Genomic Alterations in Undifferentiated Malignant Tumors with Rhabdoid Phenotype and Loss of BRG1 Immunoexpression Identified by Fine Needle Aspirates.

OBJECTIVE: Evidence shows that the switch/sucrose nonfermenting chromatin remodeling complex plays a critical role in DNA repair, cancer progression and dedifferentiation. BRG1 is one of its key catalytic subunits. While the loss of BRG1 expression by immunocytochemistry has been identified in a subset of malignancies arising in various sites with undifferentiated/rhabdoid morphology and poor prognosis, the underlying basis for its loss is unclear. METHODS: A retrospective search was conducted in our cytopathology archive for undifferentiated malignant tumors with rhabdoid phenotype and BRG1 loss. Clinical information was obtained from electronic medical records. Next-generation sequencing was performed following macro-dissection of paraffin-embedded cellblock tissue. RESULTS: Three cases were identified; all presented with widely metastatic disease with no previously diagnosed primary malignancy, and subsequently died within 6 months of initial presentation. Cytologically, the aspirates showed dyshesive and undifferentiated cells with rhabdoid features. Extensive immunocytochemical workup demonstrated immunoreactivity with vimentin only and could not establish a specific lineage. BRG1 expression was absent, while INI1 expression was retained. Two cases harbored deleterious mutations in BRG1/SMARCA4. Pathogenic mutations in TP53 were identified in all tumors. CONCLUSIONS: BRG1 deficiency reflects underlying mutation in SMARCA4 gene in some but not all cases, suggesting that additional mechanisms may be causing BRG1 silencing. Pathogenic mutations in TP53 in all tumors are consistent with their highly aggressive nature. Recognizing the cytomorphology of this group of neoplasms and confirming their BRG1-deficient status by immunocytochemistry not only has prognostic implications, but may also impart potentially therapeutic value in the near future.

Profilometric and morphometric response of murine skin to cosmeceutical agents.

OBJECTIVE: To investigate whether topical antiaging compounds can reduce wrinkle depth as noted at replica profilometry with comparable changes in histologic findings in hairless mice. METHODS: Commercial retinoic acid cream, a peptide lotion, and a soy cream were applied to the dorsal skin for 4 weeks. Silicone-negative replicas of treated and untreated skin surface were photographed and evaluated for traditional features of surface roughness. Skin samples were processed using histomorphometry and immunohistochemistry of proliferating cell nuclear antigen. Quantitative light microscopic data were acquired for estimating replication of epidermal keratinocytes, epidermal thickness, and depth of dermal collagen bundles. RESULTS: Data were analyzed by comparing means with 1-way analysis of variance, and significant changes in all measurements were noted. Augmented keratinocyte proliferation and thickening of viable epidermis were observed with all 3 compounds, although a greater effect was found in the retinoic acid and peptide treatment groups. A similar trend was noted with respect to widening of the collagen layer. Epidermal surface roughness manifested maximum smoothing after treatment with the peptide compound. CONCLUSION: The pronounced effects noted with all 3 compounds indicate that topical agents other than retinoic acid may have comparative stimulating effects on the skin in nonirradiated mice.

Radioprotection of osteoblasts by a fractionated dose regimen and amifostine.

BACKGROUND: Radioprotective modalities such as dose fractionation and pharmacologic agents such as amifostine have been used to protect bone and other types of normal tissue from the damaging effects of ionizing radiation without significantly impacting tumor kill. To better understand the cellular mechanism of radioprotection of osseous tissue, the authors sought to determine the effect of dose fractionation and amifostine on isolated osteoblasts. METHODS: Isolated primary rat calvarial osteoblasts were exposed to single or fractionated doses of ionizing radiation both with and without amifostine pretreatment. Endpoints included cell growth (n = 4), vascular endothelial growth factor production as measured by enzyme-linked immunosorbent assay (n = 3), and early osteodifferentiation as measured by a quantitative alkaline phosphatase assay (n = 3). RESULTS: Both dose fractionation and amifostine protect osteoblasts from the growth inhibitory effects of ionizing radiation. Fractionation but not amifostine was protective for hypoxia-induced vascular endothelial growth factor production (used as a surrogate marker of normal osteoblast function). Neither fractionation nor amifostine could prevent the inhibitory effect of ionizing radiation on normal osteoblast osteodifferentiation as measured by alkaline phosphatase production. CONCLUSIONS: Both dose fractionation and amifostine have valid roles as radioprotectants for osteoblasts and can act in an additive fashion. Radioprotection of cell growth and viability does not necessarily correlate with preservation of normal cellular function. Combination protocols involving dose fractionation and amifostine may be effective in radioprotection of osteoblasts and normal osseous tissue.