Anaplastic thyroid carcinoma: diagnostic challenges,histopathologic features and ancillary testing

Anaplastic thyroid carcinoma (ATC) is an aggressive thyroid malignancy with high mortality rate. This malignancy arises in thyroid follicular cells either denovo or with an associated differentiated thyroid carcinoma component. Clinically, it usually presents as a rapidly enlarging mass, pain and locally compressive symptoms. Histopathologic variability and heterogeneity often pose diagnostic challenges, especially in scant and paucicellular specimens. This article describes the clinical, histopathologic and molecular features of ATC and also addresses the associated diagnostic limitations and challenges.     

Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.     

Renal Neoplasia in Tuberous Sclerosis: A Study of 41 Patients

ObjectiveTo study the clinical features and identify unique renal neoplasia subtypes and their prognostic implications in individuals with tuberous sclerosis complex (TSC).Patients and MethodsThe Mayo Clinic nephrectomy registry included 37 patients with TSC diagnosed between 1970 and 2018. Four additional patients were identified from the pathology consultation and autopsy files. All available renal tumors were further characterized using immunohistochemistry and fluorescence in situ hybridization. Clinicopathologic features and follow-up were obtained from the medical record. The American Association for Cancer Research Project GENIE registry was accessed using cBioPortal for molecular profiling of angiomyolipoma (AML).ResultsA total of 276 renal tumors from 41 patients were analyzed. Renal tumors were classified into 9 distinct morphological subtypes, with AML predominating (238 [86%]). Interestingly, all these tumors acted in a benign fashion except one renal cell carcinoma with clear cells and fibromyomatous stroma and one epithelioid AML that metastasized. Molecular profiling studies revealed that epithelioid AMLs were enriched for alterations of TP53, RB1, and ATRX. Eight patients died of direct complications of TSC, including 3 of end-stage renal disease. To date, none have died of a renal epithelial neoplasm.ConclusionThe identification of unique renal neoplasia subtypes may provide important clues to establish a diagnosis of TSC, and in the somatic setting, this finding has important implications for accurate prognostication. These tumors tend to be indolent, and only 2 of 276 tumors in our study exhibited metastatic behavior. Our results support multidisciplinary management with a focus on preservation of renal function.     

Ten years psychosocial outcomes among adolescents following suicide attempts – early recurrence and psychosocial outcomes

ObjectivesA suicide attempt (SA) is a major risk factor of recurrent SA in adolescence and may be associated with psychological or social problems in the future. REPEATERS is a longitudinal study which examines the long-term psychosocial outcome of adolescents following attempted suicide. It focuses on the impact of early recurrence (i.e., within the first year of the index SA) – data which is, in fact, poorly documented.MethodsTen years after the index SA, a self-reporting questionnaire was sent to all adolescents who had attempted suicide and were followed up by the CHRU (Regional University Hospital Centre) de Nancy, France, between 1994 and 2003 and their parents. The purpose of this questionnaire was to assess psychosocial outcomes. Data concerning SA were collected retrospectively.ResultsAfter ten years, 146 of the 309 adolescents who had attempted suicide and were participating in the study had responded: 90% lived with a partner and 41% had children. The mean (SD) current emotional life of suicide attempt survivors scored 7.3 (2.3) on a scale of 0 to 10. Compared to the general population of the same age, responders felt more depressed than their peers (29% vs. less than 8% of males and 20% of females), had more suicidal thoughts (14% vs. 5%), and had more SAs (27% vs. 0.3%). Moreover, the risk of recurrence over the ten year period was associated with suicide recurrence in the first year after the index SA (odds ratio [OR] = 2.3; 95% confidence interval [CI] = 1.1–4.9) and with a lower level of education at ten years (OR = 0.37; 95% CI = 0.19–0.45).ConclusionsAlthough a favorable outcome was reported ten years after the event for the majority of adolescents who had attempted suicide, some with a lower level of education were nevertheless at increased risk of recurrence and depression. Post-intervention strategies are therefore essential in order to evaluate risk factors which may persist if not taken into consideration.     

Prolyl and lysyl hydroxylases in collagen synthesis

Collagens are the most abundant proteins in the extracellular matrix. They provide a framework to build organs and tissues and give structural support to make them resistant to mechanical load and forces. Several intra‐ and extracellular modifications are needed to make functional collagen molecules, intracellular post‐translational modifications of proline and lysine residues having key roles in this. In this article, we provide a review on the enzymes responsible for the proline and lysine modifications, that is collagen prolyl 4‐hydroxylases, 3‐hydroxylases and lysyl hydroxylases, and discuss their biological functions and involvement in diseases.