Explore the vast range of titles available.

A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer. Glioblastoma (GBM) is an immune cold tumour that is refractory to immunotherapy. Here, the authors identify molecular phenotypes of immune-suppressive and -promoting myeloid cells in GBM through single cell RNA sequencing and propose S100A4 as a regulator of immune suppressive T and myeloid cells in GBM.

The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications. There is an emerging interest in the use of mRNA therapeutics in cancer treatment, but their precise in vivo delivery remains a challenge. Here the authors develop IFN-γ mRNA-loaded small extracellular vesicles (sEVs) with CD64 overexpressed on their surface and demonstrate its efficacy in glioblastoma mouse models resistant to immunotherapy.

The CD47/signal regulatory protein α (SIRPα) axis, which functions as an inhibitory phagocytosis checkpoint, also serves as a key mediator in cancer immune evasion. Many cancers, including colorectal cancer (CRC), exploit the expression of CD47 to escape phagocytic clearance and activate the innate immune system. Previous work has indicated that distinct paradigms of posttranslational modifications mediate the regulatory mechanisms of the CD47/SIRPα axis. In this issue of the JCI, Li et al. show that neddylation, a ubiquitin-like modification, inactivates Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), a downstream target of this pathway. They further show that inhibition of SHP2 sensitizes CRC cells to immunotherapies to which they were previously resistant. Collectively, the results underscore the need for cotargeting SHP2 and immune checkpoints (e.g., programmed death 1 [PD1]) in CRC and possibly other immunotherapy-resistant tumors.

Myoclonus–dystonia syndrome (MDS) is an autosomal dominant disorder due to a mutated epsilon–sarcoglycan gene (SGCE) at the dystonia 11 (DYT11) locus on chromosome 7q21-31. ε-sarcoglycan has been identified in vascular smooth muscle and has been suggested to stabilize the capillary system. This report describes two siblings with MDS treated with bilateral globus pallidus interna deep brain stimulation. One patient had a history of bleeding following dental procedures, menorrhagia, and DBS placement complicated by intraoperative bleeding during cannula insertion. The other sibling endorsed frequent epistaxis. Subsequent procedures were typically treated perioperatively with platelet or tranexamic acid transfusion. Hematologic workup showed chronic borderline thrombocytopenia but did not elucidate a cause-specific platelet dysfunction or underlying coagulopathy. The bleeding history and thrombocytopenia observed suggest a potential link between MDS and platelet dysfunction. Mutated ε-sarcoglycan may destabilize the capillary system, thus impairing vasoconstriction and leading to suboptimal platelet aggregation.

Background Laser-interstitial thermal therapy (LITT) has been supported by some authors as an ablative treatment of glioblastoma multiforme (GBM). Although the effects of LITT have been modeled in vivo, the histologic effects in a clinical circumstance have not been described. We analyzed tissue from a patient who underwent LITT as primary treatment for GBM. Case presentation A 62-year-old male was diagnosed with a left temporal GBM and underwent LITT at an outside institution. Despite corticosteroid therapy, the patient was referred with increasing headache and acalculia associated with progressive peritumoral edema two weeks after LITT procedure. En bloc resection of the enhancing lesion and adjacent temporal lobe was performed with steroid-independent symptom resolution (follow-up, > 2 years). Histologic analysis revealed three distinct histologic zones concentrically radiating from the center of the treatment site. An acellular central region of necrosis (Zone 1) was surrounded by a rim of granulation tissue with macrophages (CD68) (Zone 2; mean thickness, 1.3 ± 0.3 mm [±S.D.]). Viable tumor cells (identified by Ki-67, p53 and Olig2 immunohistochemistry) were found (Zone 3) immediately adjacent to granulation tissue. The histologic volume of thermal tissue ablation/granulation was consistent with preoperative (pre-resection) magnetic resonance (MR)-imaging. Conclusion These findings are the first in vivo in humans to reveal that LITT causes a defined pattern of tissue necrosis, concentric destruction of tumor and tissue with viable tumor cells just beyond the zones of central necrosis and granulation. Furthermore, MR-imaging appears to be an accurate surrogate of tissue/tumor ablation in the early period (2 weeks) post-LITT treatment. Surgery is an effective strategy for patients with post-LITT swelling which does not respond to steroids.

Central venous occlusive disease secondary to chronic hemodialysis catheterization rarely progresses to encephalopathy, cerebral infarction, and/or hemorrhage. A 59-year-old male with 15 years of haemodialysis-dependent end-stage renal disease presented with acutely altered mental status, extensor rigidity with left hemiparesis and equal, but small and nonreactive pupils. Magnetic resonance imaging demonstrated infarction and cerebral edema. Cranial angiogram through right brachial artery injection revealed right subclavian vein opacification via a patent AV-fistula and retrograde flow to the right internal jugular vein and superior sagittal sinus secondary to occlusion of the brachiocephalic vein. All cerebral and right upper extremity venous drainage occurred via the contralateral venous outflow tract. Internal carotid artery injections revealed significant venous congestion. Despite successful angioplasty with stenting and resolution of venous flow reversal, the patient failed to recover neurologically. The devastating nature of the presented case emphasizes the need for frequent neurologic evaluation of such patients to avoid catastrophic cerebrovascular injury.

Background Prolactinomas represent the most common pituitary adenoma subtype, the majority of which are microprolactinomas. Dopamine agonists (DAs) remain the first-line intervention for microprolactinomas, however, many patients either cannot tolerate DAs or require lifelong therapy to maintain hormonal control. As endoscopic endonasal surgery (EES) continues to revolutionize the surgical management of sellar lesions, we sought to reassess the feasibility and efficacy of early surgical resection for microprolactinoma. Methods Retrospective chart review from 2010 to 2021 of adults who underwent EES for microprolactinoma was performed across three medical centers. Surgical failure was defined as a need to restart DAs, a serum prolactin level greater than 30ng/mL at last follow-up, tumor recurrence, or a need for reoperation. Results A total of 56 patients were identified with a mean age of 32.9 years and an average of 26.4 months of follow-up. The majority had been on DAs preoperatively (98.2%). The most common surgical indications were DA intolerance (73.2%), tumor unresponsiveness (19.6%), and desire for pregnancy (7.1%). Gross total resection was achieved in 51 (91.1%) cases. The overall surgical remission rate was approximately 70% with failures observed in 17 (30.4%) patients. Multivariate logistic regression identified subtotal resection as the only independent predictor of surgical failure ( p  = 0.038*). The most common postoperative complication was transient arginine vasopressin deficiency (AVP-D) (21.4%). There were no cases of permanent AVP-D, new visual deficits, or cerebrospinal fluid leak. Conclusions With a surgical remission rate of nearly 70%, EES represents a safe and viable alternative strategy to long-term DA treatment for microprolactinomas.

Abstract BACKGROUND The Preventable Shunt Revision Rate (PSRR) was recently introduced as a novel quality metric. OBJECTIVE To evaluate the PSRR across multiple centers and determine associated variables. METHODS Nine participating centers in North America provided at least 2 years of consecutive shunt operations. Index surgery was defined as new shunt implantation, or revision of an existing shunt. For any index surgery that resulted in a reoperation within 90-days, index surgery information (demographic, clinical, and procedural) was collected and a decision made whether the failure was potentially preventable. The 90-day shunt failure rate and PSRR were calculated per institution and combined. Bivariate analyses were performed to evaluate individual effects of each independent variable on preventable shunt failure followed by a final multivariable model using a backward model selection approach. RESULTS A total of 5092 shunt operations were performed; 861 failed within 90 days of index operation, resulting in a 16.9% combined 90-day shunt failure rate and 17.6% median failure rate (range, 8.7%-26.9%). Of the failures, 307 were potentially preventable (overall and median 90-day PSRR, 35.7% and 33.9%, respectively; range, 16.1%-55.4%). The most common etiologies of avoidable failure were infection (n = 134, 44%) and proximal catheter malposition (n = 83, 27%). Independent predictors of preventable failure (P < .05) were lack of endoscopy (odds ratio [OR] = 2.26), recent shunt infection (OR = 3.65), shunt type (OR = 2.06) and center. CONCLUSION PSRR is variable across institutions, but can be 50% or higher. While the PSRR may never reach zero, this study demonstrates that overall about a third of early failures are potentially preventable.