Fine‐needle aspiration of alveolar soft part sarcoma: Histologic correlation and aberrant CD68 expression

Alveolar soft part sarcoma is a rare highly malignant neoplasm of the soft tissue and usually occurs in the lower extremities of children and young adults. We report two cases of alveolar soft part sarcoma: a 24‐year‐old Latino man with a 10‐ cm neck mass and a 56‐year‐old Latino woman with a recurring thigh mass. Fine‐needle aspiration and a core biopsy were performed on both, which was followed by tumor resection on the man. The smears displayed numerous loosely cohesive or single large cells with abundant granular cytoplasm, round nuclei, vesicular chromatin, and occasional prominent nucleoli. Periodic and Schiff (PAS)‐positive, diastase‐resistant rhomboid, or needle‐shaped crystals were present. Both tumors had diffuse and strong nuclear TFE3 expression and aberrant cytoplasmic CD68 expression. Fluorescence in situ hybridization analysis was performed in the first case, which detected a characteristic translocation t(X;17)(p11;q25). The diagnosis of alveolar soft part sarcoma was rendered in both cases. Herein, we present the cytology, histology, immunohistochemistry, and molecular findings and discuss the differential diagnosis.     

Cognitive fusion and depressive symptoms in women with chronic pain: A longitudinal growth curve modelling study over 12 months

This study aims to (a) explore individual differences in women with chronic pain (CP) in regard to pain intensity, functional impairment, cognitive fusion, and depressive symptoms and (b) longitudinally test whether cognitive fusion is a significant predictor of depression symptoms, while controlling for pain intensity and functional impairment, over a 12‐month period. This study follows a longitudinal design and was conducted in a sample of 86 women with CP who responded to an online battery of questionnaires in three equally spaced assessment moments. In order to explore the growth trajectory of variables of interest, latent growth curve models were examined. Also, correlation analyses were conducted between demographic and illness‐related variables and depressive symptoms, as well as between all variables in all assessment moments. Cognitive fusion and functional impairment (but not pain intensity) were significantly associated with baseline levels of depressive symptoms. Cognitive fusion significantly predicted the growth trajectory of depressive symptoms, whereas pain intensity and functional impairment did not. No demographic (age, marital status, education, socio‐economic) nor illness‐related variables (number of CP diagnoses, duration of CP, taking medication) were associated with depressive symptoms at any point. These results suggest that the trajectory of depressive symptoms in women with CP is not predicted by the intensity of pain nor pain‐related functional impairment, but rather by the tendency to get entangled with internal experiences (e.g., thoughts, emotions, and physical sensations), which may or may not be related to pain‐specific contents. Clinical implications are discussed.     

CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials

Small molecule pharmacological inhibition of dominant human genetic disease is a feasible treatment that does not rely on the development of individual, patient‐specific gene therapy vectors. However, the consequences of protein inhibition as a clinical therapeutic are not well‐studied. In advance of human therapeutic trials for CAPN5 vitreoretinopathy, genetic inactivation can be used to infer the effect of protein inhibition in vivo. We created a photoreceptor‐specific knockout (KO) mouse for Capn5 and compared the retinal phenotype to both wild‐type and an existing Capn5 KO mouse model. In humans, CAPN5 loss‐of‐function (LOF) gene variants were ascertained in large exome databases from 60,706 unrelated subjects without severe disease phenotypes. Ocular examination of the retina of Capn5 KO mice by histology and electroretinography showed no significant abnormalities. In humans, there were 22 LOF CAPN5 variants located throughout the gene and in all major protein domains. Structural modeling of coding variants showed these LOF variants were nearby known disease‐causing variants within the proteolytic core and in regions of high homology between human CAPN5 and 150 homologs, yet the LOF of CAPN5 was tolerated as opposed to gain‐of‐function disease‐causing variants. These results indicate that localized inhibition of CAPN5 is a viable strategy for hyperactivating disease alleles.     

Extension of the Pompe mutation database by linking disease‐associated variants to clinical severity

Pompe disease is an autosomal recessive lysosomal storage disorder caused by disease‐associated variants in the acid alpha‐glucosidase (GAA) gene. The current Pompe mutation database provides a severity rating of GAA variants based on in silico predictions and expression studies. Here, we extended the database with clinical information of reported phenotypes. We added additional in silico predictions for effects on splicing and protein function and for cross reactive immunologic material (CRIM) status, minor allele frequencies, and molecular analyses. We analyzed 867 patients and 562 GAA variants. Based on their combination with a GAA null allele (i.e., complete deficiency of GAA enzyme activity), 49% of the 422 disease‐associated variants could be linked to classic infantile, childhood, or adult phenotypes. Predictions and immunoblot analyses identified 131 CRIM negative and 216 CRIM positive variants. While disease‐associated missense variants were found throughout the GAA protein, they were enriched up to seven‐fold in the catalytic site. Fifteen percent of disease‐associated missense variants were predicted to affect splicing. This should be confirmed using splicing assays. Inclusion of clinical severity rating in the Pompe mutation database provides an invaluable tool for diagnosis, prognosis of disease progression, treatment regimens, and the future development of personalized medicine for Pompe disease.