NUT midline carcinoma: an aggressive intrathoracic neoplasm.

Nuclear protein in testis (NUT) midline carcinoma (NMC) is a poorly differentiated squamous cell carcinoma that is characterized by a balanced translocation between chromosomes 15 and 19 [t(15;19)(q14;p13.1)]. This genetic aberration results in the fusion of the NUT gene on chromosome 15 to the bromodomain containing 4 (BRD4) gene on chromosome 19. The resultant BRD4-NUT fusion oncogene leads to global hypoacetylation and transcriptional repression of genes required for differentiation." Although it was first reported in 1991 by Kubonishi et al., awareness of this condition remains low and the diagnosis is overlooked initially in a number of patients. A 36-year-old man complained of cough and right-sided chest pain for 3 weeks before presentation. Imaging studies revealed a right hilar mass, and a bronchoscopic biopsy was consistent with an aggressive poorly differentiated neoplasm. A combination of cisplatin, ifosfamide, and etoposide was administered for two cycles without any improvement. A repeat core biopsy showed focal squamous differentiation; and given the clinical presentation along with the histologic features, NMC was considered in the differential diagnosis. Immunohistochemical staining for NUT was positive, and dual-color break-apart fluorescence in situ hybridization demonstrated BRD4-NUT rearrangement, thereby confirming a diagnosis of NMC. Our patient was subsequently enrolled on a phase 1 clinical trial of a novel, orally bioavailable bromodomain and extra terminal inhibitor, GSK525762 (NCT01587703). This report illustrates the challenges in diagnosing this rare malignancy, and highlights new treatment options for these patients.

Papillary renal cell carcinoma with diffuse clear cells and thyroid-like macrofollicular areas.

Papillary renal cell carcinoma may display some unusual morphologic variations, including diffuse oncocytic change not otherwise specified, oncocytic change associated with an inverted nuclear pattern or nonoverlapping low-grade nuclei, low-grade spindle cells, and diffuse clear cells. Tumors comprised predominantly of thyroid-like follicles and inspissated eosoinophilic, colloid-like secretions (thyroid-like follicular carcinoma of the kidney) have been recently recognized. We report herein an unusual renal carcinoma that displayed diffuse clear cells, papillary architecture, foamy histiocytes, psammomatous calcifications, and large areas (approximately 20% of tumor volume) with thyroid macrofollicular-like structures and eosinophilic, colloid-like secretions. The tumor was diffusely positive for alpha-methylacyl-CoA racemase, cytokeratin 7 and CD10, and was entirely negative for CD15, thyroglobulin, thyroid-transcription factor-1, TFE3, and renal cell carcinoma antigen. Fluorescence in situ hybridization using centromeric DNA probes for chromosomes 7, 17, 3, and 3p25 showed gains only in chromosome 7 and no other aberrations. The tumor was accordingly classified as an unusual morphologic variation of papillary renal cell carcinoma. This case affirms the potential for papillary renal cell carcinoma to display a diffuse complement of clear cells, and documents the heretofore unreported finding of large areas of thyroid macrofollicular structures and eosinophilic, colloid-like secretions in this histotype.

1,5-anhydroglucitol monitoring in diabetes: a mass balance perspective.

1,5-anhydroglucitol (AG) is a nonmetabolizable glucose analogue found in plasma due to ingestion. The normal steady-state concentration can be dramatically decreased by inhibition of tubular reabsorption during periods of hyperglycemia. For this reason, monitoring of AG has been plausibly advocated for detection of periodic glucosuric hyperglycemia. In this review, we examine the influence of variation in factors affecting both steady-state and transient changes in plasma AG. Among normals, the lower and upper limits of the plasma AG reference range vary by a factor of 5. Using a simplified mass balance model (a single compartment model with 3-6x larger-than-plasma volume of distribution), reasonable inter-individual variations of ingestion rate, glomerular filtration rate and fractional post-filtration reabsorption are each able to account for the wide range of normal, steady-state AG concentrations. In monitoring of changes in AG, inter-individual variations in the threshold for glucose excretion, volume of distribution and glomerular filtration rate are all likely to significantly affect correspondence of integral changes in AG to integral glucosuria/hyperglycemia. This combination of variables, affecting both steady-state and transient changes, is significantly confounding with respect to interpretation of serial plasma AG concentrations. Resolution of information content of AG monitoring is thus largely that of crossing simple characterization of deltas [+,0,-] for changes in AG concentration against the information content of hemoglobin A1c monitoring. Despite this limitation, AG monitoring can in principle provide information about glycemic control in the short term that is not apparent through monitoring of hemoglobin A1c alone. However, whether AG monitoring can lead to improved outcomes in diabetes management remains to be established.