Longitudinal characterisation of B and T-cell immune responses after the booster dose of COVID-19 mRNA-vaccine in people with multiple sclerosis using different disease-modifying therapies.

BACKGROUND: The decline of humoral response to COVID-19 vaccine led to authorise a booster dose. Here, we characterised the kinetics of B-cell and T-cell immune responses in patients with multiple sclerosis (PwMS) after the booster dose. METHODS: We enrolled 22 PwMS and 40 healthcare workers (HCWs) after 4-6 weeks from the booster dose (T3). Thirty HCWs and 19 PwMS were also recruited 6 months (T2) after the first dose. Antibody response was measured by anti-receptor-binding domain (RBD)-IgG detection, cell-mediated response by an interferon (IFN)-γ release assay (IGRA), Th1 cytokines and T-cell memory profile by flow cytometry. RESULTS: Booster dose increased anti-RBD-IgG titers in fingolimod-treated, cladribine-treated and IFN-ß-treated patients, but not in ocrelizumab-treated patients, although antibody titres were lower than HCWs. A higher number of fingolimod-treated patients seroconverted at T3. Differently, T-cell response evaluated by IGRA remained stable in PwMS independently of therapy. Spike-specific Th1-cytokine response was mainly CD4+ T-cell-mediated, and in PwMS was significantly reduced (p<0.0001) with impaired IL-2 production compared with HCWs at T3. In PwMS, total Th1 and IFN-γ CD4+ T-cell responders to spike protein were increased from T2 to T3.Compared with HCWs, PwMS presented a higher frequency of CD4+ and CD8+ terminally differentiated effector memory cells and of CD4+ effector memory (TEM) cells, independently of the stimulus suggesting the association of this phenotype with MS status. CD4+ and CD8+ TEM cell frequency was further increased at T3 compared with T2. CONCLUSIONS: COVID-19 vaccine booster strengthens humoral and Th1-cell responses and increases TEM cells in PwMS.

An epigenetic mechanism for over-consolidation of fear memories.

Excessive fear is a hallmark of anxiety disorders, a major cause of disease burden worldwide. Substantial evidence supports a role of prefrontal cortex-amygdala circuits in the regulation of fear and anxiety, but the molecular mechanisms that regulate their activity remain poorly understood. Here, we show that downregulation of the histone methyltransferase PRDM2 in the dorsomedial prefrontal cortex enhances fear expression by modulating fear memory consolidation. We further show that Prdm2 knock-down (KD) in neurons that project from the dorsomedial prefrontal cortex to the basolateral amygdala (dmPFC-BLA) promotes increased fear expression. Prdm2 KD in the dmPFC-BLA circuit also resulted in increased expression of genes involved in synaptogenesis, suggesting that Prdm2 KD modulates consolidation of conditioned fear by modifying synaptic strength at dmPFC-BLA projection targets. Consistent with an enhanced synaptic efficacy, we found that dmPFC Prdm2 KD increased glutamatergic release probability in the BLA and increased the activity of BLA neurons in response to fear-associated cues. Together, our findings provide a new molecular mechanism for excessive fear responses, wherein PRDM2 modulates the dmPFC -BLA circuit through specific transcriptomic changes.

Sleep Efficiency and Naturalistically-Observed Social Behavior Following Marital Separation: The Critical Role of Contact with an Ex-partner.

Marital disruption is associated with increased risk for a range of poor health outcomes, including disturbed sleep. This report examines trajectories of actigraphy-assessed sleep efficiency following marital separation as well as the extent to which daily social behaviors and individual differences in attachment explain variability in these trajectories over time. One hundred twenty-two recently-separated adults (N = 122) were followed longitudinally for three assessment periods over five months. To objectively assess daily social behaviors and sleep efficiency, participants wore the Electronically Activated Recorder (EAR) during the day (for one weekend at each assessment period) and an actiwatch at night (for seven days at each assessment period). Greater time spent with an ex-partner, as assessed by the EAR, was associated with decreased sleep efficiency between participants (p = .003). Higher attachment anxiety was also associated with decreased sleep efficiency (p = .03), as was the EAR-observed measure of "television on." The latter effect operated both between (p = .004) and within participants (p = .005). Finally, study timepoint moderated the association between EAR-observed measure of "television on" and sleep efficiency (p = .007). The current findings deepen our understanding of sleep disturbances following marital separation and point to contact with an ex-partner and time spent with the television on as behavioral markers of risk.

Efficacy and Safety of Ethylene-Vinyl Alcohol (EVOH) Copolymer-Based Non-Adhesive Liquid Embolic Agents (NALEAs) in Transcatheter Arterial Embolization (TAE) of Acute Non-Neurovascular Bleeding: A Multicenter Retrospective Cohort Study.

Background and Objectives: Transcatheter arterial embolization (TAE) is part of the daily practice of most interventional radiologists worldwide. The ideal liquid embolic agent is far from being identified. Non-adhesive liquid embolic agents (NALEA) harden from the outside to the inside, resulting in deep penetration, known as "magma-like" progression, which permits a more distal embolization with good control of the embolic material. This multicenter retrospective cohort study aims to assess the efficacy, feasibility and safety of transcatheter arterial embolization (TAE) with ethylene-vinyl alcohol (EVOH)-based NALEAs (Onyx and Squid) in acute bleeding outside of the neurovascular area. Materials and Methods: This study is a multicenter analysis of retrospectively collected data of consecutive patients who had undergone, from January 2015 to December 2022, transcatheter arterial embolization with non-adhesive EVOH-based agents in the setting of acute non-neurovascular bleeding. Results: Fifty-three patients underwent transcatheter arterial embolization for acute non-neurovascular bleeding. Eight (15.1%) procedures were performed in patients with coagulopathy. The most used concentration of EVOH-based NALEAs was 34 (i.e., 8%), with a mean dose of 0.5 (±0.3) mL. The mean CT-to-groin time, the mean procedure time, the mean CT-to-embolization time and the mean fluoroscopy time were 22.9 (±12.4) min, 27.5 (±7) min, 50.3 (±13.1) min and 7.5 (±2.8) min, respectively. Technical success was achieved in all cases with a 96.2% clinical success rate. Complications were recorded in six (11.3%) patients. No statistically significant differences were observed between the group of patients with coagulopathy and the group of patients without coagulopathy in terms of efficacy and safety endpoints. Conclusions: Transcatheter arterial embolization (TAE) performed with non-adhesive EVOH-based embolic agents is an effective, feasible and safe strategy for the management of acute non-neurovascular bleeding, even in the subgroup of patients with coagulopathy.

Transcatheter Arterial Embolization (TAE) of Cancer-Related Bleeding.

Background and Objectives: Roughly 10% of cancer patients experience an episode of bleeding. The bleeding severity can range from occasional trivial bleeds to major bleeding. The treatment for the bleeding may vary, depending on the clinical condition and anatomical site, and may include various strategies, among which TAE is a cornerstone of major bleeding management. However, the existing literature on tumor hemorrhages is inconsistent. The objective of this multicenter retrospective cohort study was to evaluate the effectiveness and safety of arterial embolization in the treatment of tumor hemorrhages in patients with solid cancers. Materials and Methods: The data for patients with solid cancers undergoing TAE for the management of tumor hemorrhages from January 2020 to May 2023 were gathered. Results: A total of 92 patients with cancer-related bleeding were treated between January 2020 and May 2023. No bleeding was detected by X-ray angiography (XA) in 12 (13%) cases; therefore, a blind embolization was performed. The most common bleeding site was the liver (21.7%). A total of 66 tumor hemorrhages were spontaneous. The most commonly used embolic agent was polyvinyl alcohol (PVA) particles (30.4%). Technical success was achieved in 82 (89.1%) cases, with an 84.8% clinical success rate related to 14 cases of rebleeding. Proximal embolization was performed for 19 (20.7%) patients. Complications were recorded for 10 (10.9%) patients. The 30-day bleeding-related mortality was 15.2%. The technical success, clinical success, proximal embolization rate, and 30-day rebleeding were worse in the subset of patients undergoing TAE with coils. Conclusions: Transcatheter arterial embolization (TAE) represents a viable and potentially life-saving therapeutic approach in the management of tumor hemorrhages, demonstrating a notable effectiveness and safety. The TAE of bleeding tumors using coils resulted in a higher rate of non-superselective proximal embolization, with a trend toward lower clinical success rates and higher rebleeding episodes.

A Multicenter Retrospective Cohort Study Evaluating the Clinical Outcomes of Patients with Coagulopathy Undergoing Transcatheter Arterial Embolization (TAE) for Acute Non-Neurovascular Bleeding.

Background and Objectives: Transcatheter arterial embolization (TAE) is the mainstay of treatment for acute major hemorrhage, even in patients with coagulopathy and spontaneous bleeding. Coagulopathy is associated with worsening bleeding severity and higher mortality and clinical failure rates. Furthermore, some unanswered questions remain, such as the definition of coagulopathy, the indication for TAE or conservative treatment, and the choice of embolic agent. This study aims to assess the efficacy and safety of TAE for spontaneous non-neurovascular acute bleeding in patients with coagulopathy. Materials and Methods: This study is a multicenter analysis of retrospectively collected data of consecutive patients with coagulopathy who had undergone, from January 2018 to May 2023, transcatheter arterial embolization for the management of spontaneous hemorrhages. Results: During the study interval (January 2018-May 2023), 120 patients with coagulopathy underwent TAE for spontaneous non-neurovascular acute bleeding. The abdominal wall was the most common bleeding site (72.5%). The most commonly used embolic agent was polyvinyl alcohol (PVA) particles or microspheres (25.0%), whereas coils and gelatin sponge together accounted for 32.5% of the embolic agents used. Technical success was achieved in all cases, with a 92.5% clinical success rate related to 9 cases of rebleeding. Complications were recorded in 12 (10%) patients. Clinical success was significantly better in the group of patients who underwent correction of the coagulopathy within 24 h of TAE. Conclusions: Transcatheter arterial embolization (TAE) is effective and safe for the management of acute non-neurovascular bleeding in patients with coagulopathy. Correction of coagulopathy should not delay TAE and vice versa, as better clinical outcomes were noted in the subgroup of patients undergoing correction of coagulopathy within 24 h of TAE.

Transcatheter Arterial Embolization (TAE) in the Management of Bleeding in the COVID-19 Patient.

Background and Objectives: Increasing attention is being paid to the coagulation disorders associated with SARS-CoV-2 infection. Bleeding accounts for 3-6% of COVID-19 patient deaths, and is often a forgotten part of the disease. The bleeding risk is enhanced by several factors, including spontaneous heparin-induced thrombocytopenia, thrombocytopenia, the hyperfibrinolytic state, the consumption of coagulation factors, and thromboprophylaxis with anticoagulants. This study aims to assess the efficacy and safety of TAE in the management of bleeding in COVID-19 patients. Materials and Methods: This multicenter retrospective study analyzes data from COVID-19 patients subjected to transcatheter arterial embolization for the management of bleeding from February 2020 to January 2023. Results: Transcatheter arterial embolization was performed in 73 COVID-19 patients for acute non-neurovascular bleeding during the study interval (February 2020-January 2023). Coagulopathy was observed in forty-four (60.3%) patients. The primary cause of bleeding was spontaneous soft tissue hematoma (63%). A 100% technical success rate was recorded; six cases of rebleeding resulted in a 91.8% clinical success rate. No cases of non-target embolization were observed. Complications were recorded in 13 (17.8%) patients. The efficacy and safety endpoints did not differ significantly between the coagulopathy and non-coagulopathy groups. Conclusions: Transcatheter Arterial Embolization (TAE) is an effective, safe and potentially life-saving option for the management of acute non-neurovascular bleeding in COVID-19 patients. This approach is effective and safe even in the subgroup of COVID-19 patients with coagulopathy.

Endovascular Treatment of Visceral Artery Pseudoaneurysms with Ethylene-Vinyl Alcohol (EVOH) Copolymer-Based Non-Adhesive Liquid Embolic Agents (NALEAs).

Background and Objectives: Treatment of visceral artery pseudoaneurysms (VAPs) is always indicated regardless of their diameters, as their risk of rupture is significantly higher than that of visceral artery aneurysms. The invasiveness of surgery and its associated complications have led to a shift in favor of radiological interventions as the initial treatment of choice. However, there are still some unanswered questions on endovascular treatment of VAPs regarding the optimal endovascular technique and the efficacy and safety outcomes. The purpose of this multicenter study was to retrospectively evaluate the effectiveness and safety of endovascular treatment of visceral pseudoaneurysms using Ethylene-Vinyl Alcohol (EVOH) Copolymer-Based Non-Adhesive Liquid Embolic Agents (NALEAs). Materials and Methods: Consecutive patients who underwent endovascular embolization with EVOH-based NALEAs for visceral artery pseudoaneurysms between January 2018 and June 2023 were retrospectively evaluated. Results: 38 embolizations were performed. Technical success was achieved in all patients. The clinical success rate was high (92.1% overall), with no significant differences between ruptured and unruptured VAPs (p = 0.679). Seven patients (18.4%) experienced procedure-related complications, related to one case of non-target embolization, four splenic abscesses due to end-organ infarction, and two femoral pseudoaneurysms. The rates of procedure-related complications, end-organ infarction, and vascular access-site complications did not significantly differ between ruptured and unruptured VAPs (p > 0.05). Conclusions: Both ruptured and unruptured visceral pseudoaneurysms can be effectively and safely treated with NALEA-based endovascular embolization. We suggest considering the use of NALEAs, particularly in specific clinical cases that highlight their advantages, including patients with coagulopathy, fragile vessels, and embolization targets that are located at a considerable distance from the microcatheter tip and are otherwise difficult to reach.

Laparoscopic splenic artery aneurysmectomy with ICG guided partial splenectomy: alternative approach.

We herein report the case of a voluminous splenic artery aneurysm (SAA) diagnosed in a 48 year-old Caucasian male patient. After endovascular treatment failure, considering the volumetric aneurysm increase and recurrent symptoms, a laparoscopic splenic artery aneurysmectomy with partial splenectomy guided by indocyanine green fluorescence (ICG) was performed. This conservative strategy leads to save a spleen volume of about 10 cm3 to avoid postsplenectomy thrombocytosis and infections, potential immunodeficiency and overwhelming postsplenectomy infection syndrome (OPSS) and to preserve pancreatic vascularization preventing distal pancreas injuries.

Combination of radiation therapy for brain metastasis and anti-PD-1/PD-L1 treatment in non-small cell lung cancer: two cases and review of the literature.

Lung cancer is the most frequent cause of cancer-related death worldwide and is usually diagnosed in advanced stages. Among those, approximately 7.4% of non-small cell lung cancer (NSCLC) patients will have brain metastasis (BM) at presentation, and 25-30% will develop BM during the course of their disease. To date, patients with BMs are increasingly considered for combined treatment using systemic immune checkpoint inhibition (ICI) and cranial radiation therapy (RT); yet, there is limited data regarding the safety of this approach. Here, we report two cases of NSCLC patients treated with two different types of cranial RT and ICIs.

Stress-induced escalation of alcohol self-administration, anxiety-like behavior, and elevated amygdala Avp expression in a susceptible subpopulation of rats.

Comorbidity between alcohol use and anxiety disorders is associated with more severe symptoms and poorer treatment outcomes than either of the conditions alone. There is a well-known link between stress and the development of these disorders, with post-traumatic stress disorder as a prototypic example. Post-traumatic stress disorder can arise as a consequence of experiencing traumatic events firsthand and also after witnessing them. Here, we used a model of social defeat and witness stress in rats, to study shared mechanisms of stress-induced anxiety-like behavior and escalated alcohol self-administration. Similar to what is observed clinically, we found considerable individual differences in susceptibility and resilience to the stress. Both among defeated and witness rats, we found a subpopulation in which exposure was followed by emergence of increased anxiety-like behavior and escalation of alcohol self-administration. We then profiled gene expression in tissue from the amygdala, a key brain region in the regulation of stress, alcohol use, and anxiety disorders. When comparing "comorbid" and resilient socially defeated rats, we identified a strong upregulation of vasopressin and oxytocin, and this correlated positively with the magnitude of the alcohol self-administration and anxiety-like behavior. A similar trend was observed in comorbid witness rats. Together, our findings provide novel insights into molecular mechanisms underpinning the comorbidity of escalated alcohol self-administration and anxiety-like behavior.

Activation of Peripheral Blood Mononuclear Cells and Leptin Secretion: New Potential Role of Interleukin-2 and High Mobility Group Box (HMGB)1.

Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1ß from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM.

Percutaneous microwave ablation of uterine fibroids: correlation between shrinkage and trend symptoms.

PURPOSE: To assess a correlation between the shrinkage of the fibroid and the course of the symptoms. MATERIAL AND METHODS: Fourteen patients with symptomatic uterine leiomyomas (mean fibroid volume: 111.45 cm3) underwent percutaneous microwave ablation. Contrast-enhanced MRI follow-up was performed before and after treatment to evaluate the volume shrinkage. Two scores obtained from the Uterine Fibroids Symptom and Quality of Life questionnaire were used to perform a clinical follow-up to evaluate the symptoms and the quality of life at baseline, and at 3, 6 and 12 months after treatment. RESULTS: All patients were treated, no complications occurred. During a mean MR follow-up of 8.1 months we observed shrinkage of the fibroids in all patients (mean 70.3 cm3). During 12 months clinical follow-up, we observed a significant improvement of symptoms and an excellent improvement of quality of life (p < .001). CONCLUSION: Uterine fibroids percutaneous microwave ablation is a safe tool to obtain a significant improvement in quality of life for all the patients of our cohort.

CD16-158-valine chimeric receptor T cells overcome the resistance of KRAS-mutated colorectal carcinoma cells to cetuximab.

KRAS mutations hinder therapeutic efficacy of epidermal growth factor receptor (EGFR)-specific monoclonal antibodies cetuximab and panitumumab-based immunotherapy of EGFR+ cancers. Although cetuximab inhibits KRAS-mutated cancer cell growth in vitro by natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), KRAS-mutated colorectal carcinoma (CRC) cells escape NK cell immunosurveillance in vivo. To overcome this limitation, we used cetuximab and panitumumab to redirect Fcγ chimeric receptor (CR) T cells against KRAS-mutated HCT116 colorectal cancer (CRC) cells. We compared four polymorphic Fcγ-CR constructs including CD16158F -CR, CD16158V -CR, CD32131H -CR, and CD32131R -CR transduced into T cells by retroviral vectors. Percentages of transduced T cells expressing CD32131H -CR (83.5 ± 9.5) and CD32131R -CR (77.7 ± 13.2) were significantly higher than those expressing with CD16158F -CR (30.3 ± 10.2) and CD16158V -CR (51.7 ± 13.7) (p < 0.003). CD32131R -CR T cells specifically bound soluble cetuximab and panitumumab. However, only CD16158V -CR T cells released high levels of interferon gamma (IFNγ = 1,145.5 pg/ml ±16.5 pg/ml, p < 0.001) and tumor necrosis factor alpha (TNFα = 614 pg/ml ± 21 pg/ml, p < 0.001) upon incubation with cetuximab-opsonized HCT116 cells. Moreover, only CD16158V -CR T cells combined with cetuximab killed HCT116 cells and A549 KRAS-mutated cells in vitro. CD16158V -CR T cells also effectively controlled subcutaneous growth of HCT116 cells in CB17-SCID mice in vivo. Thus, CD16158V -CR T cells combined with cetuximab represent useful reagents to develop innovative EGFR+KRAS-mutated CRC immunotherapies.

Long-term therapy with Bevacizumab in a young patient affected by NF2. Stop or continue treatment? An update of a case report and review of the literature.

Neurofibromatosis type 2 (NF2) is an autosomal dominant condition caused by pathogenic variants in the NF2 gene. To date, cytotoxic chemotherapy has no established role in the treatment of NF-2. Historical case reports of malignant schwannomas have documented responses to chemotherapies with cyclophosphamide, vincristine and doxorubicin, in patients who develop pulmonary metastases. Recently, several studies proposed the use of anti-HER2, anti-EGFR, anti-platelet-derived growth factor receptors. As reported in our previous review of the literature, vascular endothelial growth factor (VEGF) and its receptor VEGFR-1 have been detected in schwannomas with the best results. We described the case of a young patient with NF2 treated for long time with Bevacizumab. Here, we report the update of the previous case report.

Percutaneous cervical discectomy: retrospective comparison of two different techniques.

AIM: To compare clinical success and patient satisfaction of percutaneous cervical nucleoplasty (PCN) and percutaneous cervical discectomy (PCD) in contained cervical disc herniation treatment. MATERIALS AND METHODS: We retrospectively identified 50 consecutive patients in our institution: 24 underwent the PCD treatment and 26 patients were treated by the PCN procedure. All patients complained of radicular pain with or without neck pain; diagnosis of contained cervical disc herniation was obtained by MRI; all patients had received conservative therapy which did not result in symptom improvement. Exclusion from our series consisted of patients who had undergone previous surgery at the indicated level, or those with myelopathy, or those in whom more than a sole herniation was treated in the same session. Overall procedure time, fluoroscopy time, radiation dose and complications were recorded. The MacNab scale score was used to assess clinical success in terms of pain relief at 2- and 6-month follow-up. After 4-6 months, a cervical MRI was obtained in 24 patients. RESULTS: Neither major nor minor complications were reported. Regarding patient satisfaction, overall median modified MacNab score was excellent both at 2 and 6 months after treatment. No significant statistical difference was found in mean modified MacNab score at 2 and 6 months among patients grouped by treatment choice (p = 0.319 and 0.847, respectively); radiation dose was inferior in PCN group than in PCD, with no significant statistical difference. CONCLUSION: PCD and PCN were found to be safe and effective in terms of pain relief in contained cervical herniation treatment.

Percutaneous microwave ablation of renal angiomyolipomas in tuberous sclerosis complex to improve the quality of life: preliminary experience in an Italian center.

AIM: To evaluate efficacy, safety and quality of life of the patients with renal angiomyolipomas (AMLs) associated with tuberous sclerosis complex (TSC) treated with percutaneous microwave ablation (MWA). MATERIALS AND METHODS: Nine patients (7 females and 2 males; mean age 27.6 years, range 23-34), with 10 renal AMLs with a mean size of 6.3 cm (range 4.5-8.5) were treated with image-guided percutaneous MWA. Indications for treatment were the risk of rupture/hemorrhage due to size greater than 4 cm and symptomatology; in one case, a previous hemorrhage was the indication for treatment. During follow-up, the volume of the ablated AMLs and its relationship with the relief of symptoms were registered. Technical and clinical success, safety, and quality of life (QOL) were evaluated in a mean follow-up of 9 months (range 3-12). RESULTS: Technical success was obtained in all cases. Clinical success was obtained in all cases; the volume of the ablated AMLs was not related with symptoms relief; all patients referred a significant improvement in their QOL, with a regularization of daily activities. There were no major procedural complications or delayed adverse events. A small self-limited post-procedural subcapsular hematoma was registered. Post-ablation syndrome was registered in 5 cases and was self-limited in all cases. CONCLUSIONS: Symptoms relief, lower risk of hemorrhage and a normalized QOL were obtained in all patients with a safe and mini-invasive procedure.