Spatial metabolomics reveals glycogen as an actionable target for pulmonary fibrosis.

Matrix assisted laser desorption/ionization imaging has greatly improved our understanding of spatial biology, however a robust bioinformatic pipeline for data analysis is lacking. Here, we demonstrate the application of high-dimensionality reduction/spatial clustering and histopathological annotation of matrix assisted laser desorption/ionization imaging datasets to assess tissue metabolic heterogeneity in human lung diseases. Using metabolic features identified from this pipeline, we hypothesize that metabolic channeling between glycogen and N-linked glycans is a critical metabolic process favoring pulmonary fibrosis progression. To test our hypothesis, we induced pulmonary fibrosis in two different mouse models with lysosomal glycogen utilization deficiency. Both mouse models displayed blunted N-linked glycan levels and nearly 90% reduction in endpoint fibrosis when compared to WT animals. Collectively, we provide conclusive evidence that lysosomal utilization of glycogen is required for pulmonary fibrosis progression. In summary, our study provides a roadmap to leverage spatial metabolomics to understand foundational biology in pulmonary diseases.

Spatiotemporal Analysis of Lung Cancer Histological Types in Kentucky, 1995-2014.

Recent metabolic and genetic research has demonstrated that risk for specific histological types of lung cancer varies in relation to cigarette smoking and obesity. This study investigated the spatial and temporal distribution of lung cancer histological types in Kentucky, a largely rural state with high rates of smoking and obesity, to discern population-level trends that might reflect variation in these and other risk factors. The Kentucky Cancer Registry provided residential geographic coordinates for lung cancer cases diagnosed from 1995 through 2014. We used multinomial and discrete Poisson spatiotemporal scan statistics, adjusted for age, gender, and race, to characterize risk for specific histological types-small cell, adenocarcinoma, squamous cell, and other types-throughout Kentucky and compared to maps of risk factors. Toward the end of the study period, adenocarcinoma was more common among all population subgroups in north-central Kentucky, where smoking and obesity are less prevalent. During the same time frame, squamous cell, small cell, and other types were more common in rural Appalachia, where smoking and obesity are more prevalent, and in some high poverty urban areas. Spatial and temporal patterns in the distribution of histological types of lung cancer are likely related to regional variation in multiple risk factors. High smoking and obesity rates in the Appalachian region, and likely in high poverty urban areas, appeared to coincide with high rates of squamous cell and small cell lung cancer. In north-central Kentucky, environmental exposures might have resulted in higher risk for adenocarcinoma specifically.

EML4-ALK rearrangement in squamous cell carcinoma shows significant response to anti-ALK inhibitor drugs crizotinib and alectinib.

EML4-ALK alterations are more common in adenocarcinomas and are rarely found in squamous cell histology. In documented cases, the majority of EML4-ALK translocations are identified in squamous cell histology and occur in patients with no or light smoking history. We report an EML4-ALK4 translocation in a 50-year-old patient with squamous cell carcinoma and an 18 pack-year smoking history. The patient had a near complete response in the CNS to alectinib treatment. Our observation suggests that EML4-ALK genomic testing may be clinically useful in patients with heavy smoking history.

Chondromyxoid fibroma of the second rib.

Chondromyxoid fibromas are benign tumors which are found most frequently in the metaphyses of long bones. They comprise less than 1% of primary bone neoplasms and display a hypermetabolic appearance on PET imaging. Oftentimes, they are misdiagnosed as chondrosarcomas and are excised due to concern for malignancy. We present a case of a condromyxoid fibroma originating from the second rib of a 15-year-old girl.

Lung transplantation in patients with coal workers' pneumoconiosis.

Patients with coal workers' pneumoconiosis (CWP) can develop chronic respiratory failure and require lung transplantation. A retrospective review was performed of the 712 referrals and 143 patients undergoing unilateral or bilateral lung transplantation at the University of Kentucky Medical Center between January 1999 and July 2009. Twenty-one of the 712 referrals (3%) had a diagnosis of CWP with eight patients eventually undergoing lung transplant (six single, two bilateral). The mean age of the cohort was 53 ± 5 (mean ± SD) yr (range 45-59). There was no increased risk of perioperative or postoperative complications. Six patients (75%) remain alive after a mean follow-up of 1013 ± 857 d with the two deaths attributable to sepsis 683 and 145 d after transplant, respectively. There were no pulmonary complications because of the native lung in patients after a single lung transplant, with otherwise good clinical outcomes seen after lung transplantation.

FDG PET/CT findings of a glomangiopericytoma.

Glomangiopericytoma (GPC) is a rare vascular neoplasm that arises almost exclusively from the nasal cavity or paranasal sinuses. GPC is also called sinonasal-type hemangiopericytoma, although current nomenclature, as well as classification in a group with myopericytomas, better emphasizes the relatively indolent behavior of this tumor. The authors present the FDG PET/CT findings of GPC in a 53-year-old with symptoms of nasal congestion and facial pressure. CT and MRI showed a nasal mass to extend along the sphenoid ridge from the posterior nasal cavity into the posterior nasopharynx. PET showed the mass to have uniformly low-grade FDG hypermetabolism. Pathologic examination of the surgical specimen showed classic features of GPC.

FDG PET of alveolar soft part sarcoma.

Alveolar soft part sarcoma (ASPS) is a very rare, but distinctive type of soft tissue sarcoma, whose name is derived from the pseudoalveolar appearance of its histology. In this report, the FDG PET/CT findings of ASPS are described in a 17-year-old asthmatic female who presented with worsening respiratory symptoms and a pelvic mass. The staging PET showed heterogeneous intense incorporation of FDG within the mass and variable FDG incorporation within the multiple lung nodules. In concordance with other soft tissue sarcomas, PET/CT helped to confirm the anatomic origin of the ASPS, to direct its biopsy, and to assess the distribution of disease.

Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia: potential contribution to AML progression.

Acute myeloid leukemia (AML) is an aggressive hematological cancer. Despite therapeutic regimens that lead to complete remission, the vast majority of patients undergo relapse. The molecular mechanisms underlying AML development and relapse remain incompletely defined. To explore whether loss of DNA mismatch repair (MMR) function is involved in AML, we screened two key MMR genes, MSH2 and MLH1, for mutations and promoter hypermethylation in leukemia specimens from 53 AML patients and blood from 17 non-cancer controls. We show here that whereas no amino acid alteration or promoter hypermethylation was detected in all control samples, 18 AML patients exhibited either mutations in MMR genes or hypermethylation in the MLH1 promoter. In vitro functional MMR analysis revealed that almost all the mutations analyzed resulted in loss of MMR function. MMR defects were significantly more frequent in patients with refractory or relapsed AML compared with newly diagnosed patients. These observations suggest for the first time that the loss of MMR function is associated with refractory and relapsed AML and may contribute to disease pathogenesis.

Reproducibility of subclassification of squamous intraepithelial lesions: conventional versus ThinPrep paps.

OBJECTIVE: Liquid-based cytologic methods are increasingly used, and classification of squamous intraepithelial lesions (SIL) affects patient management. This study compared interobserver reproducibility in SIL subclassification on conventional (CV) and ThinPrep (TP) cytologic specimens. MATERIALS AND METHODS: Four reviewers independently subclassified SIL on 69 CV and 60 TP Paps. Specimens were retrieved by computer search of biopsy-confirmed SIL cases. A consensus interpretation of low-grade SIL (LSIL) or high-grade SIL (HSIL) was assigned when three or four observers agreed. RESULTS: All four observers agreed in 40 of 69 CV with consensus reached in 56 of 69 CV Paps (81%; 20 LSIL, 36 HSIL). For TP Paps, 38 of 60 had 100% agreement, with consensus reached in 56 of 60 TP Paps (93%; 28 LSIL, 26 HSIL, 2 SIL, difficult to grade). kappa values for all four observers were 0.48 for CV (fair agreement) and 0.63 for TP (substantial). Pairwise kappa values ranged from 0.44 to 0.60 for CV and 0.54 to 0.76 for TP. Most of the nonconsensus cases included SIL, difficult to grade interpretations; in several, the original cytologic or biopsy SIL classification, or both, was also indeterminate, or cytologic and biopsy results did not correlate exactly. High-grade biopsies followed 15% of LSIL CV and 36% of LSIL TP. CONCLUSIONS: Interobserver reproducibility in SIL subclassification may be better on TP Paps; however, both CV and TP have indeterminate lesions with low interobserver agreement. The TP specimens did not show improved correlation with histologic analysis, and specimens with consensus do not always have correlating biopsy findings.

Parathyroid cytology: avoiding diagnostic pitfalls.

BACKGROUND: Interpretation of parathyroid fine-needle aspirates (FNA) remains problematic not only because this type of specimen is rare but also because the pertinent literature is very limited. We systematically reviewed parathyroid FNAs in our files and sought to delineate additional diagnostic criteria. DESIGN: Review of all thyroid and parathyroid aspirates from January 1990 to June 1998 disclosed 12 parathyroid lesions. The final diagnoses included four parathyroid adenomas, one intrathyroidal hyperplastic parathyroid, one intrathyroidal parathyroid adenoma, one atypical parathyroid adenoma (all confirmed by histologic screening or immunocytochemistry), and five parathyroid cysts (all confirmed by immunoassay). Papanicolaou and Diff Quik-stained smears of the parathyroid FNAs were reviewed. The cytologic features were compared and contrasted with those of thyroid FNAs to establish criteria for differential diagnoses. RESULTS: The FNAs of the five parathyroid cysts yielded virtually acellular fluid with a characteristic water-clear appearance and markedly elevated levels of parathyroid hormone. The remaining seven aspirates consisted of moderately cellular smears that showed an admixture of architectural features. Common patterns included cohesive three-dimensional groups, disorganized sheets, papillary fragments, microfollicles, and a single case showing lymphoidlike smears. Although the cells were generally small and round to oval, all cases demonstrated mild to moderate anisokaryosis. The nuclei were hyperchromatic E with coarsely granular chromatin reminiscent of that of small lymphocytes. Occasional nucleoli were noted. Although the cytoplasm was usually pale blue and finely granular with ill-defined borders, two cases showed well-delineated cytoplasmic membranes. Less common findings included cytoplasmic granulation, vacuolization, and rare oxyphilic cells. Naked nuclei were noted in the background of all of the aspirates to varying degrees. Other background findings included the presence of colloidlike material, macrophages, and lymphocytes. One interesting finding that to date has not been reported is the presence of nuclear overlapping (100%) and nuclear molding (71%), which is an uncommon finding in thyroid aspirates. CONCLUSIONS: FNAs of the parathyroid can be easily confused with that of the thyroid, not only because of the clinical similarity between these two types of lesions but also because of the overlap in cytomorphologic features of the aspirated cells. Although no one single cytomorphologic feature is diagnostic, a combination of cytologic parameters noted earlier should raise the possibility of a parathyroid lesion. Aspirates of parathyroid cysts show acellular water-clear fluid with elevated parathyroid hormone measurements.