Hidradenoma Papilliferum With Oncocytic Metaplasia: A Histopathological and Immunohistochemical Study.

Hidradenoma papilliferum is a benign cutaneous adnexal neoplasm, commonly occurring in the vulva and perianal region of adult women. It has characteristic histopathological features composed of anastomosing and branching tubules, lined by columnar cells, and a basal layer of myoepithelial cells. A 39-year-old woman was evaluated for 2 asymptomatic labial masses. The histopathological examination revealed a Bartholin's cyst and a hidradenoma papilliferum. The latter contains a distinct area of oncocytic/oxyphilic metaplasia. Immunohistochemical stains revealed positive staining for gross cystic disease fluid protein (GCDFP)-15 and androgen receptor. GATA-3, a protein expressed in sweat glands, highlights a similar positive staining pattern with weaker staining in areas of oncocytic metaplasia. P63 highlighted the myoepithelial differentiation. In situ hybridization for Human Papilloma Virus 6, 11, 16, and 18 was negative. P53 was negative and Ki-67 was low, confirming its benign nature. Oncocytes are enlarged epithelial cells with voluminous eosinophilic granular cytoplasm resulting from staining of nonribosomal cytoplasmic components. Few reports documented it in hidradenoma papilliferum. Our case demonstrated a florid distinct appearance of this metaplasia. The immunoprofiles of this oncocytic metaplasia such as p53 negativity and positivity for androgen receptor and GCDFP-15 demonstrates similarity to apocrine metaplasia in the breast. The authors' case demonstrates the benign nature of oncocytic metaplasia and supports the common origin of oncocytic cells and columnar cells in hidradenoma papilliferum.

Isoform-specific and protein kinase C-mediated regulation of CTP:phosphoethanolamine cytidylyltransferase phosphorylation.

CTP:phosphoethanolamine cytidylyltransferase (Pcyt2) is the main regulatory enzyme for de novo biosynthesis of phosphatidylethanolamine by the CDP-ethanolamine pathway. There are two isoforms of Pcyt2, -α and -ß; however, very little is known about their specific roles in this important metabolic pathway. We previously demonstrated increased phosphatidylethanolamine biosynthesis subsequent to elevated activity and phosphorylation of Pcyt2α and -ß in MCF-7 breast cancer cells grown under conditions of serum deficiency. Mass spectroscopy analyses of Pcyt2 provided evidence for isoform-specific as well as shared phosphorylations. Pcyt2ß was specifically phosphorylated at the end of the first cytidylyltransferase domain. Pcyt2α was phosphorylated within the α-specific motif that is spliced out in Pcyt2ß and on two PKC consensus serine residues, Ser-215 and Ser-223. Single and double mutations of PKC consensus sites reduced Pcyt2α phosphorylation, activity, and phosphatidylethanolamine synthesis by 50-90%. The phosphorylation and activity of endogenous Pcyt2 were dramatically increased with phorbol esters and reduced by specific PKC inhibitors. In vitro translated Pcyt2α was phosphorylated by PKCα, PKCßI, and PKCßII. Pcyt2α Ser-215 was also directly phosphorylated with PKCα. Mapping of the Pcyt2α- and -ß-phosphorylated sites to the solved structure of a human Pcyt2ß showed that they clustered within and flanking the central linker region that connects the two catalytic domains and is a novel regulatory segment not present in other cytidylyltransferases. This study is the first to demonstrate differences in phosphorylation between Pcyt2 isoforms and to uncover the role of the PKC-regulated phosphorylation.

Obesity and the risk of stillbirth: a population-based cohort study.

OBJECTIVE: Obesity is a known risk factor for stillbirth. However, this relationship has not been characterized fully. We attempted to further examine this relationship with a focus on delivery near and at term. STUDY DESIGN: We designed a retrospective cohort study of singleton nonanomalous live births and stillbirths in the states of Washington and Texas to examine the associations of maternal prepregnancy body mass index (BMI) and risk of stillbirth. Confounder-adjusted hazard ratio of stillbirth in relation to BMI was estimated through Cox proportional hazards regression model. The hazard ratio was used to estimate the population-attributable risk. We also estimated the fetuses who were at risk for stillbirth based on gestational age. RESULTS: Among 2,868,482 singleton births, the overall stillbirth risk was 3.1 per 1000 births (n = 9030). Compared with normal-weight women, the hazard ratio for stillbirth was 1.36 for overweight women, 1.71 for class I obese women, 2.00 for class II obese women, 2.48 for class III obese women, and 3.16 for women with a BMI of ≥50 kg/m(2). The fetuses who are at risk for stillbirth increased after 39 weeks' gestation for each obesity class; however, the risk increased more rapidly with increasing BMI. Women with a BMI of ≥50 kg/m(2) were at 5.7 times greater risk than normal weight women at 39 weeks' gestation and 13.6 times greater at 41 weeks' gestation. Obesity was associated with nearly 25% of stillbirth that occurred between 37 and 42 weeks' gestation. CONCLUSION: There is a pronounced increase in the risk of stillbirth with increasing BMI; the association is strongest at early- and late-term gestation periods. Extreme maternal obesity is a significant risk factor for stillbirth.

Forms, crosstalks, and the role of phospholipid biosynthesis in autophagy.

Autophagy is a highly conserved cellular process occurring during periods of stress to ensure a cell's survival by recycling cytosolic constituents and making products that can be used in energy generation and other essential processes. Three major forms of autophagy exist according to the specific mechanism through which cytoplasmic material is transported to a lysosome. Chaperone-mediated autophagy is a highly selective form of autophagy that delivers specific proteins for lysosomal degradation. Microautophagy is a less selective form of autophagy that occurs through lysosomal membrane invaginations, forming tubes and directly engulfing cytoplasm. Finally, macroautophagy involves formation of new membrane bilayers (autophagosomes) that engulf cytosolic material and deliver it to lysosomes. This review provides new insights on the crosstalks between different forms of autophagy and the significance of bilayer-forming phospholipid synthesis in autophagosomal membrane formation.

Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib.

PURPOSE: In patients with epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma, treatment with erlotinib or gefitinib is associated with a 75% radiographic response rate and progression-free survival of approximately 12 months. The most common mechanism of acquired resistance to erlotinib is development of a secondary mutation in EGFR, suggesting that these tumors continue to depend on EGFR signaling. We hypothesized that combined EGFR blockade would overcome acquired resistance to erlotinib in patients with lung adenocarcinoma. To evaluate the toxicity and efficacy of cetuximab and erlotinib in patients with acquired resistance to erlotinib, we conducted this phase I/II clinical trial. EXPERIMENTAL DESIGN: Patients with lung adenocarcinoma and clinically defined acquired resistance to erlotinib were treated with erlotinib 100 mg daily, along with cetuximab every 2 weeks in three escalating dose cohorts (250 mg/m(2), 375 mg/m(2), and 500 mg/m(2)). The recommended phase II dose was then evaluated in a two-stage trial, with a primary end point of objective response rate. RESULTS: A total of 19 patients were enrolled. The most common toxicities for the combination of cetuximab and erlotinib were rash, fatigue, and hypomagnesemia. The recommended phase II dose identified was cetuximab 500 mg/m(2) every 2 weeks and erlotinib 100 mg daily. At this dose and schedule, no radiographic responses were seen (0 of 13, 0%, 95% CI, 0-25). CONCLUSIONS: Combined EGFR inhibition, with cetuximab 500 mg/m(2) every 2 weeks and erlotinib 100 mg daily, had no significant activity in patients with acquired resistance to erlotinib.

Sexual oncology: sexual health issues in women with cancer.

Sexual problems are widespread among female cancer patients and survivors. Dysfunction may result from various oncologic therapies such as surgery, radiation therapy, chemotherapy, hormonal manipulation, and cytostatic medication. Additionally, psychologic distress that the patient or her partner experiences during diagnosis and treatment of malignancy can impair a healthy female sexual response cycle. A sexual rehabilitation program in an oncology setting is necessary to provide comprehensive care to the cancer patient and her partner. A multidisciplinary treatment approach to sexual dysfunction includes psychological and psychiatric intervention, medical intervention, cognitive behavioral therapy, and recommended lifestyle adjustments. A holistic approach to assessing and treating sexual concerns should be individually tailored to the female patient in light of her disease stage and prognosis, age, marital status, fertility concerns, and social and professional environment.