PIK3R1, HRAS and AR Gene Alterations Associated with Sclerosing Polycystic Adenoma of the Parotid Gland.

Sclerosing polycystic adenoma (SPA) is a rare neoplasm occurring in the salivary glands, mainly the parotid gland. Although it was originally thought to represent a non-neoplastic process, recent genetic data have proven its monoclonality, supporting its neoplastic origin. We report a case of a 73-year-old woman who presented with left neck swelling and pain. A 3 cm hypoechoic, heterogeneous, solid mass was identified on neck ultrasonography within the left parotid gland. Fine needle aspiration revealed benign acinar cells and lymphocytes. Left partial superficial parotidectomy was performed and a diagnosis of SPA was made. Targeted next-generation sequencing (NGS) revealed three clinically significant alterations in the PIK3R1, HRAS, and AR genes. Alterations in the PIK3R1 gene have been previously reported in cases of SPA; however, this study is the first to report two novel clinically significant genomic alterations in the HRAS and AR genes. AR protein expression by immunohistochemistry was strongly and diffusely positive in the neoplastic epithelial cells compared to the adjacent normal salivary gland tissue, which was dead negative for AR. This molecular profile will enhance our understanding of the molecular pathways underlying the development of this tumor. Although this entity was initially thought to be a reactive process, evidence from our case and similar cases strongly support the notion that it is neoplastic due to the presence of specific genetic alterations linked to it.

Prognostic significance of TP53 mutations and single nucleotide polymorphisms in acute myeloid leukemia: a case series and literature review.

BACKGROUND: The response to treatment and overall survival (OS) of patients with acute myeloid leukemia (AML) is variable, with a median ranging from 6 months to 11.5 years. TP53 is associated with old age, chemotherapy resistance, and worse OS. Using genetic sequencing, we set out to look at our own experience with AML, and hypothesized that both TP53 mutations and SNPs at codon 72 would mimic the literature by occurring in a minority of patients, and conferring a worse OS. MATERIALS AND METHODS: We performed a pilot study of randomly selected, newly diagnosed AML patients at Mount Sinai Medical Center, diagnosed from 2005-2008 (n=10). TP53 PCR sequencing was performed using DNA from bone marrow smears. Analysis was accomplished using Mutation Surveyor software with confirmation of the variants using the COSMIC and dbSNP databases. RESULTS: Fewer than half of the patients harbored TP53 mutations (40%). There was no significant difference in OS based on gender, AML history, risk-stratified karyotype, or TP53 mutation. There were possible trends toward improved survival among patients less than 60 (11 vs 4 months, p=0.09), Hispanics (8 vs 1 months, p=0.11), and those not harboring SNP P72R (8 vs 2 months, p=0.10). There was a significant improvement in survival among patients with better performance status (28 vs 4 months, p=0.01) and those who did not have a complex karyotype (8 vs 1 months, p=0.03). The most commonly observed TP53 mutation was a missense N310K (40%) and the most commonly observed SNP was P72R (100.0%). CONCLUSIONS: Our study confirms previous reports that poor PS and the presence of a complex karyotype are associated with a decreased OS. In our cohort, TP53 mutations were relatively common, occurring more frequently in male patients with an adverse karyotype. Although there was no significant difference in survival between TP53 mutated and un-mutated patients, there was a possible trend toward worse OS among patients with SNP P72R. Larger studies are needed to validate these findings.

Uterine cysts in female mice deficient for caveolin-1 and insulin-like 3 receptor RXFP2.

Gene mutations of insulin-like 3 (INSL3) peptide or its G protein-coupled receptor RXFP2 (relaxin family peptide receptor 2) lead to cryptorchidism. The role of INSL3 in adult females is less known, although INSL3 expression has been described in female reproductive organs. Caveolin-1 (CAV1), the main component of caveoli cell membrane invaginations, has been shown to play an important role in epithelial organization and stromal-epithelial interactions. We created a null allele of Cav1 mice by deleting its second exon through embryonic stem cell targeting. Immunohistochemical analysis demonstrated that CAV1 expression was primarily localized to endothelial blood vessel cells and the myometrium uterus, whereas the strongest expression of Rxfp2 was detected in the endometrial epithelium. By 12 months of age approximately 18% of Cav1-/- females developed single or multiple dilated endometrial cysts lined by a flattened, simple low epithelium. A deficiency for Rxfp2 on Cav1-deficient background led to more than a 2-fold increase in the incidence of uterine cysts (54-58%). Appearance of cysts led to a severe disorganization of uterine morphology. We have found that the cysts had an increased expression of ß-catenin and estrogen receptor ß in endometrial stromal and epithelial cells and increased epithelial proliferation. An analysis of simple dilated cysts in human patients for CAV1 expression did not show appreciable differences with control regardless of menstrual phase, suggesting an involvement of additional factors in human disease. The results of this study suggest a novel synergistic role of INSL3/RXFP2 and CAV1 in structural maintenance of the uterus.

Postmortem demonstration of the source of pulmonary thromboembolism: the importance of the autopsy.

Periprostatic or paravaginal venous thromboses are rarely considered clinically as sites of clot origin in patients with pulmonary thromboembolism. The majority of emboli have been demonstrated to originate in the veins of the legs. This report raises awareness of pelvic vein thrombosis as a potential source of pulmonary embolism that is rarely considered or detected clinically, and which usually requires postmortem examination for recognition. It also reviews the possible routes emboli may take to reach the lungs.

Clinical application of modest hypothermia after spinal cord injury.

There is widespread interest in the use of hypothermia in the treatment of CNS injury. While there is considerable experience in the use of cooling for a variety of brain pathologies, limited data exist after spinal cord injury. In the past few years, technological advances in the induction and maintenance of cooling have been achieved and can potentially allow for a more accurate evaluation of this form of treatment. We report a series of 14 patients with an average age of 39.4 years (range, 16-62 years) with acute, complete (AIS A) cervical spinal cord injuries who underwent a protocol using an intravascular cooling catheter to achieve modest (33 degrees C) systemic hypothermia. There was an excellent correlation between intravascular and intrathecal cerebrospinal fluid temperature. The average time between injury and induction of hypothermia was 9.17 +/- 2.24 h (mean +/- SEM); the time to target temperature was 2.72 +/- 0.42 h; the duration of cooling at target temperature was 47.6 +/- 3.1 h; the average total length of time of cooling was 93.6 +/- 4 h. There was a positive correlation between temperature and heart rate. Most documented adverse events were respiratory in nature. We were able to effectively deliver systemic cooling using the cooling catheters with minimal variation in body temperature. The study represents the largest, modern series of hypothermia treatment of acute spinal cord injury with intravascular cooling techniques and provides needed baseline data for outcome studies to include larger multi-center, randomized trials.