Molecular landscapes of longitudinal NF2/22q and non‐NF2/22q meningiomas show different life histories

alexandrossfakianakis shared this article with you from Inoreader Molecular landscapes of longitudinal NF2/22q and non‐NF2/22q meningiomas show different life histories via Brain Pathology Abstract Recurrence is a major complication of some meningiomas. Although there were many studies on biomarkers associated with higher grades or increased aggressiveness, few studies specifically examined longitudinal samples of primary meningiomas and recurrences from the same patients for molecular life history. We studied 99 primary and recurrent meningiomas from 42 patients by FISH for 22q, 1q, 1p, 3p, 5q, 6q, 10p, 10q, 14q, 18q, CDKN2A/B homozygous deletion, ALT (Alternative Lengthening of Telomere), TERT re-arrangement, targeted sequencing and TERTp sequencing. Although NF2 mutation and 22q were well known to be aetiological events in meningiomas, we found that in these paired meningiomas, combining the two events resulted in an NF2/22q group (57 tumors from 25 patients) which were almost mutually exclusive with those cases without these two changes (42 tumors from 17 patients) for NF2/22q. No other molecular changes were totally unique to NF2/22q or non-NF2/22q tumors. For molecular evolution, NF2/22q meningiomas had higher cytogenetic abnormalities than non-NF2/22q meningiomas (p = 0.003). Most of the cytogenetic changes in NF2/22q meningiomas were present from the outset whereas for non-NF2/22q meningiomas, cytogenetic events were uncommon in the primary tumors and most were acquired in recurrences. For non-NF2/22q tumors, CDKN2A/B homozygous deletion, 1q gain, 18p loss, 3p loss, and ALT were preferentially found in recurrences. Mutations were largely conserved between primary and recurrent tumors. Phylogenetic trees showed 11/11 patients with multiple recurrent tumors had a conserved evolutionary pattern. We conclude that for molecular life history, NF2 and 22q should be regarded as a group. NF2/22q recurring meningiomas showed more cytogenetic abnormalities in the primary tumors, whereas non-NF2/22q meningiomas showed C DKN2A/B deletion and other cytogenetic abnormalities and ALT at recurrences. Although chromosome 1p loss is a known poor prognostic marker in meningiomas, it was also associated with a shorter TBR (time between resection) in this cohort (p = 0.002). View on Web

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Innate immune activation without immune cell infiltration in brains of murine models of Aicardi–Gutiérrez Syndrome

alexandrossfakianakis shared this article with you from Inoreader Innate immune activation without immune cell infiltration in brains of murine models of Aicardi–Gutiérrez Syndrome via Brain Pathology The brains of 8-week-old wildtype (WT) mice (left) and mice carrying mutations (D1113H) in the ADAR1 gene (right) probed for expression of Interferon Stimulated Gene 15 (ISG-15) using In situ hybridization (red). WT mice show little to no expression of ISG-15 while ADAR1 mutant mouse brain shows a broad and chaotic distribution of expression throughout the brain (8 of many foci circled). Abstract Chronic inflammation is frequently invoked as a mechanism of neurodegeneration and yet inflammatory cell infiltrates are seldom seen in brains of these disorders. Different disciplines utilize different technologies and methodologies to describe what is immunologically defined as the innate immune response (IIR). We examined murine models of the human neurodegenerative disease Aicardi–Gutiérrez Syndrome, where an IIR is initiated by aberrant RNA metabolism secondary to a mutation in adenosine deaminase acting on RNA gene (ADAR1). We previously showed that these mice demonstrated a deficit in RNA editing that lead to MDA-5 mediated RNA sensing pathway activation of the IIR with massive interferon stimulated gene transcription and translation. As early as 2 weeks of age, in situ hybridization demonstrated that different central nervous system (CNS) cell lineages expressed very high levels of distinct interferon stimulated genes (ISGs) in the absence of interferon and absence of immune cell infiltrates. We have expanded these studies to more completely describe the breadth of ISG expression systemically and in CNS using double label in situ hybridization. Within the CNS aberrant ISG expression was mostly limited to neurons, microglia, ependyma, choroid plexus, and endothelial cells with little expression in oligodendroglia and astrocytes except for STAT1. Wild type controls showed a similar pattern of ISG expression but only in aged mice and at levels minimally detectable by in situ hybridization. Despite months of elevated ISG expression in mutant mice, there was essentially no inflammatory infiltrate, no interferon production and minimal glial reaction. Histomorphological neurodegenerative pathology of ventricular dilatation and deep gray matter mineralization were evident in mutant mice 8–13 months of age but this did not show a spatial relationship to ISG expression. This IIR without immune cell infiltration leads to neurodegeneration through non-c anonical pathways that may accentuate normal aging pathways. View on Web

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Long-term Locoregional Control With Unilateral Radiation for AJCC-7 T1-2N2b Tonsillar Cancer

alexandrossfakianakis shared this article with you from Inoreader Long-term Locoregional Control With Unilateral Radiation for AJCC-7 T1-2N2b Tonsillar Cancer via American Journal of Clinical Oncology - Current Issue Objectives: Unilateral radiation to cervical nodes has been used as a de-escalation strategy in well-lateralized tonsil cancers. The efficacy of this approach with multiple ipsilateral nodes is not established. The study hypothesis was that unilateral radiation for American Joint Committee on Cancer (AJCC)-7 T1-2N2b tonsillar cancer results in a low rate of contralateral nodal failure. Materials and Methods: This study was a retrospective chart review of patients with AJCC-7 T1-2N2b tonsillar cancer from 2 academic institutions who were treated with unilateral radiation. The primary endpoint was the contralateral nodal failure rate. Locoregional control, overall survival, and the need for gastrostomy tube placement were additional endpoints. Results: The study cohort included 66 patients treated between 2005 and 2016. The median follow-up time was 80.9 months; contralateral nodal failure occurred in 2/66 (3.0%) patients at 4.1 and 20.9 months, respectively. Both patients underwent salvage treatment with long-term subsequent survival. Overall locoregional control at both 2 and 5 years was 93.9% and the median duration of control was not reached. Overall survival at 5 years was 92.4%. Conclusions: The use of unilateral radiation for AJCC-7 T1-2N2b tonsillar cancer resulted in low rates of contralateral nodal failure. This outcome demonstrates the safety of considering unilateral radiation treatment in patients with a relatively high ipsilateral nodal burden. View on Web

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A Novel Nomogram for Predicting Breast Cancer–specific Survival in Male Patients

alexandrossfakianakis shared this article with you from Inoreader A Novel Nomogram for Predicting Breast Cancer–specific Survival in Male Patients via American Journal of Clinical Oncology - Current Issue Objectives: To compare breast cancer–specific survival (BCSS) of nonmetastatic invasive breast cancer between male (MBC) and female (FBC) patients, define clinicopathologic variables related to BCSS in nonmetastatic invasive MBC patients, and establish a nomogram for individual risk prediction. Materials and Methods: On the basis of Surveillance, Epidemiology, and End Results database, 2094 MBC and 48,104 FBC cases underwent propensity score matching (PSM). We compared the prognosis of patients before and after PSM and developed a nomogram for BCSS of nonmetastatic invasive MBC patients. Internal validation was performed using the consistency index, calibration curves, and receiver operating characteristic curves. Simultaneously, data from 49 nonmetastatic invasive MBC patients diagnosed between January 2012 and May 2016 were collected for external validation. Results: Before PSM, overall survival and BCSS were significantly shorter in MBC than those in FBC patients. After PSM, MBC patients continued to have a shorter overall survival, but not BCSS, than FBC patients. Marital status, age, histologic grade, estrogen/progesterone receptor status, Tumor Lymph Node stage, and surgery were included in the prediction model. Conclusions: The nomogram developed in this study seems to be more accurate than conventional Tumor-nodal-metastasis staging staging to predict BCSS and may serve as an effective tool for assessing the prognosis of nonmetastatic invasive MBC. View on Web

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Controlling Nutritional Status (CONUT) score is a prognostic marker for laryngeal cancer patients with curative resection

alexandrossfakianakis shared this article with you from Inoreader Controlling Nutritional Status (CONUT) score is a prognostic marker for laryngeal cancer patients with curative resection via Head & Neck Abstract Background To investigate the prognostic value of pre-treatment Controlling Nutritional Status (CONUT) score in laryngeal cancer. Methods Preoperative CONUT score was retrospectively calculated in 154 laryngeal cancer patients who underwent curative resection in our hospital from 2013 to 2016. The associations of CONUT with clinicopathological factors and survival were evaluated. The efficacy of CONUT score to predict prognosis was evaluated. Results The CONUT score was associated with body mass index (p = 0.033), neutrophil (p = 0.011), tumor size (p = 0.017), pTNM stage (p = 0.001), adjuvant radiotherapy (p < 0.001), negative pathologic factors (p < 0.001), and larynx preservation (p < 0.001). Patients with a higher CONUT score had worse overall survival (hazard ratio: 1.94, 95% confidence interval [CI]: 1.13–3.72, p = 0.039) and disease-free survival (hazard ratio: 2.16, 95% CI: 1.19–3.90, p = 0.011). The area under the curve of CONUT score (0.728) was higher than Preoperative Nutritional Index (0.72), platelet-to-lymphocyte ratio (0.675), and neutrophil-to-lymphocyte ratio (0.687). Conclusion The CONUT score can be useful for predicting survival in laryngeal cancer patients after curative resection. View on Web

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Transmission of Carbapenem-resistant Klebsiella pneumoniae in US hospitals

alexandrossfakianakis shared this article with you from Inoreader Transmission of Carbapenem-resistant Klebsiella pneumoniae in US hospitals via Clinical Infectious Diseases Advance Access ABSTRACT Background Carbapenem-resistant Klebsiella pneumoniae (CRKp) is the most prevalent carbapenem-resistant Enterobacterales in the United States. We evaluated clustering of CRKp in hospitalized patients in US hospitals. Methods From April 2016 to August 2017, 350 patients with clonal group 258 were included as part of the Consortium on Re sistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-2), a prospective, multicenter, cohort study. A maximum-likelihood tree was constructed using RAxML. Static clusters shared ≤21 single nucleotide polymorphisms (SNP) and a most recent common ancestor. Dynamic clusters incorporated SNP distance, culture timing, and rates of SNP accumulation and transmission using the R program TransCluster. Results Most patients were admitted from home (n = 150, 43%) or a long-term care facility (n = 115, 33%). Urine (n = 149, 43%) was the most common site of isolation. In total, 55 static and 47 dynamics clusters were identified involving 210/350 (60%) and 194/350 (55%) patients, respectively. About half of static clusters were identical to dynamic clusters. Static clusters consisted of 33 (60%) intra-system and 22 (40%) inter-system clusters. Dynamic clusters consiste d of 32 (68%) intra-system and 15 (32%) inter-system clusters and had fewer SNP differences compared to static clusters (8 versus 9, P= 0.045, 95% CI: [-4, 0]). Dynamic inter-system clusters contained more patients than dynamic intra-system clusters (median [IQR]: 4 [2, 7] vs 2 [2, 2], P= 0.007, 95% CI: [-3, 0]). Conclusions Widespread intra-system and inter-system transmission of CRKp was identified in hospitalized US patients. Employing different methods for assessing genetic similarity resulted in only minor differences in interpretation. View on Web

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Evaluation of an Opt-Out Protocol for Antibiotic De-escalation in Patients with Suspected Sepsis: a multicenter randomized controlled trial

alexandrossfakianakis shared this article with you from Inoreader Evaluation of an Opt-Out Protocol for Antibiotic De-escalation in Patients with Suspected Sepsis: a multicenter randomized controlled trial via Clinical Infectious Diseases Advance Access Abstract Background Sepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. This randomized controlled trial evaluated an opt-out protocol to decrease unnecessary antibiotics in patients with suspected sepsis. Methods We evaluated non-ICU adults on broad-spectrum antibiotics despite negative blood cultures at ten U.S. hospitals from September 2018 through May 2020. A 23-item safety check excluded patients with ongoing signs of systemic infection, concerning or inadequate microbiologic data, or high-risk conditions. Eligible patients were randomized to the opt-out protocol vs. usual care. The primary outcome was 30-day post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted to encourage antibiotic discontinuation using opt-out language. If antibiotics were continued, clinicians discussed rationale for continuing antibiotics and de-escalation plans. To evaluate those with zero post-enrollment DOT, hurdle models provided two measures: 1) the odds ratio of antibiotic continuation and 2) ratio of mean DOT among those who continued antibiotics. Results Among 9606 patients screened, 767 (8%) were enrolled. Intervention patients had 32% lower odds of antibiotic continuation (79% vs. 84%, OR 0.68, 95% confidence interval (CI) [0.47, 0.98]). DOT among those who continued antibiotics were similar (ratio of means 1.06, 95% CI [0.88-1.26]). Few er intervention patients were exposed to extended-spectrum antibiotics (36% v. 44%. Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was unsafe (31%). Thirty-day safety events were similar. Conclusions An antibiotic opt-out protocol targeting patients with suspected sepsis resulted in more antibiotic discontinuations, similar DOT when antibiotics were continued, and no evidence of harm. View on Web

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