Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average ...of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.
Craniopharyngiomas are epithelial tumors that typically arise in the suprasellar region of the brain. Patients experience substantial clinical sequelae from both extension of the tumors and ...therapeutic interventions that damage the optic chiasm, the pituitary stalk and the hypothalamic area. Using whole-exome sequencing, we identified mutations in CTNNB1 (β-catenin) in nearly all adamantinomatous craniopharyngiomas examined (11/12, 92%) and recurrent mutations in BRAF (resulting in p.Val600Glu) in all papillary craniopharyngiomas (3/3, 100%). Targeted genotyping revealed BRAF p.Val600Glu in 95% of papillary craniopharyngiomas (36 of 39 tumors) and mutation of CTNNB1 in 96% of adamantinomatous craniopharyngiomas (51 of 53 tumors). The CTNNB1 and BRAF mutations were clonal in each tumor subtype, and we detected no other recurrent mutations or genomic aberrations in either subtype. Adamantinomatous and papillary craniopharyngiomas harbor mutations that are mutually exclusive and clonal. These findings have important implications for the diagnosis and treatment of these neoplasms.
Despite complete surgical resection, patients with stage I non–small-cell lung cancer (NSCLC) are at risk for disease recurrence. The impact of common oncogenic driver mutations on prognosis in stage ...I NSCLC is limited. The pure prognostic value of KRAS mutational status was explored in resected stage I lung adenocarcinoma.
Mutation status was tested in patients who had complete resection of stage I lung adenocarcinoma without any adjuvant therapy, using a multiplex polymerase chain reaction)–based assay. Disease-free survival (DFS) and overall survival (OS) were compared between patients with KRAS-mutant (KRAS-MUT), KRAS-MUT subtypes, and KRAS wild-type (KRAS-WT) tumors.
A total of 312 patients were included in this analysis; 127 harbored KRAS mutations and 185 had KRAS-WT tumors. When compared with KRAS-WT, KRAS-MUT was associated with significantly shorter OS (hazard ratio 4.36, 95% confidence interval 2.09–9.07; p < 0.0001) and DFS (hazard ratio 3.62, 95% confidence interval 2.11–6.22; p < 0.0001). When stratifying KRAS-WT patients based on EGFR status, KRAS-MUT patients had worse OS (p = 0.0001) and DFS (p < 0.0001) than patients with EGFR-MUT and EGFR-WT/KRAS-WT (WT/WT). Patients with codon 12 mutations had superior DFS (p = 0.0314), but there were no differences in OS compared with mutations found in codons 13 and 61 (p = 0.1772). We observed better DFS associated with G12C/G12V mutations compared with other amino acid specific KRAS mutations (p = 0.0271) with a trend towards improved OS (p = 0.0636). Multivariate analysis identified KRAS mutation as independent predictor of worse OS (p = 0.001) and DFS (p < 0.0001).
KRAS is an independent prognostic marker in resected stage I lung adenocarcinoma. Differential outcomes are associated with codon and amino acid specific KRAS mutations.
Aims
Lipomatous tumours of the orbit are rare, and can sometimes be difficult to characterize. Herniated orbital fat is thought to be a reactive process, but its presentation can mimic a lipomatous ...tumour such as an atypical lipomatous tumour or spindle cell/pleomorphic lipoma. Genetic studies to determine if it is indeed a reactive process rather than an adipocytic neoplasm have not been performed.
Methods and results
Four samples of herniated orbital fat were reviewed clinically, histopathologically and immunohistochemically. Array comparative genomic hybridization (aCGH) was used to search for genome‐wide copy number alterations within the tumours. Histological evaluation revealed that all four tumours contained collections of adipocytes surrounded by fibrous septae. Lochkern cells and floret‐like multinucleated giant cells were present, consistent with herniated orbital fat. CD34 was positive in all tumours. Staining for MDM2 and CDK4 was negative. ACGH analysis demonstrated no copy number alterations.
Conclusions
Herniated orbital fat may share some histopathological features with lipoma and atypical lipomatous tumour, but the absence of copy number gains or losses is consistent with the impression that herniated orbital fat is a reactive process. Genetic analysis may be another method to help differentiate herniated orbital fat from a lipomatous orbital tumour when the diagnosis is in question.
We present histological and molecular analyses of the developing human cerebellum from 30 days after conception to 9 months after birth. Differences in developmental patterns between humans and mice ...include spatiotemporal expansion of both ventricular and rhombic lip primary progenitor zones to include subventricular zones containing basal progenitors. The human rhombic lip persists longer through cerebellar development than in the mouse and undergoes morphological changes to form a progenitor pool in the posterior lobule, which is not seen in other organisms, not even in the nonhuman primate the macaque. Disruptions in human rhombic lip development are associated with posterior cerebellar vermis hypoplasia and Dandy-Walker malformation. The presence of these species-specific neural progenitor populations refines our insight into human cerebellar developmental disorders.
Cefazolin is the preoperative antibiotic of choice because it is safer and more efficacious than second-line alternatives. Surgical patients labeled as having penicillin allergy are less likely to ...prophylactically receive cefazolin and more likely to receive clindamycin or vancomycin, which results in higher rates of surgical site infections.
To examine the incidence of dual allergy to cefazolin and natural penicillins.
MEDLINE/PubMed, Web of Science, and Embase were searched without language restrictions for relevant articles published from database inception until July 31, 2020.
In this systematic review and meta-analysis, a search of MEDLINE/PubMed, Web of Science, and Embase was performed for articles published from database inception to July 31, 2020, for studies that included patients who had index allergies to a natural penicillin and were tested for tolerability to cefazolin or that included patients who had index allergies to cefazolin and were tested for tolerability to a natural penicillin. A total of 3228 studies were identified and 2911 were screened for inclusion.
Data were independently extracted by 2 authors. Bayesian meta-analysis was used to estimate the frequency of allergic reactions.
Dual allergy to cefazolin and a natural penicillin.
Seventy-seven unique studies met the eligibility criteria, yielding 6147 patients. Cefazolin allergy was identified in 44 participants with a history of penicillin allergy, resulting in a dual allergy meta-analytical frequency of 0.7% (95% credible interval CrI, 0.1%-1.7%; I2 = 74.9%). Such frequency was lower for participants with unconfirmed (0.6%; 95% CrI, 0.1%-1.3%; I2 = 54.3%) than for those with confirmed penicillin allergy (3.0%; 95% CrI, 0.01%-17.0%; I2 = 88.2%). Thirteen studies exclusively assessed surgical patients (n = 3884), among whom 0.7% (95% CrI, 0%-3.3%; I2 = 85.5%) had confirmed allergy to cefazolin. Low heterogeneity was observed for studies of patients with unconfirmed penicillin allergy who had been exposed to perioperative cefazolin (0.1%; 95% CrI, 0.1%-0.3%; I2 = 13.1%). Penicillin allergy was confirmed in 16 participants with a history of cefazolin allergy, resulting in a meta-analytical frequency of 3.7% (95% CrI, 0.03%-13.3%; I2 = 64.4%). The frequency of penicillin allergy was 4.4% (95% CrI, 0%-23.0%; I2 = 75%) for the 8 studies that exclusively assessed surgical patients allergic to cefazolin.
These findings suggest that most patients with a penicillin allergy history may safely receive cefazolin. The exception is patients with confirmed penicillin allergy in whom additional care is warranted.
While gliomas are the most common primary brain tumors, their etiology is largely unknown. To identify novel risk loci for glioma, we conducted genome-wide association (GWA) analysis of two ...case-control series from France and Germany (2269 cases and 2500 controls). Pooling these data with previously reported UK and US GWA studies provided data on 4147 glioma cases and 7435 controls genotyped for 424 460 common tagging single-nucleotide polymorphisms. Using these data, we demonstrate two statistically independent associations between glioma and rs11979158 and rs2252586, at 7p11.2 which encompasses the EGFR gene (population-corrected statistics, P
c = 7.72 × 10−8 and 2.09 × 10−8, respectively). Both associations were independent of tumor subtype, and were independent of EGFR amplification, p16INK4a deletion and IDH1 mutation status in tumors; compatible with driver effects of the variants on glioma development. These findings show that variation in 7p11.2 is a determinant of inherited glioma risk.
Abstract
Growing research in geriatric medicine is a priority area. Currently, involvement of geriatricians in research lags behind other specialties. The reasons for this are multifactorial, but a ...lack of training infrastructure within geriatric medicine higher specialist training is contributory. This is widespread across European countries and internationally. The Geriatric Medicine Research Collaborative (GeMRC) offers an opportunity to engage trainees in research, regardless of their previous individual research experiences. Utilising national trainee networks, GeMRC is able to conduct large-scale projects within short periods of time that can have real impact upon patient care. We consider that embedding GeMRC within higher specialist training with formal college support will assist to upskill trainee geriatricians in research methodology. Collaboratives are internationally recognised across disciplines. Expansion across European and international countries offers the opportunity for international collaboration in geriatric medicine. International trainee-led networks will enable the conduct of large-scale global projects in geriatric medicine.
Most nurses in the United States have experienced workplace bullying, also referred to as lateral violence. Workplace bullying is serious within professional nursing practice. These behaviors are ...often associated with detrimental consequences for nurses, their patients, and the greater health care organization. We performed a literature review to summarize recent studies on this pervasive yet persistent problem as well as evidence-based solutions. In environments where managers, supervisors, and administrators are unable or unwilling to address lateral violence, a common pattern is that offenders continue to target new employees and cause turmoil for workers and patients in healthcare settings. This work environment also causes harm and endangers patients. Although workplace bullying cannot be fixed with just one solution, there are different initiatives healthcare settings and educational institutions can implement to help prevent and eliminate workplace bullying, such as improving leadership training and interprofessional communication. Once these initiatives are put into practice, healthcare practices can start saving money, increasing employee satisfaction, retaining workers, and providing better healthcare services for their patients.
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