Sterile inflammation via TRPM8 RNA-dependent TLR3-NF-kB/IRF3 activation promotes antitumor immunity in prostate cancer.

Inflammation is a common condition of prostate tissue, whose impact on carcinogenesis is highly debated. Microbial colonization is a well-documented cause of a small percentage of prostatitis cases, but it remains unclear what underlies the majority of sterile inflammation reported. Here, androgen- independent fluctuations of PSA expression in prostate cells have lead us to identify a prominent function of the Transient Receptor Potential Cation Channel Subfamily M Member 8 (TRPM8) gene in sterile inflammation. Prostate cells secret TRPM8 RNA into extracellular vesicles (EVs), which primes TLR3/NF-kB-mediated inflammatory signaling after EV endocytosis by epithelial cancer cells. Furthermore, prostate cancer xenografts expressing a translation-defective form of TRPM8 RNA contain less collagen type I in the extracellular matrix, significantly more infiltrating NK cells, and larger necrotic areas as compared to control xenografts. These findings imply sustained, androgen-independent expression of TRPM8 constitutes as a promoter of anticancer innate immunity, which may constitute a clinically relevant condition affecting prostate cancer prognosis.

Cell Plasticity in a Mouse Model of Benign Prostate Hyperplasia Drives Amplification of Androgen-Independent Epithelial Cell Populations Sensitive to Antioxidant Therapy.

Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms. Although current medical treatments are unsatisfactory in many patients, the limited understanding of the mechanisms driving disease progression prevents the development of alternative therapeutic strategies. The probasin-prolactin (Pb-PRL) transgenic mouse recapitulates many histopathological features of human BPH. Herein, these alterations parallel urodynamic disturbance reminiscent of lower urinary tract symptoms. Single-cell RNA-sequencing analysis of Pb-PRL mouse prostates revealed that their epithelium mainly includes low-androgen signaling cell populations analogous to Club/Hillock cells enriched in the aged human prostate. These intermediate cells are predicted to result from the reprogramming of androgen-dependent luminal cells. Pb-PRL mouse prostates exhibited increased vulnerability to oxidative stress due to reduction of antioxidant enzyme expression. One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency. In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism, cell proliferation, and stemness features. ATT prevented the growth of organoids generated by sorted Pb-PRL basal and LSCmed cells, the two major BPH-associated, androgen-independent epithelial cell compartments. Taken together, these results support cell plasticity as a driver of BPH progression and therapeutic resistance to androgen signaling inhibition, and identify antioxidant therapy as a promising treatment of BPH.

Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients.

BACKGROUND: Allogenic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are potentially curative treatments for severe combined immunodeficiency (SCID). Late-onset posttreatment manifestations (such as persistent hepatitis) are not uncommon. OBJECTIVE: We sought to characterize the prevalence and pathophysiology of persistent hepatitis in transplanted SCID patients (SCIDH+) and to evaluate risk factors and treatments. METHODS: We used various techniques (including pathology assessments, metagenomics, single-cell transcriptomics, and cytometry by time of flight) to perform an in-depth study of different tissues from patients in the SCIDH+ group and corresponding asymptomatic similarly transplanted SCID patients without hepatitis (SCIDH-). RESULTS: Eleven patients developed persistent hepatitis (median of 6 years after HSCT or GT). This condition was associated with the chronic detection of enteric viruses (human Aichi virus, norovirus, and sapovirus) in liver and/or stools, which were not found in stools from the SCIDH- group (n = 12). Multiomics analysis identified an expansion of effector memory CD8+ T cells with high type I and II interferon signatures. Hepatitis was associated with absence of myeloablation during conditioning, split chimerism, and defective B-cell function, representing 25% of the 44 patients with SCID having these characteristics. Partially myeloablative retransplantation or GT of patients with this condition (which we have named as "enteric virus infection associated with hepatitis") led to the reconstitution of T- and B-cell immunity and remission of hepatitis in 5 patients, concomitantly with viral clearance. CONCLUSIONS: Enteric virus infection associated with hepatitis is related to chronic enteric viral infection and immune dysregulation and is an important risk for transplanted SCID patients with defective B-cell function.

The Day-To-Day Practice of MMR and MSI Assessment in Colorectal Adenocarcinoma: What We Know and What We Still Need to Explore.

BACKGROUND: The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination. MMR protein status is identified using immunohistochemistry. Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR. In colorectal cancer (CRC), MMR/MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy. SUMMARY: In this Review, we describe the challenges the practicing pathologist may face in relation to the assessment of MMR/MSI status and any open issues which still need to be addressed, focusing on pre-analytic issues, pitfalls in the interpretation, and technical aspects of the different assays. KEY MESSAGES: The current methods of detecting dMMR/MSI status have been optimized for CRCs, and whether these techniques can be applied to all tumor and specimen types is still not fully understood. Following the Food and Drug Administration (FDA), tissue/site agnostic drug approval of pembrolizumab for advanced/metastatic MSI tumors, MMR/MSI status in gastrointestinal tract is a common request from the oncologist. In this setting, several issues still need to be addressed, including criteria for sample adequacy.

CT renal arteriography as a novel imaging guidance for the percutaneous ablation of small renal tumors.

PURPOSE: To report procedural data and outcomes of a novel image guidance technique, CT renal arteriography (CTRA), performed to target and ablate small intraparenchymal renal tumors. MATERIALS AND METHODS: We retrospectively analyzed data of 2 patients undergoing CTRA-guided ablation for 3 renal intraparenchymal tumors, from February to March 2023. We previously evaluated tumor visibility with US/CEUS, and in all cases conspicuity was poor, whereas contrast-enhanced CT (CECT) clearly depicted all hypervascular nodules. Our primary endpoint was CTRA-guidance feasibility for renal ablation, defined as the precise probe deployment inside the target tumor. The secondary endpoint was CTRA-guided ablation technical success, intended as the inclusion of the whole tumor inside the necrotic volume, with 5 mm safety margins. RENAL scores, complications, procedural time, dose length product (DLP), serum creatinine variation and hospital stay length were also recorded. RESULTS: A confident deployment of the probe tip inside the nodule was accomplished in all 3 cases, with a 100% of correct targeting. We observed immediate technical success after all 3 ablations. The 3 nodules had a RENAL score <7 points, and we encountered no complications due to line placement or ablation. The average time from preablative to postablative CTRA was 54 min (50-58min), with a DLP of 3632mGy*cm (2807-4458mGy*cm). Serum creatinine didn't show a significant variation after the procedures; both patients were hospitalized for 2 days. CONCLUSION: Preliminary data showed that CTRA-guidance might provide unique advantages over conventional CECT-guidance to assist the ablation of small renal intraparenchymal tumor not visualized on US/CEUS.

US-guided percutaneous thrombin injection to treat non-femoral artery pseudoaneurysms: preliminary experience and review of the literature.

PURPOSE: To evaluate the clinical outcome of US-guided percutaneous thrombin injection in the treatment of non-femoral artery pseudoaneurysms (NFAP). MATERIALS AND METHODS: Among all pseudoaneurysms treated in our institution, we retrospectively collected NFAP embolized with percutaneous thrombin injections from January 1, 2015, to December 31, 2021. The embolization was prompted for an ongoing antiaggregating/anticoagulation therapy, NFAP optimal US visibility, or high surgery-related risks. Causes, location, size and neck of NFAP, complications, number of repeated treatments, clinical success and patients clinical conditions at discharge were annotated. The endpoint for clinical success was the resolution of NFAP at postprocedural imaging, with no resort to surgery. RESULTS: Eight consecutive patients (5 females, median age 73 years, range 46-84) underwent 16 procedures. Arterial damage was due to catheterization (3), CVC mispositioning (2), trauma, hemorrhagic diathesis and endoprosthesis endoleak. We treated humeral (2), subclavian (2), thyrocervical, anterior tibial, radial and pancreaticoduodenal arteries. Median pseudoaneurysm size was 530 mm2 (range 32-2400 mm2), with a thin (7/8) or non-visible (1/8) neck. No complications occurred. Clinical success was obtained in 7/8 patients (88%), with a single treatment in 4, multiple in 3 cases (4 embolizations, 3 and 2, respectively). One patient underwent surgical suture after the second failed attempt of percutaneous embolization. Seven patients were discharged in good clinical conditions; one died during hospitalization, due to the worsening of the underlying cardiac disease. CONCLUSIONS: Percutaneous US-guided thrombin injection to treat NFAP is feasible in selected cases, with rare complications. Clinical success is often reached, also by repeated injections.

Biliary complications in pediatric liver transplantation: findings of percutaneous transhepatic cholangiography in a large single-center cohort.

BACKGROUND: Although biliary complications after orthotopic liver transplantation represent a common source of morbidity and mortality, decreasing graft survival, consensus is lacking on their management in the pediatric population. OBJECTIVE: The aim of this study was to present the prevalence of such biliary complications and their interventional radiologic management with representative images. MATERIALS AND METHODS: This retrospective study reports our experience with percutaneous transhepatic cholangiography in the management of biliary complications after orthotopic liver transplantation in pediatric patients. This study enrolled all pediatric patients (<18 years old) who underwent percutaneous transhepatic cholangiography for the management of biliary complications after orthotopic liver transplantation at a tertiary care center between January 2010 and December 2020. Diagnosis of biliary complications and indication to perform percutaneous transhepatic cholangiography were based on clinical, laboratory or radiologic data. RESULTS: Among the 301 orthotopic liver transplantations, 78 (26%) developed biliary complications that were managed by interventional radiology: these included 52 (17.3%) biliary strictures, 19 (6.3%) bile leaks, 5 (1.7%) biliary stones, 1 (0.3%) iatrogenic biliary obstruction and 1 (0.3%) vanishing syndrome. The median time interval between orthotopic liver transplantation and the diagnosis of biliary complications was 6.0 years (interquartile range [IQR] 8.2 years). Percutaneous transhepatic cholangiography and biliary duct catheterization were successful in all cases, with low rates of complications that were variable among subgroups. CONCLUSION: A wide spectrum of biliary complications can occur after pediatric orthotopic liver transplantation. In this large single-center experience, we highlight the value of percutaneous transhepatic cholangiography in their diagnosis and management. Percutaneous treatments in pediatric patients are safe and effective, providing resolution or serving as a bridge to surgery, including re-transplantation.

TRPM8 protein expression in hormone naïve local and lymph node metastatic prostate cancer.

OBJECTIVE: Prostate cancer (PCa) is the second most common malignancy in men. Radiotherapy and surgery successfully control organ-confined tumors, although, locally advanced/high-risk PCa frequently progress to the metastatic stage of the disease, which is uncurable. Identification of novel strategies to improve the efficacy of standard clinical protocols is a primary need. Among the molecular targets of potential clinical interest recently highlighted by accurate preclinical studies, the TRPM8 cation channel is particularly promising. In this study, we aim at establishing a standardized immunohistochemistry protocol to evaluate TRPM8 expression in normal and pathological prostate tissues. METHODS: The specificity and sensitivity of TRPM8 antibody ACC-049 was validated in different human prostate cell lines by western blot and immunocytochemistry analyses. Expression of the TRPM8 channel in normal and pathological prostate tissue was evaluated by immunohistochemistry using a tissue microarray containing 58 cases of prostate adenocarcinomas and in primary and lymph nodes metastatic human PCa matched specimens. RESULTS: TRPM8 expression marks luminal epithelial cells in benign prostate tissue. In malignant lesions of the prostate, TRPM8 expression is frequently more abundant in advanced stages of the disease (PCa stage III/IV). Finally, lymph node metastases and matched primary tumors show similar amounts of the channel. CONCLUSIONS: Collectively, our results reinforce the importance of TRPM8 as prostate biomarker and emphasize the value of the channel as promising novel molecular target for the treatment of prostate adenocarcinoma.

Diagnostic Value of Global Cardiac Strain in Patients With Myocarditis.

BACKGROUND: Cardiac strain represents an imaging biomarker of contractile dysfunction. PURPOSE: The purpose of this study was to investigate the diagnostic value of cardiac strain obtained by feature-tracking cardiac magnetic resonance (MR) in acute myocarditis. MATERIALS AND METHODS: Cardiac MR examinations of 46 patients with myocarditis and preserved ejection fraction at acute phase and follow-up were analyzed along with cardiac MR of 46 healthy age- and sex-matched controls. Global circumferential strain and global radial strain were calculated for each examination, along with myocardial edema and late gadolinium enhancement, and left ventricle functional parameters, through manual contouring of the myocardium. Correlations were assessed using Spearman ρ. Wilcoxon and Mann-Whitney U test were used to assess differences between data. Receiver operating characteristics curves and reproducibility were obtained to assess the diagnostic role of strain parameters. RESULTS: Global circumferential strain was significantly lower in controls (median, -20.4%; interquartile range [IQR], -23.4% to -18.7%) than patients in acute phase (-18.4%; IQR, -21.0% to -16.1%; P = 0.001) or at follow-up (-19.2%; IQR, -21.5% to -16.1%; P = 0.020). Global radial strain was significantly higher in controls (82.4%; IQR, 62.8%-104.9%) than in patients during the acute phase (65.8%; IQR, 52.9%-79.5%; P = 0.001). Correlations were found between global circumferential strain and global radial strain in all groups (acute, ρ = -0.580, P < 0.001; follow-up, ρ = -0.399, P = 0.006; controls, ρ = -0.609, P < 0.001), and between global circumferential strain and late gadolinium enhancement only in myocarditis patients (acute, ρ = 0.035, P = 0.024; follow-up, ρ = 0.307, P = 0.038). CONCLUSIONS: Cardiac strain could potentially have a role in detecting acute myocarditis in low-risk acute myocarditis patients where cardiac MR is the main diagnosing technique.

Interactive tools for safety 4.0: virtual ergonomics and serious games in real working contexts.

This paper presents an innovative safety training method based on digital ergonomics simulations and serious games, which are games that focus on education. Digital ergonomics is intended to disseminate the culture of safety among workers, while serious games are used to train the operators on specific safety procedures and verify their skills. The results of the experimentation in a real industrial environment showed that, compared to the traditional training methodology, multimedia contents and quantitative ergonomic analyses improve the level of attention and the awareness of the workers about their own safety. However, serious games turned out to be promising training tools with regard to standard operating procedures that are usually difficult or dangerous to simulate in a real working scenario without stopping production. Practitioner summary: Digital ergonomics and serious games are used to disseminate the culture of safety among the workers and for safety training. Our results show that the proposed methodology improves the level of attention and provides a better feedback about the actual skills of the workers than the standard educational strategies. Abbreviations.

Association of Glutathione S-Transferase P-1 (GSTP-1) rs1695 polymorphism with overall survival in glioblastoma patients treated with combined radio-chemotherapy.

Glioblastoma (GBM) is the most frequent malignant primary brain tumor in adults and, despite recent advances, the prognosis for this cancer remains dismal. The aims of this study were to test the influence of XRCC1 rs25487, XRCC3 rs861539, XRCC3 rs1799794, RAD51 rs1801320 and GSTP-1 rs1695 single nucleotide polymorphisms on progression free survival (PFS) and overall survival (OS) in GBM patients treated with radiotherapy (RT) and temozolomide (TMZ). Fifty GBM patients treated with upfront radio-chemotherapy (RT 60 Gy/30 sessions; TMZ 75 mg/m2 during RT and 200 mg/m2 days 1 â†’ 5 every 28 days) were enrolled. Survival curves were calculated using the Kaplan-Meier method, and the log-rank test was used to evaluate differences between curves. A trend to a statistically significant association with PFS in univariate and multivariate COX regression analysis was found with GSTP-1 rs1695 polymorphism (p = 0.087 and p = 0.097 on univariate and multivariate analyses, respectively). Conversely, the same GSTP-1 rs1695 SNP revealed a statistically significant association with OS (p = 0.007 and p = 0.042 on univariate and multivariate analysis, respectively). Our pharmacogenetic prospective study suggests that GSTP-1 rs1695 genotypes can be associated with different OS in GBM patients treated with RT and TMZ.

Experimental analysis of intermittency in electrohydrodynamic instability.

The properties of turbulent electroconvective fluctuations generated in a nematic liquid crystal under the action of an external oscillating electric field are investigated. In particular, the spectral properties and the scaling behaviour of probability density functions (PDFs) of light intensity fluctuations are considered at different voltages. At intermediate voltage, in the weak turbulent regime, PDFs are Gaussian at large scales and show increasingly enhanced wings at smaller scales, recalling the typical signature of intermittency in isotropic fluid flows. When the voltage is increased, dynamical scattering regimes appear, characterized by increasing complexity. In order to get a quantitative estimate of intermittency, PDFs are modeled through the Castaing distribution, and structure functions are estimated in the framework of Extended Self-Similarity. Results support the generation of small-scale fluctuations through a fragmentation process of large-scale structures. The persistent anisotropic properties of the fluctuations are highlighted by the results.

Route to chaos and resonant triads interaction in a truncated rotating nonlinear shallow-water model.

The route to chaos and the phase dynamics of the large scales in a rotating shallow-water model have been rigorously examined through the construction of an autonomous five-mode Galerkin truncated system employing complex variables, useful in investigating how large/meso-scales are destabilized and how their dynamics evolves and transits to chaos. This investigation revealed two distinct transitions into chaotic behaviour as the level of energy introduced into the system was incrementally increased. The initial transition manifests through a succession of bifurcations that adhere to the established Feigenbaum sequence. Conversely, the subsequent transition, which emerges at elevated levels of injected energy, is marked by a pronounced shift from quasi-periodic states to chaotic regimes. The genesis of the first chaotic state is predominantly attributed to the preeminence of inertial forces in governing nonlinear interactions. The second chaotic state, however, arises from the augmented significance of free surface elevation in the dynamical process. A novel reformulation of the system, employing phase and amplitude representations for each truncated variable, elucidated that the phase components present a temporal piece-wise locking behaviour by maintaining a constant value for a protracted interval, preceding an abrupt transition characterised by a simple rotation of ±π, even as the amplitudes display chaotic behaviour. It was observed that the duration of phase stability diminishes with an increase in injected energy, culminating in the onset of chaos within the phase components at high energy levels. This phenomenon is attributed to the nonlinear term of the equations, wherein the phase components are introduced through linear combinations of triads encompassing disparate modes. When the locking durations vary across modes, the resultant dynamics is a stochastic interplay of multiple π phase shifts, generating a stochastic dynamic within the coupled phase triads, observable even at minimal energy injections.

Association between the morphological features of the central sulcus and the somatomotory representation: anatomo-functional evaluation of neuroplasticity through nTMS.

In recent years navigated transcranial magnetic stimulation (nTMS) has emerged as a useful tool for the preoperative mapping of brain cortical areas surrounding neoplastic tissues allowing for maximal safe tumor resection and minimizing new postoperative permanent neurological deficits. Three patients presenting with an intrinsic brain tumor (one metastasis from mammary carcinoma, one high-grade glioma, and one low-grade glioma) located within or in close relationship to the central sulcus were enrolled for this study. The MRI-based morphological and nTMS mapping of the central sulcus of the intact hemisphere was complemented by the examination of the contralateral region harboring the lesion. The findings were independently compared, in search of evidence of tumor-induced neuroplasticity and/or signs of parenchymal dislocation/infiltration caused by the tumor. An individual description of each mapping session is provided. Significant discrepancies were observed between morphological MRI and functional nTMS mapping in two patients, demonstrating a tumor-induced shift of distinct cortical areas controlling hand and/or facial movements. In the cases of gliomas, a lower MT was detected in the lesioned hemisphere, possibly due to increased electrical excitability caused by the tumor itself. The integration of MRI-based morphological mapping of the central sulcus with the detection of its somatomotor representations through nTMS can assist neurosurgeons when planning the resection of a motor-eloquent tumor, stratifying the risks of secondary neurological deficits. The combination of the two preoperative techniques is able to disclose tumor-induced neural plasticity subsequently guiding a more precise resection.

Multimodal Use of Contact Endoscopy in Neurosurgery: Case Series with Technical Note and Literature Review.

BACKGROUND: Originally adopted for the cytological screening of cervical and uterine cancer, contact endoscopy (CE) is now widely used in several fields of oncological surgery. The CE method, with magnification power up to 150x, was designed to enhance visualization and identify microscopic changes indicative of precancerous and cancerous lesions at early stages. In this pilot study, we evaluated the multimodal applications of CE during different endoscopic intracranial neurosurgical procedures. METHODS: Twenty patients with skull base lesions underwent surgery using different minimally invasive endoscopic approaches (endonasal, transorbital, and supraorbital). CE was used to distinguish the pathology from the surrounding healthy tissue by positioning the endoscope either in proximity or directly onto the target tissue. Special attention was given to the visualization of the margins of the lesion to differentiate compression/displacement from infiltration of the normal surrounding tissue. RESULTS: With its unprecedented range of magnification, CE could clearly identify the microvascular pattern and cytological architecture of a tissue not detectable by simple white light endoscopy, with no reported damage due to heat transmission or iatrogenic injuries. All the lesions diagnosed as "presumed neoplastic tissue" by CE were confirmed by histopathology. The most promising results were observed in surgeries for meningioma and pituitary adenoma, as these lesions exhibit distinctive microvascular networks. CONCLUSIONS: CE represents a new and effective technique for the in vivo identification of pathological microvascular and tissue features, allowing preservation of normal tissue during different endoscopic approaches. The use of CE could improve diagnostic accuracy and assist in intraoperative decision-making, becoming a key tool in various applications in neurosurgical field.

Complete pathological response to pembrolizumab in pretreated pancreatic acinar cell carcinoma.

BACKGROUND: Therapeutic approach used for pancreatic ductal adenocarcinoma is usually translated also for the rarer acinar counterpart, which shows a different mutational landscape nevertheless. While dMMR/MSI-H status is rare in the ductal histotype, it appears to be more prevalent in pancreatic acinar cell carcinoma (PACC). CASE PRESENTATION: We report the case of a patient with locally advanced MSI-H PACC in whom the treatment with the anti-PD-1 pembrolizumab, administered as third line, made possible surgical resection, achieving even an exceptional pathological complete response. CONCLUSIONS: Treatment of PACC should be tailored based on the peculiar molecular features that distinguish PACC from ductal adenocarcinoma. Evaluation of potentially therapeutically targetable alterations should be mandatory in case of PACC diagnosis.

Increased genomic instability and reshaping of tissue microenvironment underlie oncogenic properties of Arid1a mutations.

Oncogenic mutations accumulating in many chromatin-associated proteins have been identified in different tumor types. With a mutation rate from 10 to 57%, ARID1A has been widely considered a tumor suppressor gene. However, whether this role is mainly due to its transcriptional-related activities or its ability to preserve genome integrity is still a matter of intense debate. Here, we show that ARID1A is largely dispensable for preserving enhancer-dependent transcriptional regulation, being ARID1B sufficient and required to compensate for ARID1A loss. We provide in vivo evidence that ARID1A is mainly required to preserve genomic integrity in adult tissues. ARID1A loss primarily results in DNA damage accumulation, interferon type I response activation, and chronic inflammation leading to tumor formation. Our data suggest that in healthy tissues, the increased genomic instability that follows ARID1A mutations and the selective pressure imposed by the microenvironment might result in the emergence of aggressive, possibly immune-resistant, tumors.

VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation.

Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1ß and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome.

Anterior cervical corpectomy for the treatment of spondylotic myelopathy: results of a prospective double-armed study with a three-year follow-up.

BACKGROUND: Since the first description in the 1950s, cervical spondylotic myelopathy (CSM) has posed many challenges to neurosurgeons and spine surgeons. Direct comparison among different operative approaches has failed to produce valuable results due to either an insufficient number of enrolled patients or a lack of standardization of baseline conditions. This prospective double-armed non-randomized study with a 3-year follow-up involved 80 patients with degenerative cervical myelopathy surgically and conservatively treated. The primary aim was to determine the efficacy of corpectomy in mild-moderate and severe CSM and to compare the outcomes of conservative and surgical treatment. METHODS: Eighty patients were stratified into two arms, on the basis of the mJOA score: mild-moderate (mJOA ≥12) and severe myelopathy (mJOA score <12). Each arm was subdivided into two treatment groups (operative or conservative): A1, mild-moderate myelopathy treated with corpectomy; A2, mild-moderate myelopathy treated conservatively; B1, severe myelopathy treated with corpectomy; B2, severe cervical myelopathy treated conservatively. The clinical outcome was evaluated with the modified JOA score, timed 10-meter walk, Mehalic grade, motor evoked potentials, the SF-12, and further assessed by external observers blinded to the type of treatment. RESULTS: No significant differences in the recovery rates were found between the A1 and A2 groups at 6 months, although better results were recorded in the surgical groups (A1 and B1) at 12 months and at the final follow-up, as suggested by the significantly higher recovery rates. Multivariate analysis showed an inverse correlation between the duration of symptoms and the recovery rate (P<0.0001). Moreover, the preoperative timed 10-meter walk (P<0.004), the preoperative hypointensity on T1-weighted MR images (P<0.001), a higher Mehalic grade (P<0.02), the pre-treatment MEP (P<0.002), and the preoperative spinal canal diameter (P<0.004) significantly influenced the recovery rate. CONCLUSIONS: This prospective double-armed non-randomized study demonstrates that corpectomy is an effective and safe treatment, especially for severe forms of myelopathy. In mild-moderate conditions, a discrepancy between neurological improvement and expressed level of satisfaction was found. The present results also show that a multiparametric evaluation is crucial for proper patient selection for corpectomy.