Genomic landscape of inverted urothelial papilloma and urothelial papilloma of the bladder.

Inverted urothelial papilloma (IUP) and urothelial papilloma (UP) are rare urothelial neoplasms that typically follow a benign clinical course. Oncogenic mutations in FGFR3, HRAS, and the TERT promoter have been reported in these entities but no comprehensive molecular analysis has been performed. We sought to characterize the genomic landscape of IUP and UP using whole-exome and targeted next-generation sequencing. In IUP, 10 of 11 tumors harbored oncogenic hotspot mutations in HRAS and the remaining tumor had an oncogenic KRAS mutation. None of the IUP tumors harbored TERT promoter or FGFR3 mutations. In UP, 8 of 11 tumors had oncogenic KRAS mutations and two had oncogenic HRAS mutations. One UP tumor had oncogenic mutations in FGFR3, PIK3CA, and the TERT promoter, and arose in a patient with recurrent non-invasive papillary urothelial carcinomas. In contrast to urothelial carcinoma, the APOBEC mutational signature was not present in any IUP and UP tumors, and oncogenic alterations in chromatin remodeling genes were uncommon in both IUP and UP. The current study suggests that IUP and UP are driven primarily by RAS pathway activation and lack the more common genomic features of urothelial cancers. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

MED12 somatic mutations in fibroadenomas and phyllodes tumours of the breast.

AIMS: Somatic mutations in exon 2 of the mediator complex subunit 12 (MED12) gene have been identified in 60% of breast fibroadenomas (FAs). The aim of this study was to define whether phyllodes tumours (PTs) would harbour MED12 somatic mutations in a way akin to FAs. METHODS AND RESULTS: A collection of 73 fibroepithelial tumours (including 26 FAs, 25 benign PTs, nine borderline PTs and 13 malignant PTs) from 64 patients was retrieved from the authors' institution. Sections from formalin-fixed paraffin-embedded (FFPE) blocks were microdissected to ensure an enrichment in neoplastic stromal elements of >70%. DNA samples extracted from tumour and matched normal tissues were subjected to Sanger sequencing of exon 2 of the MED12 gene. MED12 exon 2 somatic mutations, including 28 somatic single nucleotide variants and 19 insertions and deletions, were found in 65%, 88%, 78% and 8% of FAs, benign PTs, borderline PTs and malignant PTs, respectively. Malignant PTs harboured MED12 exon 2 somatic mutations significantly less frequently than FAs, benign and borderline PTs. CONCLUSIONS: Although MED12 exon 2 somatic mutations probably constitute the driver genetic event of most FAs, benign and borderline PTs, our results suggest that the majority of malignant PTs may be driven by other genetic/epigenetic alterations.

The emerging technique of electromagnetic navigation bronchoscopy-guided fine-needle aspiration of peripheral lung lesions: promising results in 50 lesions.

BACKGROUND: Literature on the diagnostic yield of electromagnetic navigation bronchoscopy (ENB) with ENB-guided fine-needle aspiration (ENB-FNA) in peripheral lung lesions (PLLs) that measure ≤ 2 cm is scarce. Data on the diagnostic yield of ENB-FNA for PLLs when performed in conjunction with positron emission tomography-computed tomography (PET-CT), rapid on-site evaluation (ROSE), ENB-guided bronchial brushing (ENB-BB), and ENB-guided transbronchial biopsy (ENB-TBx) is also limited. In this study, the authors evaluated their experience with ENB-FNA performed in conjunction with all 4 modalities: PET-CT, ROSE, ENB-BB, and ENB-TBx. METHODS: ENB-FNA and other tests over a 2-year-period (from July 2011 to July 2013) were retrospectively reviewed. RESULTS: There were 50 PLLs from 40 patients, and the mean lesion size (available for 45 PLLs) was 2.6 cm: these included 24 PLLs that measured ≤ 2 cm and 21 PLLs that measured > 2.0 cm. The ENB-FNA diagnosis was malignant in 17 lesions, atypical in 1 lesion, benign in 31 lesions, and nondiagnostic in 1 lesion. On the basis of lesion size, the diagnostic yield of PLLs was 87% in lesions ≤ 2 cm and 100% in lesions > 2.0 cm (P = 0.5; not significant). Follow-up available in 49 of 50 PLLs from 39 patients had an overall diagnostic yield of 94% for ENB-FNA. The diagnostic yield of PET-CT (available in 31 of 50 PLLs) and of ENB-BB and ENB-TBx (available in 40 of 50 PLLs) in conjunction with ENB-FNA was 61% and 95%, respectively. ROSE was performed in 46 of 50 PLLs: the overall sensitivity of ROSE and ENB-FNA was 85% and 89.4%, respectively, and their specificity was 96.5% and 100%, respectively. There were no procedure-related complications. CONCLUSIONS: The high overall diagnostic yield of 94% and fewer complications make ENB-FNA a useful modality for the assessment of PLLs. In this study, ROSE was useful, whereas PET-CT, ENB-BB, and ENB-TBx were not useful in the evaluation of PLLs.

Contribution of bacterial and viral infections to attributable mortality in patients with severe burns: an autopsy series.

Bacterial infections are a common cause of mortality in burn patients and viral infections, notably herpes simplex virus (HSV) and cytomegalovirus (CMV) have also been associated with mortality. This study is a retrospective review of all autopsy reports from patients with severe thermal burns treated at the US Army Institute of Research (USAISR) burn unit over 12 years. The review focused on those patients with death attributed to a bacterial or viral cause by autopsy report. Of 3751 admissions, 228 patients died with 97 undergoing autopsy. Death was attributed to bacteria for 27 patients and to virus for 5 patients. Bacterial pathogens associated with mortality included Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus. This association with mortality was independent of % total body surface area burn, % full-thickness burn, inhalation injury, and day of death post-burn. Bloodstream infection was the most common cause of bacteria related death (50%), followed by pneumonia (44%) and wound infection (6%). Time to death following burn was < or =7 days in 30%, < or =14 days in 59% and < or =21 days in 67%. All of the viral infections associated with mortality involved the lower respiratory tract, HSV for 4 and CMV for 1. Four of these 5 patients had evidence of inhalation injury by bronchoscopy, all had facial and neck burns, and 2 had concomitant Staphylococcus pneumonia. Time to death following burn ranged from 14 to 42 days for the 5 patients. Despite advances in care, gram negative bacterial infections and infection with S. aureus remain the most common cause of bacteria related mortality early in the hospital course. Viral infections are also associated with mortality and numbers have remained stable when compared to data from prior years.

Incidence of systemic fungal infection and related mortality following severe burns.

Advancements in burn care therapy have extended survival of seriously burned patients, exposing burn patients to increased risk of infectious complications, notably fungal infections. We performed a 12-year review of autopsied patients with severe burns for the presence of fungal infection at the US Army Institute of Surgical Research Burn Center between February 1991 and November 2003. The primary goal was to identify the relationship between fungal element noted in autopsy and mortality, and to determine contributing factors that increase a patient's susceptibility to fungal infection. A total of 228 deaths (6.1%) resulted from the 3751 admissions of which 97 underwent autopsy. Fungal elements were identified on histopathology in 44% (43 of 97) of autopsied patients with an attributable mortality of 33% (14 of 43). Aspergillus and Candida were the most frequently recovered fungi, but Aspergillus was recovered in 13 of the 14 cases with fungus identified as an attributable cause of death. The most common sites of infections with attributable mortality were wounds (86%) and the pulmonary system (14%). Total body surface area (TBSA) burn and length of stay (survival after burn) were identified as contributing factors for the incidence of fungal element in autopsy on ROC curve analysis. More severely injured patients with greater %TBSA burn injury and full-thickness burns require a longer recovery period resulting in a longer hospital stay. The propensity for fungal infection increases the longer the wound is present. Therefore, the development of products to close the wound more rapidly, improvement in topical antifungal therapy with mold activity for treating wounds, and implementation of appropriate systemic antifungal therapy may improve outcome for severely injured burn victims susceptible to fungal infections.