An Uncommon Case of Fungal Rhinosinusitis Caused by the Mold Exserohilum rostratum in a Patient with Relapsed Acute Myeloid Leukemia: Case Report and Review of the Literature.

Invasive fungal infections remain a devastating and potentially deadly complication in the setting of immunocompromised patients, such as in the setting of cancer, transplants, and other immune deficiencies. Infection with dematiaceous molds remains a less common but clear and present etiology. We present here a patient with relapsed acute myeloid leukemia who was neutropenic for a prolonged period. Symptoms worsened during the hospital course, including left-sided sinus swelling, which was also noted on imaging. ENT performed a bedside endoscopy and biopsied an eschar forming in the left nasal cavity. This was ultimately found to be acute invasive rhinosinusitis due to infection with the mold Exserohilum rostratum The patient was started on Posaconazole and Amphotericin B. He eventually also underwent surgical debridement. Infections with this organism are very uncommon, as noted in our literature search. In the diagnostic methods employed in this case, we utilized pathology, culture and microscopy, as well as mass spectrometry which was used to confirm the diagnosis.

Rare surfactant-related variants in familial and sporadic pulmonary fibrosis.

The role of constitutional genetic defects in idiopathic pulmonary fibrosis (IPF) is increasingly appreciated. Monogenic disorders associated with IPF affect two pathways: telomere maintenance, accounting for approximately 10% of all patients with IPF, and surfactant biology, responsible for 1%-3% of cases and often co-occurring with lung cancer. We examined the prevalence of rare variants in five surfactant-related genes, SFTPA1, SFPTA2, SFTPC, ABCA3, and NKX2-1, that were previously linked to lung disease in whole genome sequencing data from 431 patients with IPF. We identified functionally deleterious rare variants in SFTPA2 with a prevalence of 1.3% in individuals with and without a family history of IPF. All individuals had no personal history of lung cancer, but substantial bronchiolar metaplasia was noted on lung explants and biopsies. Five patients had novel missense variants in NKX2-1, but the contribution to disease is unclear. In general, patients were younger and had longer telomeres compared with the majority of patients with IPF suggesting that these features may be useful for identifying this subset of patients in the clinic. These data suggest that SFTPA2 variants may be more common in unselected IPF cohorts and may manifest in the absence of personal/family history of lung cancer or IPF.

Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis.

A comprehensive understanding of the changes in gene expression in cell types involved in idiopathic pulmonary fibrosis (IPF) will shed light on the mechanisms underlying the loss of alveolar epithelial cells and development of honeycomb cysts and fibroblastic foci. We sought to understand changes in IPF lung cell transcriptomes and gain insight into innate immune aspects of pathogenesis.We investigated IPF pathogenesis using single-cell RNA-sequencing of fresh lung explants, comparing human IPF fibrotic lower lobes reflecting late disease, upper lobes reflecting early disease and normal lungs.IPF lower lobes showed increased fibroblasts, and basal, ciliated, goblet and club cells, but decreased alveolar epithelial cells, and marked alterations in inflammatory cells. We found three discrete macrophage subpopulations in normal and fibrotic lungs, one expressing monocyte markers, one highly expressing FABP4 and INHBA (FABP4hi), and one highly expressing SPP1 and MERTK (SPP1hi). SPP1hi macrophages in fibrotic lower lobes showed highly upregulated SPP1 and MERTK expression. Low-level local proliferation of SPP1hi macrophages in normal lungs was strikingly increased in IPF lungs.Co-localisation and causal modelling supported the role for these highly proliferative SPP1hi macrophages in activation of IPF myofibroblasts in lung fibrosis. These data suggest that SPP1hi macrophages contribute importantly to lung fibrosis in IPF, and that therapeutic strategies targeting MERTK and macrophage proliferation may show promise for treatment of this disease.

Next-Generation Sequencing Approach to Non-Small Cell Lung Carcinoma Yields More Actionable Alterations.

CONTEXT: - Different testing algorithms and platforms for EGFR mutations and ALK rearrangements in advanced-stage lung adenocarcinoma exist. The multistep approach with single-gene assays has been challenged by more efficient next-generation sequencing (NGS) of a large number of gene alterations. The main criticism of the NGS approach is the detection of genomic alterations of uncertain significance. OBJECTIVE: - To determine the best testing algorithm for patients with lung cancer in our clinical practice. DESIGN: - Two testing approaches for metastatic lung adenocarcinoma were offered between 2012-2015. One approach was reflex testing for an 8-gene panel composed of DNA Sanger sequencing for EGFR, KRAS, PIK3CA, and BRAF and fluorescence in situ hybridization for ALK, ROS1, MET, and RET. At the oncologist's request, a subset of tumors tested by the 8-gene panel was subjected to a 50-gene Ion AmpliSeq Cancer Panel. RESULTS: - Of 1200 non-small cell lung carcinomas (NSCLCs), 57 including 46 adenocarcinomas and NSCLCs, not otherwise specified; 7 squamous cell carcinomas (SCCs); and 4 large cell neuroendocrine carcinomas (LCNECs) were subjected to Ion AmpliSeq Cancer Panel. Ion AmpliSeq Cancer Panel detected 9 potentially actionable variants in 29 adenocarcinomas that were wild type by the 8-gene panel testing (9 of 29, 31.0%) in the following genes: ERBB2 (3 of 29, 10.3%), STK11 (2 of 29, 6.8%), PTEN (2 of 29, 6.8%), FBXW7 (1 of 29, 3.4%), and BRAF G469A (1 of 29, 3.4%). Four SCCs and 2 LCNECs showed investigational genomic alterations. CONCLUSIONS: - The NGS approach would result in the identification of a significant number of actionable gene alterations, increasing the therapeutic options for patients with advanced NSCLCs.