Predictors of salvage therapy for parasagittal meningiomas treated with primary surgery, radiosurgery, or surgery plus adjuvant radiotherapy.

OBJECTIVE: Parasagittal meningiomas (PM) are treated with primary microsurgery, radiosurgery (SRS), or surgery with adjuvant radiation. We investigated predictors of tumor progression requiring salvage surgery or radiation treatment. We sought to determine whether primary treatment modality, or radiologic, histologic, and clinical variables were associated with tumor progression requiring salvage treatment. METHODS: Retrospective study of 109 consecutive patients with PMs treated with primary surgery, radiation (RT), or surgery plus adjuvant RT (2000-2017) and minimum 5 years follow-up. Patient, radiologic, histologic, and treatment data were analyzed using standard statistical methods. RESULTS: Median follow up was 8.5 years. Primary treatment for PM was surgery in 76 patients, radiation in 16 patients, and surgery plus adjuvant radiation in 17 patients. Forty percent of parasagittal meningiomas in our cohort required some form of salvage treatment. On univariate analysis, brain invasion (OR: 6.93, p < 0.01), WHO grade 2/3 (OR: 4.54, p < 0.01), peritumoral edema (OR: 2.81, p = 0.01), sagittal sinus invasion (OR: 6.36, p < 0.01), sagittal sinus occlusion (OR: 4.86, p < 0.01), and non-spherical shape (OR: 3.89, p < 0.01) were significantly associated with receiving salvage treatment. On multivariate analysis, superior sagittal sinus invasion (OR: 8.22, p = 0.01) and WHO grade 2&3 (OR: 7.58, p < 0.01) were independently associated with receiving salvage treatment. There was no difference in time to salvage therapy (p = 0.11) or time to progression (p = 0.43) between patients receiving primary surgery alone, RT alone, or surgery plus adjuvant RT. Patients who had initial surgery were more likely to have peritumoral edema on preoperative imaging (p = 0.01). Median tumor volume was 19.0 cm3 in patients receiving primary surgery, 5.3 cm3 for RT, and 24.4 cm3 for surgery plus adjuvant RT (p < 0.01). CONCLUSION: Superior sagittal sinus invasion and WHO grade 2/3 are independently associated with PM progression requiring salvage therapy regardless of extent of resection or primary treatment modality. Parasagittal meningiomas have a high rate of recurrence with 80.0% of patients with WHO grade 2/3 tumors with sinus invasion requiring salvage treatment whereas only 13.6% of the WHO grade 1 tumors without sinus invasion required salvage treatment. This information is useful when counseling patients about disease management and setting expectations.

Symptomatic gallstone disease: Recurrence patterns and risk factors for relapse after first admission, the RELAPSTONE study.

BACKGROUND: Delayed cholecystectomy in patients with symptomatic gallstone disease is associated with recurrence. Limited data on the recurrence patterns and the factors that determine them are available. OBJECTIVE: We aimed to determine the pattern of relapse in each symptomatic gallstone disease (acute pancreatitis, cholecystitis, cholangitis, symptomatic choledocholithiasis, and biliary colic) and determine the associated factors. METHODS: RELAPSTONE was an international multicenter retrospective cohort study. Patients (n = 3016) from 18 tertiary centers who suffered a first episode of symptomatic gallstone disease from 2018 to 2020 and had not undergone cholecystectomy during admission were included. The main outcome was relapse-free survival. Kaplan-Meier curves were used in the bivariate analysis. Multivariable Cox regression models were used to identify prognostic factors associated with relapses. RESULTS: Mean age was 76.6 [IQR: 59.7-84.1], and 51% were male. The median follow-up was 5.3 months [IQR 2.1-12.4]. Relapse-free survival was 0.79 (95% CI: 0.77-0.80) at 3 months, 0.71 (95% CI: 0.69-0.73) at 6 months, and 0.63 (95% CI: 0.61-0.65) at 12 months. In multivariable analysis, older age (HR = 0.57; 95% CI: 0.49-0.66), sphincterotomy (HR = 0.58, 95% CI: 0.49-0.68) and higher leukocyte count (HR = 0.79; 95% CI: 0.70-0.90) were independently associated with lower risk of relapse, whereas higher levels of alanine aminotransferase (HR = 1.22; 95% CI: 1.02-1.46) and multiple cholelithiasis (HR = 1.19, 95% CI: 1.05-1.34) were associated with higher relapse rates. CONCLUSION: The relapse rate is high and different in each symptomatic gallstone disease. Our independent predictors could be useful for prioritizing patients on the waiting list for cholecystectomies.

Determinants and impact of splanchnic vein thrombosis in acute pancreatitis.

BACKGROUND: Splanchnic vein thrombosis (SVT) is a well-recognised though little-studied complication in acute pancreatitis (AP). SVT risk factors, its clinical consequences and the role of anticoagulation (AC) therapy is scarce. AIMS: To evaluate the incidence and natural history of SVT in AP. METHODS: Post hoc analysis of a prospective multicentre cohort study involving 23 hospitals in Spain. AP complications were identified by computer tomography, and patients with SVT were re-evaluated after two years. RESULTS: A total of 1655 patients with AP were included. The overall incidence of SVT was 3.6%. SVT was significantly associated with male gender, younger age and alcoholic aetiology. Every local complication increased SVT incidence, and this risk rose gradually with larger extension and infection of necrosis. These patients had a longer hospital stay and underwent a greater number of invasive treatments, regardless of AP severity. Forty-six patients with SVT were followed up. SVT resolution rate was 54.5% in the AC group and 30.8% in the non-AC group with lower thrombotic complications in the SVT resolution group (83.3% vs 22.7%; p<0.001). No AC-related adverse events occurred. CONCLUSION: This study identifies the risk factors and negative clinical impact of SVT in AP. Our results justify future trials to demonstrate the role of AC in this clinical scenario.

Ventriculopleural shunt outcomes for pediatric hydrocephalus: a single-institution experience.

PURPOSE: The aim of this study is to analyze rates of ventriculopleural (VPL) shunt failure and complications among patients with pediatric hydrocephalus, and to analyze which factors may predict early (< 1 year) or late (> 1 year) VPL shunt failure in this sample. METHODS: A retrospective chart review was conducted of all consecutive VPL shunt placements from 2000 to 2019 at our institution. Data was collected on patient characteristics, shunt history, and shunt type. Primary endpoints include rates of VPL shunt survival and rates of symptomatic pleural effusion. The Kaplan-Meier method was used to calculate shunt survival, and Fisher's exact test and t-test were used to compare differences between categorical variables and means, respectively (p < 0.05). RESULTS: Thirty-one patients with pediatric hydrocephalus underwent VPL shunt placement (mean age 14.2 years). Of the 27 patients with long-term follow-up (mean 46 months), VPL shunt revision was required in 19, seven of which were due to pleural effusion. Overall shunt survival rates at 1, 3, 5, and 7 years were 76%, 62%, 55%, and 46%, respectively. Mean duration of shunt survival was 26.74 months. Overall pleural effusion rate was 26%. No patient-specific factors, including shunt valve type, were significantly associated with shunt survival, risk of early revision, or risk of pleural effusion. CONCLUSIONS: Our results are comparable to those reported in the literature and represent one of the largest case series on the topic. VPL shunts are a viable second-line option when ventriculoperitoneal (VP) shunt placement is not possible or desirable, though there are high rates of shunt revision and pleural effusion.

Secondary CNS myeloma with remission after systemic CNS-penetrating agents.

Background: CNS myeloma is a rare manifestation of multiple myeloma and is often associated with a dismal prognosis; however, cases are increasing in frequency as overall survival improves for MM. There is currently no standardized treatment for CNS myeloma; however, different chemotherapy and radiotherapy regimens have been described. Methods: We had previously reported on the efficacy of proton-based craniospinal irradiation in a patient with CNS myeloma; here we present a patient with a history of extramedullary plasmacytoma, 10 years in remission status post standard systemic chemotherapy, with biopsy-proven CNS myeloma successfully treated with systemic chemotherapy as a first-line treatment. Results: The patient achieved clinical and radiographic remission on 2 separate occasions with systemic chemotherapy alone. Conclusions: This case demonstrates that systemically administered agents may have activity in CNS myeloma. Further investigations are necessary to establish the optimal combination of agents and treatment schedules.

Next-generation sequencing of bile cell-free DNA for the early detection of patients with malignant biliary strictures.

OBJECTIVE: Despite significant progresses in imaging and pathological evaluation, early differentiation between benign and malignant biliary strictures remains challenging. Endoscopic retrograde cholangiopancreatography (ERCP) is used to investigate biliary strictures, enabling the collection of bile. We tested the diagnostic potential of next-generation sequencing (NGS) mutational analysis of bile cell-free DNA (cfDNA). DESIGN: A prospective cohort of patients with suspicious biliary strictures (n=68) was studied. The performance of initial pathological diagnosis was compared with that of the mutational analysis of bile cfDNA collected at the time of first ERCP using an NGS panel open to clinical laboratory implementation, the Oncomine Pan-Cancer Cell-Free assay. RESULTS: An initial pathological diagnosis classified these strictures as of benign (n=26), indeterminate (n=9) or malignant (n=33) origin. Sensitivity and specificity of this diagnosis were 60% and 100%, respectively, as on follow-up 14 of the 26 and eight of the nine initially benign or indeterminate strictures resulted malignant. Sensitivity and specificity for malignancy of our NGS assay, herein named Bilemut, were 96.4% and 69.2%, respectively. Importantly, one of the four Bilemut false positives developed pancreatic cancer after extended follow-up. Remarkably, the sensitivity for malignancy of Bilemut was 100% in patients with an initial diagnosis of benign or indeterminate strictures. Analysis of 30 paired bile and tissue samples also demonstrated the superior performance of Bilemut. CONCLUSION: Implementation of Bilemut at the initial diagnostic stage for biliary strictures can significantly improve detection of malignancy, reduce delays in the clinical management of patients and assist in selecting patients for targeted therapies.

Pilot Multi-Omic Analysis of Human Bile from Benign and Malignant Biliary Strictures: A Machine-Learning Approach.

Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign (n = 36) and malignant conditions, CCA (n = 36) or PDAC (n = 57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (1H-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids (n = 10) and proteins (n = 5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy.

Robotic Tissue Manipulation and Resection in Spine Surgery.

Spine surgery has evolved from the advent of imaging and navigation guidance, particularly with the rise of robotic surgical assistance. Navigation guidance has demonstrated potential for increased accuracy of transpedicular screw placement and resecting primary and metastatic spinal tumors. Robotic surgery is widely accepted in other surgical fields because laparoscopic techniques applied to robots can increase operator dexterity and improve visualization. Robotic assistance with spinal tumors has enjoyed rising interest owing to the potential for safe and minimally traumatic resection. We discuss available robots used for navigation-guided transpedicular screw placement and state-of-the-art robotic techniques for spinal or paraspinal tumor resection.

Glioblastoma-Derived IL6 Induces Immunosuppressive Peripheral Myeloid Cell PD-L1 and Promotes Tumor Growth.

PURPOSE: Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation. EXPERIMENTAL DESIGN: Conditioned media from patient-derived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate naïve myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors. RESULTS: GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8+ T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy. CONCLUSIONS: Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated antitumor responses against GBM.

The immune checkpoint protein PD-L1 induces and maintains regulatory T cells in glioblastoma.

Glioblastoma (GBM) promotes immunosuppression through upregulation of PD-L1 and regulatory T cell (Treg) expansion, but the association of these suppressive factors has not been well elucidated. Here, we investigate a role of PD-L1 in expanding Tregs and the value of targeting the PD-1 receptor to inhibit Treg expansion. Quantitative RNA sequencing data from The Cancer Genome Atlas were evaluated for an association between CD274 and FOXP3 transcript expressions and impact of FOXP3 on clinical outcomes. Peripheral leukocytes from patients with newly diagnosed GBM were profiled for PD-L1+ myeloid expressions and Treg abundance. Healthy lymphocytes were assessed for impact of recombinant PD-L1 on expansion of the inducible Treg (iTreg) population. iTreg function was evaluated by the capacity to suppress effector T cell proliferation. Specificity of responses were confirmed by pharmacologic inhibition of the PD-1 receptor. Increased PD-L1 mRNA expression in GBM corresponded to increased FOXP3 mRNA (p = 0.028). FOXP3 elevation had a negative impact on overall survival (HR = 2.0; p < 0.001). Peripheral PD-L1 positivity was associated with an increased Treg fraction (p = 0.008). Lymphocyte activation with PD-L1 co-stimulation resulted in greater iTreg expansion compared to activation alone (18.3% vs. 6.5%; p < 0.001) and improved preservation of the Treg phenotype. Suppressive capacity on naïve T cell proliferation was sustained. Nivolumab inhibited PD-L1-induced Treg expansion (p < 0.001). These results suggest that PD-L1 may expand and maintain immunosuppressive Tregs, which are associated with decreased survival in glioma patients. Blockade of the PD-L1/PD-1 axis may reduce Treg expansion and further improve T cell function beyond the direct impact on effector cells.

Sellar plasmacytomas masquerading as pituitary adenomas: A systematic review.

Given the rarity of intracranial plasmacytomas, these lesions are frequently misdiagnosed as pituitary adenomas. We report on the distinguishing characteristics of sellar plasmacytomas from cases in the literature and our experience. A literature search was conducted to collect all documented cases of a plasmacytoma originating in the sellar region. Patient characteristics, medical history, presentation, tumor characteristics, and survival data were collected. An additional case from our institution not previously reported was included. Thirty-one patients with sellar plasmacytomas were studied. Presenting symptoms were most commonly headache (68%), diplopia (65%) and visual field disturbances (10%). Fifteen patients (48%) were initially suspected of having a pituitary adenoma. Pathologic diagnosis of plasmacytoma preceded a finding of multiple myeloma in 14 cases (45%). Thirty patients (90%) had surgical intervention. Adjuvant therapy consisted of radiotherapy for twenty-five patients (81%) and chemotherapy for sixteen (52%). Tumor recurrence was reported for 7 cases (23%). Nine deaths were reported (23%). We demonstrate that cranial nerve involvement is far more common in sellar plasmacytomas than conventional pituitary adenomas. Given the successful management of these tumors with radiotherapy, such deficits, particularly in patients with known multiple myeloma, should impact the diagnostic workup and treatment considerations.

Immunomonitoring in glioma immunotherapy: current status and future perspectives.

Given the continued poor clinical outcomes and refractory nature of glioblastoma multiforme to traditional interventions, immunotherapy is gaining traction due to its potential for specific tumor-targeting and long-term antitumor protective surveillance. Currently, development of glioma immunotherapy relies on overall survival as an endpoint in clinical trials. However, the identification of surrogate immunologic biomarkers can accelerate the development of successful immunotherapeutic strategies. Immunomonitoring techniques possess the potential to elucidate immunological mechanisms of antitumor responses, monitor disease progression, evaluate therapeutic effect, identify candidates for immunotherapy, and serve as prognostic markers of clinical outcome. Current immunomonitoring assays assess delayed-type hypersensitivity, T cell proliferation, cytotoxic T-lymphocyte function, cytokine secretion profiles, antibody titers, and lymphocyte phenotypes. Yet, no single immunomonitoring technique can reliably predict outcomes, relegating immunological markers to exploratory endpoints. In response, the most recent immunomonitoring assays are incorporating emerging technologies and novel analysis techniques to approach the goal of identifying a competent immunological biomarker which predicts therapy responsiveness and clinical outcome. This review addresses the current status of immunomonitoring in glioma vaccine clinical trials with emphasis on correlations with clinical response.

Vaccine therapies in malignant glioma.

Glioblastoma is a grade IV astrocytoma that is widely accepted in clinical neurosurgery as being an extremely lethal diagnosis. Long-term survival rates remain dismal, and even when tumors undergo gross resection with confirmation of total removal on neuroimaging, they invariably recur with even greater virulence. Standard therapeutic modalities as well as more contemporary treatments have largely resulted in disappointing improvements. However, the therapeutic potential of vaccine immunotherapy for malignant glioma should not be underestimated. In contrast to many of the available treatments, vaccine immunotherapy is unique because it offers the means of delivering treatment that is highly specific to both the patient and the tumor. Peptide, heat-shock proteins, and dendritic cell vaccines collectively encapsulate the majority of research efforts involving vaccine-based treatment modalities. In this review, important recent findings for these vaccine types are discussed in the context of ongoing clinical trials. Broad challenges to immunotherapy are also considered.

Bladder cancers arise from distinct urothelial sub-populations.

Bladder cancer is the sixth most common cancer in humans. This heterogeneous set of lesions including urothelial carcinoma (Uca) and squamous cell carcinoma (SCC) arise from the urothelium, a stratified epithelium composed of K5-expressing basal cells, intermediate cells and umbrella cells. Superficial Uca lesions are morphologically distinct and exhibit different clinical behaviours: carcinoma in situ (CIS) is a flat aggressive lesion, whereas papillary carcinomas are generally low-grade and non-invasive. Whether these distinct characteristics reflect different cell types of origin is unknown. Here we show using lineage tracing in a murine model of carcinogenesis that intermediate cells give rise primarily to papillary lesions, whereas K5-basal cells are likely progenitors of CIS, muscle-invasive lesions and SCC depending on the genetic background. Our results provide a cellular and genetic basis for the diversity in bladder cancer lesions and provide a possible explanation for their clinical and morphological differences.

Principles of surgery for malignant astrocytomas.

Malignant astrocytomas constitute the most aggressive and common primary tumors of the central nervous system. The standard treatment protocol for these tumors involves maximum safe surgical resection with adjuvant chemoradiotherapy. Despite numerous advances in surgical techniques and adjuncts, as well as the ongoing renaissance in the genetic and molecular characterization of these tumors, malignant astrocytomas continue to be associated with poor prognosis, with median overall survival averaging 15 months for grade IV astrocytomas after standard-of-care treatment. In this article, the goals, principles, techniques, prognostic factors, and modern outcomes of malignant astrocytoma surgery are reviewed. Particular attention is paid to contemporary methods of neuronavigation and functional mapping, the prognostic significance of the extent of resection, surgically delivered adjunctive therapies, and future avenues of research.