after the surgery. Two tumors recurred and underwent a second surgery achieving GTR. The mean follow-up was 42.7 months (SD ± 51.0 months). CONCLUSIONS: Predominant cystic HGB is usually easily treated as the surgery is straightforward. Those with a solid predominance present a more complex challenge sharing features similar to arteriovenous malformations. Given the important vascular association of solid predominance HGB with these added risk factors, the preoperative assessment should include DSA, as in arteriovenous malformations, and endovascular intervention should be considered before surgery.

Endovascular thrombectomy is beneficial for functional nonagenarians - a multicenter cohort analysis.

INTRODUCTION: The use of endovascular thrombectomy (EVT) has dramatically increased in recent years. However, most existing studies used an upper age limit of 80 and data regarding the safety and efficacy of EVT among nonagenarians is still lacking. METHODS: 767 consecutive patients undergoing EVT for large vessel occlusion (LVO) in three participating centers were recruited into a prospective ongoing database. Demographic, clinical and imaging characteristics were documented. Statistical analysis was done to evaluate EVT outcome among nonagenarians compared to younger patients. RESULTS: The current analysis included 41 (5.4%) patients older than 90 years. Compared to younger patients, nonagenarians were more often female (78% versus 50.3%, p ≤ 0.001), had worse baseline mRS scores (2 [0-3] versus 0 [0-2], p < 0.001), higher rates of hypertension and hyperlipidemia and a higher admission NIHSS (20 [14-23] versus 16 [11-20], p < 0.001). No differences were found between groups regarding the involved vessel, stroke etiology, time from symptoms to door or symptoms to EVT, successful recanalization rates and hemorrhagic transformation rates. Nonagenarians had worse mRS at 90 days (5 [3-6] versus 3 [2-5], p = 0.001), similar discharge NIHSS (5 [1-11] versus 4 [1-11], p = 0.78) and higher mortality rates (36.6% versus 15.8%, p < 0.001). All nonagenarians with baseline mRS 4 have died within 90 days. 36.4% of nonagenarian patients with baseline MRS of 3 or less had favorable outcome. DISCUSSION: This study demonstrates that nonagenarian stroke patients with baseline mRS of 3 or less benefit from EVT with no significant difference in the rate of favorable outcome compared to octogenarians.

Cell surface nucleolin as active bait for nanomedicine in cancer therapy: a promising option.

Conventional chemotherapy used against cancer is mostly limited due to their non-targeted nature, affecting normal tissue and causing undesirable toxic effects to the affected tissue. With the aim of improving these treatments both therapeutically and in terms of their safety, numerous studies are currently being carried out using nanoparticles (NPs) as a vector combining tumor targeting and carrying therapeutic tools. In this context, it appears that nucleolin, a molecule over-expressed on the surface of tumor cells, is an interesting therapeutic target. Several ligands, antagonists of nucleolin of various origins, such as AS1411, the F3 peptide and the multivalent pseudopeptide N6L have been developed and studied as therapeutic tools against cancer. Over the last ten years or so, numerous studies have been published demonstrating that these antagonists can be used as tumor targeting agents with NPs from various origins. Focusing on nucleolin ligands, the aim of this article is to review the literature recently published or under experimentation in our research team to evaluate the efficacy and future development of these tools as anti-tumor agents.

Characteristics of cerebral sinus venous thrombosis in men.

OBJECTIVES: Cerebral sinus venous thrombosis (CSVT) is a rare stroke subtype that is more common in women, yet data regarding sex-specific characteristics are sparse. We aimed to study male-specific characteristics among patients with CSVT. MATERIALS & METHODS: Data of consecutive patients with CSVT, admitted to a single medical centre between 2005 and 2020, were retrospectively studied. Demographics, clinical presentations, radiological and outcome parameters were compared between male and female patients. Male patients were further divided into older and younger than 35 years old for additional comparisons. RESULTS: Out of 15,224 patients diagnosed with stroke, 150 patients (1%) presented with CSVT and 47 (31.3%) of them were males. Males had significantly higher rates of previous thrombotic events (22% vs. 7%, p = .009), malignancies (32% vs. 16%, p = .022) and Behcet's disease (22% vs. 2%, p < .001). Additionally, we found that malignancies were significantly more prevalent in older males (48% vs. 17%, p = .022), while Behcet's disease was more often found in younger patients (35% vs. 9%, p = .032). Additional age-related differences in disease characteristics among male patients included a higher frequencies of papilledema (42% vs. 13%, p = .028), and cortical vein thromboses (21% vs. 0% p = .021) observed in the younger men. CONCLUSIONS: There are important differences in risk factors for thrombosis between men and women with CSVT. Behcet's disease is common in younger men, while malignancies are major causes of CSVT in older men.

Post-stroke ASPECTS predicts outcome after thrombectomy.

PURPOSE: Infarct growth and final infarct volume are established outcome modifiers following endovascular thrombectomy (EVT) for patients with large vessel occlusion stroke (LVO). Simple techniques for final infarct volume measurement are lacking, and therefore, we tested whether post-EVT ASPECTS can be used for prognostic evaluation after EVT. METHODS: Infarct size at baseline was measured in a prospective cohort of patients with LVO that underwent EVT with the ASPECTS score on admission non-contrast CT. Final infarct size was assessed with a post-EVT ASPECTS (ASPECTS-POST) obtained from a follow-up CT 24-72 h post-EVT. The best performing ASPECTS-POST was chosen based on comparisons of different thresholds. Outcome measures included survival rates and modified Rankin Score at 90 days. RESULTS: A total of 272 patients were included and 166 of them had an ASPECTS-POST ≥ 7. ASPECTS-POST ≥ 7 was associated with increased likelihood of favorable outcome at 90 days (67% vs. 21%, p < 0.001) with sensitivity, specificity, and positive and negative predictive values of 86%, 58%, 61%, and 85%, respectively. On multivariate analysis, ASPECTS-POST ≥ 7 was found to be a significant modifier of favorable outcome (Odds Ratio [OR] 6.2, 95% confidence intervals [CI] 3.1-12.4) and survival (OR 5.8 95% CI 2.4-14.3). CONCLUSION: ASPECTS can be rapidly and easily obtained from the post-EVT NCCT and ASPECTS-POST ≥ 7 correlates with good outcome.

Impact of carotid tortuosity on outcome after endovascular thrombectomy.

BACKGROUND AND OBJECTIVES: Endovascular thrombectomy (EVT) is efficacious in patients with large vessel occlusion stroke (LVO). We explored whether internal carotid (ICA) tortuosity increases the technical difficulty of EVT thereby lowering the chances of successful recanalization and favorable outcomes. PATIENTS AND METHODS: Consecutive patients with LVO and patent ICAs who underwent EVT were included. Carotid tortuosity was determined on pre-EVT CTA and classified by raters blinded to outcomes into: type 1-straight ICA trunk and type 2-severe tortuosity potentially impeding adequate catheter placement. Thrombolysis in cerebral infarction (TICI) 2b-3 was considered successful recanalization, and 90-day-modified Rankin Scale ≤ 2 was considered favorable functional outcome. RESULTS: Among 302 patients (mean age 70 ± 15, median NIHSS 17), 53% had type 1, and 47% type 2 tortuosity. Overall, 85% had successful recanalization. Patients with type 2 tortuosity were significantly older (p < 0.0001) and less frequently achieved successful recanalization (80% vs. 90%; p = 0.019) but had similar outcomes compared with those without tortuosity. On regression analysis, marked tortuosity was associated with lower chances of successful recanalization (OR 0.43 95% CI 0.20-0.92) but had no effect on clinical outcomes. CONCLUSIONS: Carotid tortuosity does not appear to impact the likelihood of favorable functional outcome but may influence recanalization.

Traumatic cerebral dural sinus vein thrombosis/stenosis in pediatric patients-is anticoagulation necessary?

INTRODUCTION: Cerebral dural vein thrombosis/stenosis (CDVT/S) is a condition that affects the venous drainage of the brain. Risk factors and causes associated with CDVT/S include systemic risk factors that cause hypercoagulability, or local factors such as head trauma. While consensus is that non-traumatic sinus vein thrombosis should be treated with anticoagulation therapy, treatment of patients with TBI-induced CDVT is not yet established. METHODS: Retrospective review of clinical data of pediatric patients presented to our medical center from July 2017 to August 2020. Inclusion criteria were age, birth to 18 years, admission due to head trauma, head CT scan with positive traumatic findings, and follow-up in our clinic. Exclusion criteria were a normal head CT on admission and failure to follow-up. Data regarding demographics, clinical presentation, imaging findings, treatment, and status on follow-up were recorded. Study protocol was approved by our institutional ethics committee. RESULTS: One hundred sixty-two patients were enrolled. Falling accident occurred in 90.1%, a minority suffered from direct head trauma or gunshot wound. Of the patients, 95.1% suffered from mild TBI. Forty-two percent suffered from an associated intracranial injury. Fourteen cases with CDVT were included in the cohort. Linear fractures were significantly correlated with CDVT. Additionally, occipital/suboccipital fractures, associated intracranial injury, and proximity of injury to the sinus were correlated with CDVT. From this group, 12 were treated conservatively; one patient was treated surgically due to EDH. All patients with CDVT were neurologically intact at discharge. Only one patient was treated with therapeutic dose of LMWH. A total of 86.7% of patients with CDVT who were treated conservatively had full recanalization on follow-up imaging. Four patients had CDVS; all were neurologically intact at admission and discharge, and all were treated conservatively and had full recanalization on follow-up. DISCUSSION: Treatment with ACT is established in pediatric CDVT but not in the sub-group of TBI. While ACT prevents progression of thrombosis, it might cause worsening of extra-axial hemorrhage. In our study, no clinical deterioration was noted with expectant management; thus, we present an algorithm for diagnosis and treatment of trauma-induced CDVT/S in children with frequent clinical and radiologic imaging while avoiding anticoagulation. CONCLUSION: In most cases, anticoagulation therapy is not necessary in traumatic CDVT/S. Initial expectant management in children is safe. However, each case should be evaluated individually and further studies should be performed.

Superficial Temporal Artery-Middle Cerebral Artery Microvascular Bypass: Its Role in Treatment of Patients with Moyamoya Disease, Cerebral Aneurysms, and Vascular Occlusive Disease.

BACKGROUND: Superficial temporal artery-middle cerebral artery microvascular bypass (STA-MCA MVB) is an important strategy for the management of selected patients OBJECTIVES: To present our 19-year experience with STA-MCA MVB METHODS: Data for consecutive patients who underwent STA-MCA MVB from 2000­2019 due to moyamoya/moyamoya-like disease, complex intracranial aneurysms, or intractable brain ischemia due to internal carotid artery or MCA occlusive disease with repeated ischemic events were retrospectively analyzed under a waiver of informed consent. Key surgical steps and the important role of neuroendovascular interventions are presented. Surgical results and late outcomes were analyzed RESULTS: The study included 32 patients (17 women [53%], 15 men [47%]), mean age 42.94 years (range 16­66). The patients underwent 37 STA-MCA MVB procedures during the study period: 22 with moyamoya/moyamoya-like disease (69%) underwent 27 surgeries (five bilateral); 7 patients with complex aneurysms (22%) and 3 patients with vascular occlusive disease (9%) underwent unilateral bypass. Five of seven aneurysms were treated with coiling or flow-diverter stent implant prior to bypass surgery; two were clipped during the bypass procedure. There were no surgical complications, no perioperative mortality, and no death from complications related to neurovascular disease at late follow-up. Transient neurological deficits following 7/37 surgeries (19%) resolved with no permanent neurologic sequelae. Transient ischemic attacks occurred only in the immediate postoperative period in four patients (11%) CONCLUSIONS: In specific cases, STA-MCA MVB is a feasible and clinically effective procedure. It is important to preserve this technique in the surgical armamentarium

The TNF/TNFR2 signaling pathway is a key regulatory factor in endothelial progenitor cell immunosuppressive effect.

BACKGROUND: Endothelial progenitor cells (EPCs) are non-differentiated endothelial cells (ECs) present in blood circulation that are involved in neo-vascularization and correction of damaged endothelial sites. Since EPCs from patients with vascular disorders are impaired and inefficient, allogenic sources from adult or cord blood are considered as good alternatives. However, due to the reaction of immune system against allogenic cells which usually lead to their elimination, we focused on the exact role of EPCs on immune cells, particularly, T cells which are the most important cells applied in immune rejection. TNFα is one of the main activators of EPCs that recognizes two distinct receptors. TNFR1 is expressed ubiquitously and its interaction with TNFα leads to differentiation and apoptosis, whereas, TNFR2 is expressed predominantly on ECs, immune cells and neural cells and is involved in cell survival and proliferation. Interestingly, it has been shown that different immunosuppressive cells express TNFR2 and this is directly related to their immunosuppressive efficiency. However, little is known about immunological profile and function of TNFR2 in EPCs. METHODS: Using different in-vitro combinations, we performed co-cultures of ECs and T cells to investigate the immunological effect of EPCs on T cells. We interrupted in the TNFα/TNFR2 axis either by blocking the receptor using TNFR2 antagonist or blocking the ligand using T cells derived from TNFα KO mice. RESULTS: We demonstrated that EPCs are able to suppress T cell proliferation and modulate them towards less pro-inflammatory and active phenotypes. Moreover, we showed that TNFα/TNFR2 immune-checkpoint pathway is critical in EPC immunomodulatory effect. CONCLUSIONS: Our results reveal for the first time a mechanism that EPCs use to suppress immune cells, therefore, enabling them to form new immunosuppressive vessels. Furthermore, we have shown the importance of TNFα/TNFR2 axis in EPCs as an immune checkpoint pathway. We believe that targeting TNFR2 is especially crucial in cancer immune therapy since it controls two crucial aspects of tumor microenvironment: 1) Immunosuppression and 2) Angiogenesis. Video Abstract. (MP4 46355 kb).

STAT5B: A Differential Regulator of the Life and Death of CD4+ Effector Memory T Cells.

Understanding the control of Ag restimulation-induced T cell death (RICD), especially in cancer immunotherapy, where highly proliferating T cells will encounter potentially large amounts of tumor Ags, is important now more than ever. It has been known that growth cytokines make T cells susceptible to RICD, but the precise molecular mediators that govern this in T cell subsets is unknown until now. STAT proteins are a family of transcription factors that regulate gene expression programs underlying key immunological processes. In particular, STAT5 is known to favor the generation and survival of memory T cells. In this study, we report an unexpected role for STAT5 signaling in the death of effector memory T (TEM) cells in mice and humans. TEM cell death was prevented with neutralizing anti-IL-2 Ab or STAT5/JAK3 inhibitors, indicating that STAT5 signaling drives RICD in TEM cells. Moreover, we identified a unique patient with a heterozygous missense mutation in the coiled-coil domain of STAT5B that presented with autoimmune lymphoproliferative syndrome-like features. Similar to Stat5b-/- mice, this patient exhibited increased CD4+ TEM cells in the peripheral blood. The mutant STAT5B protein dominantly interfered with STAT5-driven transcriptional activity, leading to global downregulation of STAT5-regulated genes in patient T cells upon IL-2 stimulation. Notably, CD4+ TEM cells from the patient were strikingly resistant to cell death by in vitro TCR restimulation, a finding that was recapitulated in Stat5b-/- mice. Hence, STAT5B is a crucial regulator of RICD in memory T cells in mice and humans.

Control of Humoral Response in Renal Transplantation by Belatacept Depends on a Direct Effect on B Cells and Impaired T Follicular Helper-B Cell Crosstalk.

Generation of de novo donor-specific antibodies (dnDSAs) after renal transplant is recognized as the leading cause of late transplant failure. Hence, the optimal immunosuppressive strategies to limit dnDSA development need to be defined. Recent clinical trials using the novel costimulatory blockade agent CTLA4-Ig (Belatacept) have shown that kidney transplant recipients (KTRs) treated with Belatacept have better graft survival and function and a lower proportion of dnDSAs than control-treated KTRs. Mechanisms involved in the control of humoral responses by Belatacept remain to be investigated. Here, we analyzed the effect of Belatacept on different steps of the B cell-mediated response in humans. In vitro, Belatacept reduced plasmablast differentiation, Ig production, and the expression of the major transcription factor involved in plasma cell function, Blimp-1, in a T cell-independent manner. Moreover, Belatacept induced activation of the STAT3 transcription factor in stimulated B cells and reduced the expression of CD86. Additionally, Belatacept blocked CD28-mediated activation of T follicular helper cells (Tfhs) in an autologous Tfh-memory B cells model. We then validated these observations in KTRs treated with Belatacept, who had a reduced proportion of blood effector B cells and activated Tfh (PD1+ICOS+) compared with control-treated KTRs. Our in vitro and in vivo results suggest that Belatacept modulates B cell function directly and at the level of B cell-Tfh interaction. These mechanisms likely account for the optimal control of humoral responses observed in KTRs treated with Belatacept.

Number of stentriever passes and outcome after thrombectomy in stroke.

BACKGROUND AND PURPOSES: Stroke secondary to emergent large vessel occlusions (ELVO) involving the anterior circulation can be treated with intravenous tissue plasminogen activator (IV-tPA) or thrombectomy. Data regarding the influence of the number of stentriever passes needed for vessel recanalization on outcome is lacking. PATIENTS AND METHODS: We prospectively accrued data on consecutive patients with ELVO that were treated with thrombectomy. Procedural details including the number of stentriever passes needed to achieve vessel recanalization and clot length were collected. Functional outcome was determined with the modified Rankin Scale (mRS) at 90 days post stroke with mRS ≤ 2 considered favorable outcome. Data on demographics, risk factors, stroke severity, survival, and occurrence of symptomatic intracranial hemorrhage (sICH) was also collected. RESULTS: On univariate analysis more than one pass needed to achieve recanalization impacted survival and functional outcome after 90 days as did age, stroke severity and collateral and reperfusion status. On multivariate logistic regression the number of passes needed to achieve revascularization (OR: 10.0, 95% CI: 2.28-43.94, P = 0.002), age (OR: 0.90, 95% CI: 0.84-0.96, P = 0.001) and collateral status (OR: 7.90, 95% CI: 1.87-33.35, P = 0.005) remained significant modifiers for favorable outcome. On logistic regression the only variable associated with the need to perform more than a single stentriever pass was time from symptom onset to target vessel recanalization (OR: 1.007, 95% CI: 1.002-1.012). CONCLUSIONS: The number of passes needed to achieve target vessel recanalization modifies outcome after thrombectomy and successful recanalization after a single pass is associated with favorable outcome.

Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells.

Therapeutic CD4(+)Foxp3(+) natural regulatory T cells (Tregs) can control experimental graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) by suppressing conventional T cells (Tconvs). Treg-based therapies are currently tested in clinical trials with promising preliminary results in allo-HCT. Here, we hypothesized that as Tregs are capable of modulating Tconv response, it is likely that the inflammatory environment and particularly donor T cells are also capable of influencing Treg function. Indeed, previous findings in autoimmune diabetes revealed a feedback mechanism that renders Tconvs able to stimulate Tregs by a mechanism that was partially dependent on tumor necrosis factor (TNF). We tested this phenomenon during alloimmune response in our previously described model of GVHD protection using antigen specific Tregs. Using different experimental approaches, we observed that control of GVHD by Tregs was fully abolished by blocking TNF receptor type 2 (TNFR2) or by using TNF-deficient donor T cells or TNFR2-deficient Tregs. Thus, our results show that Tconvs exert a powerful modulatory activity on therapeutic Tregs and clearly demonstrate that the sole defect of TNF production by donor T cells was sufficient to completely abolish the Treg suppressive effect in GVHD. Importantly, our findings expand the understanding of one of the central components of Treg action, the inflammatory context, and support that targeting TNF/TNFR2 interaction represents an opportunity to efficiently modulate alloreactivity in allo-HCT to either exacerbate it for a powerful antileukemic effect or reduce it to control GVHD.

Increased Risk for Unfavorable Outcome in Patients with Pre-Existing Disability Undergoing Endovascular Therapy.

INTRODUCTION: Most studies evaluating endovascular therapy (EVT) for stroke only included patients without pre-existing disabilities. However, in real life many patients have pre-existing disabilities, and whether they can benefit from EVT remains unknown. METHODS: Patients with emergent large vessel occlusions undergoing EVT were prospectively enrolled. Patients with no or mild pre-existing disabilities (modified Rankin Scale [mRS], 0-2) were compared with patients presenting with pre-existing moderate disability (mRS ≥ 3). Baseline demographics and risk factors, stroke severity (studied with the National Institutes of Health Stroke Scale [NIHSS]), imaging data including pretreatment Alberta Stroke Program Early Computerized Tomography Score (ASPECTS) and ASPECTS collateral scores, as well as procedure-related variables were accrued. Unfavorable outcome was defined as mRS ≥ 4 at day 90. RESULTS: Of 131 enrolled patients, 108 had a baseline mRS of 2 or lower, and 23 had a prestroke mRS score of 3 or higher. Patients with pre-existing mRS scores of 3 or higher were significantly older (80.3 ± 10 versus 66.9 ± 13.7; P = .001) and more often had previous strokes (39% versus 16%; P = .02). Patients with mRS scores of 3 or higher were more likely to have poor outcomes or death (odds ratio [OR], 4.4; 95% confidence interval [CI], 1.3-15.0). Of the 23 patients with pre-existing moderate disability, 8 (35%) maintained their previous degree of disability. On multivariate analysis, age (OR, .92; 95% CI, .88-.97; P = .001), admission NIHSS (OR, .92; 95% CI, .85-.99; P = .042) and pretreatment ASPECTS (OR, 6.4; 95% CI, 1.4-29.5; P = .017) remained significant modifiers of favorable outcome. DISCUSSION AND CONCLUSIONS: Patients with pre-existing moderate disabilities have higher chances of sustaining unfavorable outcomes despite EVT. Nevertheless, some patients maintain the same level of moderate disabilities, and therefore, patients with pre-existing moderate disabilities should not be excluded from EVT.

Clinical and angioarchitectural factors influencing the endovascular approach to galenic dural arteriovenous fistulas in adults: case series and review of the literature.

BACKGROUND: Galenic dural arteriovenous fistulas (DAVF) are rare; however, they are the most frequent type of DAVF to manifest aggressive clinical behavior and usually represent a diagnostic and therapeutic challenge for clinicians. METHODS: We retrospectively reviewed clinical and imaging data of patients managed with neuroendovascular techniques for the treatment of galenic DAVFs from 2000 to 2016. We searched the 2000-2016 English-language literature for papers discussing neuroendovascular management of galenic DAVFs, with or without companion surgical procedures. RESULTS: Five patients were treated for galenic DAVFs during the study period (four males; mean age, 61 years). Three presented with progressive neurological deterioration due to venous congestion, two with acute intracranial hemorrhage. Three were treated by staged transarterial embolization procedures (three procedures in two, four procedures in one); two underwent a single transvenous embolization procedure. Four out of five fistulas were completely occluded. All patients improved clinically; the patient whose fistula was partially occluded remains angiographically stable at 2-year follow-up. Six reports describing 17 patients are reviewed. Embolization was performed via transvenous approach in 1/17 and transarterial approach in 16/17 with additional open surgery in 9/16. The trend toward the use of transarterial approaches is based primarily on advances on embolization techniques that allow better and more controllable penetration of the embolizing agents with improved clinical and angiographic results, as well as the technical complexity of the transvenous approach. CONCLUSIONS: Although transarterial embolization is the preferred endovascular route for the management of most galenic DAVFs, selected cases can be successfully treated by transvenous approach.