Epigenetic Reprogramming of Autophagy Drives Mutant IDH1 Glioma Progression and Response to Radiation.

Mutant isocitrate dehydrogenase 1 (mIDH1; IDH1 R132H ) exhibits a gain of function mutation enabling 2-hydroxyglutarate (2HG) production. 2HG inhibits DNA and histone demethylases, inducing epigenetic reprogramming and corresponding changes to the transcriptome. We previously demonstrated 2HG-mediated epigenetic reprogramming enhances DNA-damage response and confers radioresistance in mIDH1 gliomas harboring p53 and ATRX loss of function mutations. In this study, RNA-seq and ChIP-seq data revealed human and mouse mIDH1 glioma neurospheres have downregulated gene ontologies related to mitochondrial metabolism and upregulated autophagy. Further analysis revealed that the decreased mitochondrial metabolism was paralleled by a decrease in glycolysis, rendering autophagy as a source of energy in mIDH1 glioma cells. Analysis of autophagy pathways showed that mIDH1 glioma cells exhibited increased expression of pULK1-S555 and enhanced LC3 I/II conversion, indicating augmented autophagy activity. This dependence is reflected by increased sensitivity of mIDH1 glioma cells to autophagy inhibition. Blocking autophagy selectively impairs the growth of cultured mIDH1 glioma cells but not wild-type IDH1 (wtIDH1) glioma cells. Targeting autophagy by systemic administration of synthetic protein nanoparticles packaged with siRNA targeting Atg7 (SPNP-siRNA-Atg7) sensitized mIDH1 glioma cells to radiation-induced cell death, resulting in tumor regression, long-term survival, and immunological memory, when used in combination with IR. Our results indicate autophagy as a critical pathway for survival and maintenance of mIDH1 glioma cells, a strategy that has significant potential for future clinical translation. One Sentence Summary: The inhibition of autophagy sensitizes mIDH1 glioma cells to radiation, thus creating a promising therapeutic strategy for mIDH1 glioma patients. Graphical abstract: Our genetically engineered mIDH1 mouse glioma model harbors IDH1 R132H in the context of ATRX and TP53 knockdown. The production of 2-HG elicited an epigenetic reprogramming associated with a disruption in mitochondrial activity and an enhancement of autophagy in mIDH1 glioma cells. Autophagy is a mechanism involved in cell homeostasis related with cell survival under energetic stress and DNA damage protection. Autophagy has been associated with radio resistance. The inhibition of autophagy thus radio sensitizes mIDH1 glioma cells and enhances survival of mIDH1 glioma-bearing mice, representing a novel therapeutic target for this glioma subtype with potential applicability in combined clinical strategies.

H3.3-G34R Mutation-Mediated Epigenetic Reprogramming Leads to Enhanced Efficacy of Immune Stimulatory Gene Therapy in Pediatric High-Grade Gliomas.

Pediatric high-grade gliomas (pHGGs) are diffuse and highly aggressive CNS tumors which remain incurable, with a 5-year overall survival of less than 20%. Within glioma, mutations in the genes encoding the histones H3.1 and H3.3 have been discovered to be age-restricted and specific of pHGGs. This work focuses on the study of pHGGs harboring the H3.3-G34R mutation. H3.3-G34R tumors represent the 9-15% of pHGGs, are restricted to the cerebral hemispheres, and are found predominantly in the adolescent population (median 15.0 years). We have utilized a genetically engineered immunocompetent mouse model for this subtype of pHGG generated via the Sleeping Beauty-transposon system. The analysis of H3.3-G34R genetically engineered brain tumors by RNA-Sequencing and ChIP-Sequencing revealed alterations in the molecular landscape associated to H3.3-G34R expression. In particular, the expression of H3.3-G34R modifies the histone marks deposited at the regulatory elements of genes belonging to the JAK/STAT pathway, leading to an increased activation of this pathway. This histone G34R-mediated epigenetic modifications lead to changes in the tumor immune microenvironment of these tumors, towards an immune-permissive phenotype, making these gliomas susceptible to TK/Flt3L immune-stimulatory gene therapy. The application of this therapeutic approach increased median survival of H3.3-G34R tumor bearing animals, while stimulating the development of anti-tumor immune response and immunological memory. Our data suggests that the proposed immune-mediated gene therapy has potential for clinical translation for the treatment of patients harboring H3.3-G34R high grade gliomas.

Spinal fractures in the setting of diffuse idiopathic skeletal hyperostosis conservatively treated via orthosis: illustrative cases.

BACKGROUND: Fractures in patients with diffuse idiopathic skeletal hyperostosis (DISH) are considered highly unstable injuries with high risk for neurological injury. Surgical intervention is the standard of care for these patients to avoid secondary spinal cord injuries. Despite this, certain cases may necessitate a nonoperative approach. Herein within, the authors describe three cases of cervical, thoracic, and lumbar fractures in the setting of DISH that were successfully treated via orthosis. OBSERVATIONS: The authors present three cases of fractures in patients with DISH. A 74-year-old female diagnosed with an acute fracture of a flowing anterior osteophyte at C6-C7 treated with a cervical orthosis. A 78-year-old male with an anterior fracture of the ankylosed T7-T8 vertebrae managed with a Jewett hyperextension brace. Finally, a 57-year-old male with an L1-L2 disc space fracture treated with a thoraco-lumbo-sacral orthosis. All patients recovered successfully. LESSONS: In certain cases, conservative treatment may be more appropriate for fractures in the setting of DISH as an alternative to the surgical standard of care. Most fractures in the setting of DISH are unstable, therefore it is necessary to manage these patients on a case-by-case basis.

H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models.

Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation led to the downregulation of DNA repair pathways. This resulted in enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG led to the accumulation of extrachromosomal DNA, which activated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG-bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier-permeable PARP inhibitor pamiparib and the cell-cycle checkpoint CHK1/2 inhibitor AZD7762), and these combinations resulted in long-term survival for approximately 50% of the mice. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induced immune-mediated therapeutic efficacy in G34-mutant pHGG.

Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy.

Glioblastoma (GBM) is an aggressive primary brain cancer, with a 5 year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include (i) tumor heterogeneity, (ii) treatment resistance, (iii) immunosuppressive tumor microenvironment (TME), and (iv) the blood-brain barrier (BBB). The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it has poor pharmacokinetic properties, and unfavorable bioavailability has hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery. We showed that AMD3100-SPNPs block CXCL12/CXCR4 signaling in three mouse and human GBM cell cultures in vitro and in a GBM mouse model in vivo. This results in (i) inhibition of GBM proliferation, (ii) reduced infiltration of CXCR4+ monocytic myeloid-derived suppressor cells (M-MDSCs) into the TME, (iii) restoration of BBB integrity, and (iv) induction of immunogenic cell death (ICD), sensitizing the tumor to radiotherapy and leading to anti-GBM immunity. Additionally, we showed that combining AMD3100-SPNPs with radiation led to long-term survival, with ∼60% of GBM tumor-bearing mice remaining tumor free after rechallenging with a second GBM in the contralateral hemisphere. This was due to a sustained anti-GBM immunological memory response that prevented tumor recurrence without additional treatment. In view of the potent ICD induction and reprogrammed tumor microenvironment, this SPNP-mediated strategy has a significant clinical translation applicability.

Comparative efficacy of lidocaine-prilocaine cream and vaginal misoprostol in reducing pain during levonorgestrel intrauterine device insertion in women delivered only by cesarean delivery: A randomized controlled trial.

OBJECTIVE: To compare efficacy of lidocaine-prilocaine (LP) cream versus misoprostol versus placebo before levonorgestrel-releasing intrauterine device (LNG-IUD) insertion. METHODS: This randomized controlled trial (RCT) was conducted in a tertiary referral hospital from April 30, 2020 to March 1, 2021 on 210 parous women willing to receive LNG-IUD and delivered only by elective cesarean delivery (CD). Participants received 200 µg vaginal misoprostol or 5 ml of LP cream 5% or placebo 3 h before LNG-IUS insertion. Primary outcome was pain during LNG-IUD insertion, while secondary outcomes were pain 10 min post-procedure, ease of insertion, patient satisfaction, insertion time, and drug side effects. RESULTS: Pain during LNG-IUS insertion was reduced in LP group and misoprostol group compared to placebo group (2.1 ± 1.0 vs 3.7 ± 1.6; p <0.001) and (2.3 ± 1.3 vs 3.7 ± 1.6; p <0.001), respectively. Ease of procedure and patient satisfaction were significantly higher in LP and misoprostol groups than placebo (P <0.001). Need for additional analgesia was significantly higher in placebo group than in the other two groups (P = 0.009). Adverse events were not significantly different between the three groups except vomiting and abdominal cramps, which were higher with misoprostol. CONCLUSION: LP cream and 200 µg of vaginal misoprostol administration before LNG-IUD insertion in women delivered only by elective CD effectively reduced pain during insertion and 10 min post-procedure with easier insertions, high patient satisfaction, and tolerable side effects. Pain reduction with LP cream was clinically significant.

Determining the Optimal Time Interval between Vaginal Dinoprostone Administration and Diagnostic Office Hysteroscopy in Nulliparous Women: A Randomized, Double-blind Trial.

STUDY OBJECTIVE: To determine the optimal timing of vaginal dinoprostone administration before office hysteroscopy (OH) in nulliparous women. DESIGN: Randomized, double-blind trial. SETTING: Tertiary referral hospital. PATIENTS: A total of 180 nulliparous women undergoing diagnostic OH. INTERVENTIONS: We randomly allocated the women to long-interval or short-interval dinoprostone groups: three mg dinoprostone was administered vaginally 12 hours before OH in the long-interval group and 3 hours before OH in the short-interval group. MEASUREMENTS AND MAIN RESULTS: The primary outcome was pain during OH measured using a 100-mm visual analog scale (0 = no pain; 100 = worst pain imaginable). The secondary outcomes were ease of hysteroscope passage, patient satisfaction score, and drug-related adverse effects. The patients in the long-interval dinoprostone group had lower pain scores during OH (p <.001). Contrarily, pain scores 30 minutes after the procedure were similar in both groups (p = .1). The patient satisfaction score was higher and clinicians found hysteroscope passage through the cervical canal easier and quicker in the long-interval dinoprostone group than in the short-interval group (p <.001, p = .003, and p <.001, respectively). Side effects were comparable in both study groups. CONCLUSION: Vaginal dinoprostone administered 12 hours before OH was more effective than that administered 3 hours before OH in reducing pain during OH in nulliparous women, with easier hysteroscope insertion, shorter procedure duration, and higher patient satisfaction score.

Temporary Internal Bracing for Pediatric Odontoid Synchondrosis Fracture.

Children are predisposed to injuries of the upper cervical spine given their relatively immature osteology, ligamentous laxity, underdeveloped musculature, and larger ratios of head to body mass. Odontoid process fractures involving the synchondroses are among the most common of these injuries. Though many of these fractures can be treated conservatively with external bracing, fractures with significant displacement that are unable to be reduced require operative management. In these cases, most patients undergo C1-2 posterior fusion with arthrodesis with permanent limitation to atlantoaxial range of motion (ROM). Here, we present a novel operative approach to manage odontoid synchondrosis fractures with temporary internal bracing via C1-2 posterior instrumentation without arthrodesis. We saw a three-year-old female who presented after a motor vehicle collision with a displaced odontoid synchondrosis fracture that was unable to be adequately reduced in a closed fashion. In an attempt to preserve maximal atlantoaxial ROM, temporary internal bracing was carried out with excellent results.

G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy.

Mutant isocitrate-dehydrogenase 1 (mIDH1) synthesizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of the glioma cells' transcriptome by inhibiting DNA and histone demethylases. We show that the efficacy of immune-stimulatory gene therapy (TK/Flt3L) is enhanced in mIDH1 gliomas, due to the reprogramming of the myeloid cells' compartment infiltrating the tumor microenvironment (TME). We uncovered that the immature myeloid cells infiltrating the mIDH1 TME are mainly nonsuppressive neutrophils and preneutrophils. Myeloid cell reprogramming was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem/progenitor-like cells. Blocking G-CSF in mIDH1 glioma­bearing mice restores the inhibitory potential of the tumor-infiltrating myeloid cells, accelerating tumor progression. We demonstrate that G-CSF reprograms bone marrow granulopoiesis, resulting in noninhibitory myeloid cells within mIDH1 glioma TME and enhancing the efficacy of immune-stimulatory gene therapy.

CD200 Immune-Checkpoint Peptide Elicits an Anti-glioma Response Through the DAP10 Signaling Pathway.

Numerous therapies aimed at driving an effective anti-glioma response have been employed over the last decade; nevertheless, survival outcomes for patients remain dismal. This may be due to the expression of immune-checkpoint ligands such as PD-L1 by glioblastoma (GBM) cells which interact with their respective receptors on tumor-infiltrating effector T cells curtailing the activation of anti-GBM CD8+ T cell-mediated responses. Therefore, a combinatorial regimen to abolish immunosuppression would provide a powerful therapeutic approach against GBM. We developed a peptide ligand (CD200AR-L) that binds an uncharacterized CD200 immune-checkpoint activation receptor (CD200AR). We sought to test the hypothesis that CD200AR-L/CD200AR binding signals via he DAP10&12 pathways through in vitro studies by analyzing transcription, protein, and phosphorylation, and in vivo loss of function studies using inhibitors to select signaling molecules. We report that CD200AR-L/CD200AR binding induces an initial activation of the DAP10&12 pathways followed by a decrease in activity within 30 min, followed by reactivation via a positive feedback loop. Further in vivo studies using DAP10&12KO mice revealed that DAP10, but not DAP12, is required for tumor control. When we combined CD200AR-L with an immune-stimulatory gene therapy, in an intracranial GBM model in vivo, we observed increased median survival, and long-term survivors. These studies are the first to characterize the signaling pathway used by the CD200AR, demonstrating a novel strategy for modulating immune checkpoints for immunotherapy currently being analyzed in a phase I adult trial.

Evaluating efficacy of intravenous carbetocin in reducing blood loss during abdominal myomectomy: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of carbetocin versus placebo in decreasing intraoperative blood loss and the need for blood transfusion during abdominal myomectomy. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Tertiary university hospital from September 2019 to February 2020. PATIENT(S): A total of 138 women with symptomatic leiomyoma who were candidates for abdominal myomectomy (n = 69 in each group). INTERVENTION(S): We randomized the study participants in a 1:1 ratio to carbetocin and placebo groups. Intravenous 100 µg carbetocin or placebo was administered slowly after induction of anesthesia. MAIN OUTCOME MEASURE(S): Intraoperative blood loss, need for blood transfusion, postoperative hemoglobin, operative time, length of hospitalization, and drug side-effects. RESULT(S): The baseline characteristics were similar among all groups. Carbetocin had significantly lower intraoperative blood loss compared with placebo (mean difference 184 mL). Hemoglobin level 24 hours after surgery was significantly lower in the placebo group than in the carbetocin group (9.1 ± 0.8 vs. 10.3 ± 0.6 g/dL). Eight women in the carbetocin group needed blood transfusion compared with 17 in placebo group. Operative time, length of hospitalization, and side-effects were similar in both groups. CONCLUSION(S): A single preoperative intravenous dose of 100 µg carbetocin is a simple, practical, and effective method of decreasing intraoperative blood loss and the need for blood transfusion during abdominal myomectomy, with tolerable, few, nonsignificant side-effects. CLINICAL TRIAL REGISTRATION NUMBER: NCT04083625.

Inhibition of 2-hydroxyglutarate elicits metabolic reprogramming and mutant IDH1 glioma immunity in mice.

Mutant isocitrate dehydrogenase 1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into 2 molecular subgroups: 1p/19q codeletion/TERT-promoter mutations or inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work focuses on glioma subtypes harboring mIDH1, TP53, and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of D-2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma-bearing mice. Also, D-2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to D-2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in WT-IDH gliomas. Thus, we combined D-2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint blockade and observed complete tumor regression in 60% of mIDH1 glioma-bearing mice. This combination strategy reduced T cell exhaustion and favored the generation of memory CD8+ T cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data support the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients.

Medical therapy options for endometriosis related pain, which is better? A systematic review and network meta-analysis of randomized controlled trials.

Our objective was to assess and rank different pharmacological interventions for relieving endometriosis-related pain. We conducted an online bibliographic search in different databases from their inception until March 2019. We included randomized controlled trials (RCTs) that assessed different medical therapies in the management of endometriosis-related pain. We applied this network meta-analysis (NMA) based on the frequentist approach using statistical package "netmeta" (version 1.0-1) in R software. Our main outcomes were the change in severity of pelvic pain, dysmenorrhea score, non-menstrual pelvic pain score, and dyspareunia score. Overall, 36 RCTs were included in this study (patients no. = 7942). Dienogest (0.94), combined hormonal contraceptives (CHCs) (0.782), and elagolix (0.38) were the highest-ranked interventions for reducing the severity of pelvic pain at three months, while at six months, gonadotropin-releasing hormone (GnRH) analogues (0.75), levonorgestrel-releasing intrauterine system (LNG-IUS) (0.73), and dienogest (0.65) were linked to more reduction in pelvic pain. The ranking p-score showed that GnRH analogues was the highest-ranked treatment for reducing dysmenorrhea at 3 months (1.00), while CHCs were the highest-ranked treatment at 6 months (0.97), followed by GnRH analogues (0.89). GnRH analogues (0.63) and elagolix (0.54) at three months while desogestrel (0.94) and CHCs (0.91) at six months were the highest-ranked treatment to reduce non-menstrual pelvic pain. GnRH analogues and elagolix were the highest-ranked pharmacologic therapies for reducing dyspareunia. In conclusion, CHCs, GnRH analogues, progesterone, and elagolix were the best approaches in reducing the pain of endometriosis.

Alalfy modified cervical inversion technique as a tamponade in controlling PPH in placenta previa, a multicentric double blind randomized controlled trial.

INTRODUCTION: Postpartum hemorrhage that occurs frequently with placenta previa is one of the causes of maternal mortality in 14% in developing countries. OBJECTIVE: To assess efficacy of cervical inversion as a tamponade in controlling bed of placenta in cases of placenta previa. PATIENTS AND METHOD: A prospective randomized controlled study was conducted among a total of 240 pregnant women with placenta previa (120 subjected to Alalfy modified cervical inversion technique plus hemostatic sutures and 120 was not subjected cervical inversion and only was subjected to hemostatic sutures in Obstetrics and Gynecology Department at Suez Canal University hospital, Helwan University and Algezeerah hospital for a planned cesarean section). RESULTS: The mean intraoperative blood loss, the intraoperative time, and the postoperative hemoglobin show a statistically significant difference between cases with placenta previa who were exposed to cervical inversion in comparison to cases that had no cervical inversion with a p-value <.001. CONCLUSION: Modified cervical inversion (Alalfy technique) as a tamponade when added to hemostatic sutures to the placental bed is an easy, rapid, and efficient procedure that can decrease the amount of blood loss, time needed to stop bleeding per bed, total operative time, also it can decrease the need for blood transfusion.

Effect of self-administered vaginal dinoprostone on pain perception during copper intrauterine device insertion in parous women: a randomized controlled trial.

OBJECTIVE(S): To assess efficacy and safety of self-administered 3 mg dinoprostone vaginally in reducing pain during copper intrauterine device (IUD) insertion in parous women. DESIGN: Randomized, double-blinded, placebo-controlled trial. SETTING: Family planning clinic in a tertiary referral hospital. PATIENT(S): Multiparous women who were attending a family planning clinic and requesting copper IUD insertion. INTERVENTIONS(S): We randomly assigned 160 participants into two groups: The dinoprostone group (n = 80) received 3 mg dinoprostone vaginally, and the placebo group (n = 80) received placebo vaginally. MAIN OUTCOME MEASURE(S): Our primary outcome was mean pain scores during IUD insertion. Our secondary outcomes were mean pain scores during tenaculum application, during uterine sounding, and 15 minutes after insertion, ease of insertion, satisfaction score, need for additional analgesics, and side-effects. RESULT(S): Both groups showed no significant difference in anticipated pain score (P=.41), pain during tenaculum placement (P=.22), and pain during sound insertion (P=.07). The dinoprostone group had significantly lower pain scores during IUD insertion (34.8 ± 10.1 vs. 57.8 ± 11.8) and 15 minutes after insertion (20.6 ± 6.4 vs. 29.6 ± 6.2), easier IUD insertion (43.6 ± 21.9 vs. 64.7 ± 18.1), and higher satisfaction (83.9 ± 11.6 vs. 63.0 ± 9.1) compared with the placebo group. Fewer patients required additional analgesics in the dinoprostone group compared with the placebo group (P=.01). Side-effects were similar between the groups. CONCLUSION(S): Self-administered 3 mg dinoprostone vaginally before copper IUD insertion in parous women reduces pain scores during IUD insertion, making insertion easier and increasing women's satisfaction, with tolerable side-effects. CLINICAL TRIAL REGISTRATION NUMBER: NCT04046302.

Tumor mutational burden predicts survival in patients with low-grade gliomas expressing mutated IDH1.

BACKGROUND: Gliomas are the most common primary brain tumors. High-Grade Gliomas have a median survival (MS) of 18 months, while Low-Grade Gliomas (LGGs) have an MS of approximately 7.3 years. Seventy-six percent of patients with LGG express mutated isocitrate dehydrogenase (mIDH) enzyme. Survival of these patients ranges from 1 to 15 years, and tumor mutational burden ranges from 0.28 to 3.85 somatic mutations/megabase per tumor. We tested the hypothesis that the tumor mutational burden would predict the survival of patients with tumors bearing mIDH. METHODS: We analyzed the effect of tumor mutational burden on patients' survival using clinical and genomic data of 1199 glioma patients from The Cancer Genome Atlas and validated our results using the Glioma Longitudinal AnalySiS consortium. RESULTS: High tumor mutational burden negatively correlates with the survival of patients with LGG harboring mIDH (P = .005). This effect was significant for both Oligodendroglioma (LGG-mIDH-O; MS = 2379 vs 4459 days in high vs low, respectively; P = .005) and Astrocytoma (LGG-mIDH-A; MS = 2286 vs 4412 days in high vs low respectively; P = .005). There was no differential representation of frequently mutated genes (eg, TP53, ATRX, CIC, and FUBP) in either group. Gene set enrichment analysis revealed an enrichment in Gene Ontologies related to cell cycle, DNA-damage response in high versus low tumor mutational burden. Finally, we identified 6 gene sets that predict survival for LGG-mIDH-A and LGG-mIDH-O. CONCLUSIONS: we demonstrate that tumor mutational burden is a powerful, robust, and clinically relevant prognostic factor of MS in mIDH patients.

Early versus delayed removal of indwelling urinary catheter after elective cesarean delivery: systematic review and meta-analysis of randomized controlled trials.

Background: Timing of removal of the indwelling urinary catheter after elective cesarean delivery (CD) is controversial. Early removal could be associated with fewer urinary symptoms.Objective: This review aims to evaluate the evidence from published randomized clinical trials (RCTs) about the outcomes of early versus delayed removal of indwelling urinary catheter after elective cesarean delivery (CD).Data sources: Electronic databases were searched using the following MeSH terms (early Or Late Or immediate OR delayed removal) AND (Urinary catheter) AND (cesarean section OR cesarean delivery OR CS)Methods of study selection: All RCTs assessing the timing of removal of urinary catheter were considered for this meta-analysis. One hundred seventy-two studies were identified of which three studies deemed eligible for this review. Quality and risk of bias assessment were performed for all studies.Data extraction: Two researchers independently extracted the data from the individual articles and entered into RevMan software. The relative risk (RR), the weighted mean difference (WMD) and 95% confidence interval (CI) were calculated. The extracted outcomes were significant bacteriuria, urinary symptoms (urinary retention necessitating re-catheterization, dysuria, urinary frequency, urgency) postoperative oral rehydration and length of hospital stay.Results: Three RCTs (early removal: n = 298 and delayed removal: n = 311) were included. The pooled estimate showed that early removal significantly reduced dysuria (RR = 0.60, 95% CI [0.38, 0.95], p=.03), urinary frequency (RR = 0.32, 95% CI [0.16, 0.66], p=.002) and significant bacteriuria (RR = 0.49, 95% CI [0.30, 0.83], p=.007) than delayed removal.Conclusions: This meta-analysis suggests that early removal of the indwelling urinary catheter in patients who underwent elective CD showed significant less dysuria, less urinary frequency and a decrease in the incidence of significant bacteriuria.

The efficacy of local anesthetics in pain relief during colposcopic-guided biopsy: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Colposcopy is an office gynecological procedure used for cervical evaluation in patients with abnormal cervical cytology. It is considered an important tool for early detection of cases of cervical cancer. OBJECTIVE: To evaluate the evidence from published randomized clinical trials (RCTs) about the efficacy of local anesthetics in pain relief during colposcopic-guided biopsy. DATA SOURCES: Several electronic databases included MEDLINE, EMBASE, Cochrane Library, ISI and Scopus were searched using the relevant MeSH terms. METHODS OF STUDY SELECTION: All RCTs assessing the effect of local anesthetics in relieving pain during colposcopy were considered for this meta-analysis. There were 1339 studies identified of which 11 studies deemed eligible for this review. We performed quality and risk of bias assessment for all included studies. DATA EXTRACTION: Three researchers independently extracted the data from the individual articles and entered it into RevMan software. The extracted outcomes included pain scores and the duration of the procedure. RESULTS: Eleven RCTs were included. Local anesthesia (LA) was associated with higher pain at speculum insertion than control (SMD = 0.23, 95% CI [0.03, 0.43]). While, LA significantly reduced biopsy pain than control (SMD= -0.57, 95% CI [-0.94, -0.20]). The overall pooled estimate showed no significant difference between LA and control regarding postprocedural pain, pain on endocervical curettage, pain expectancy, and overall pain scores. CONCLUSIONS: This meta-analysis suggests that local anesthetics are effective in pain relief during a colposcopic-guided biopsy; however there is no strong evidence to recommend its use in current practice.

Efficacy and safety of tramadol in pain relief during diagnostic outpatient hysteroscopy: systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the evidence about the safety and efficacy of tramadol in pain relief during diagnostic outpatient hysteroscopy (OH). DESIGN: Systematic review and meta-analysis of randomized controlled trials. SETTING: Not applicable. PATIENT(S): Patients undergoing diagnostic OH received tramadol versus those who were administered placebo. INTERVENTION(S): Electronic databases were searched using the following MeSH terms (tramadol OR opioids OR opioid OR narcotic OR narcotics) AND (hysteroscopy OR hysteroscopic). MAIN OUTCOME MEASURE(S): Pain assessed by visual analogue scale (VAS) during OH, immediately and 30 minutes after the procedure. RESULT(S): One hundred thirteen studies were identified of which four randomized clinical trials were deemed eligible for this review (tramadol: n = 209; placebo: n = 209). The pooled estimate showed that tramadol significantly reduced VAS during procedure than placebo (weighted mean difference [WMD] = -1.33; 95% confidence interval [CI] -1.78 to -0.88, I2 = 3%, P = .36). In addition, tramadol significantly reduced VAS immediately after the procedure (WMD = -1.05; 95% CI -1.49 to -0.61, I2= 0, P = .84) and 30 minutes after (WMD = -0.98; 95% CI -1.30 to -0.65, I2 = 0, P = .88). CONCLUSION(S): This meta-analysis suggests that tramadol is safe, effective, and gives favorable results in reducing pain during diagnostic OH.