Benefit of Radiotherapy in Extraskeletal Myxoid Chondrosarcoma: A Propensity Score Weighted Population-based Analysis of the SEER Database.

OBJECTIVES: Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignancy for which the role of radiotherapy is not well-defined. We examine the effect of external beam radiotherapy (EBRT) on cancer-specific survival (CSS) for patients with localized EMC, in a propensity score weighted, population-based analysis. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results database (1973 to 2012) was queried for cases of localized EMC arising from soft connective tissues of the trunk and extremities treated with surgery and/or EBRT. Inverse probability treatment weighting was utilized, with survival analysis by weighted Cox regression and Kaplan-Meier analysis with log-rank testing. The primary endpoint was CSS. RESULTS: One hundred seventy-two patients were identified, diagnosed from 2004 to 2012. Ninety-four percent and 32% of 156 assessable patients underwent surgery and EBRT, respectively. By inverse probability treatment weighting, balancing covariates of age group, sex, race, grade, T stage, N stage, receipt of surgery, and anatomic site, we observed CSS of 97% versus 85% and 94% versus 85% in patients receiving EBRT versus no EBRT, at 3 and 5 years, respectively, at median follow-up of 33 months, P=0.01. A trend toward an overall survival benefit associated with EBRT was noted, P=0.06. Further adjusting for type of resection performed, CSS benefit persisted, 97% versus 85% at 3 years and 94% versus 85% at 5 years, P=0.02, with trend toward an overall survival benefit, P=0.08. CONCLUSIONS: The receipt of EBRT is associated with a CSS benefit in localized EMC. Aggressive local therapy, including EBRT, should be considered in these patients.

Pancreatic mucinous cystic neoplasm in a transgender patient.

BACKGROUND: Cystic pancreatic lesions are increasingly more frequent detected clinical entities. Mucinous cystic neoplasm (MCN) is a hormone-related pancreatic tumor (HRTP) with a strong predominance in young and middle-aged females. CASE PRESENTATION: Here, we present the case of a 31-year-old surgically transgendered female-to-male patient with a history of alcoholic pancreatitis, on chronic testosterone therapy. He was found to have a pancreatic MCN and underwent distal pancreatectomy and splenectomy. CONCLUSION: To our knowledge, this is the first reported case of a transgender patient with a history of hormone replacement therapy (HRT) and pancreatic MCN. We consider possible mechanisms for the pathogenesis to explain this patient's neoplasm.

Pseudotetraploid clone with structural chromosomal rearrangements in a chondromyxoid fibroma: a case report.

Chondromyxoid fibroma is a rare benign tumor accounting for 1-2% of primary bone tumors. Most of the patients are young males in the 2nd and 3rd decades of life. Metaphyses of long bones are predominantly affected. The histology of this tumor is well established, but its genetic mechanism remains poorly characterized. To our knowledge, only 22 abnormal cytogenetic analyses have been reported, and all contained diploidy or near-diploidy karyograms as their primary event, and inv(6)(p25)(q13) and rearrangements involving regions 6p23-25, 6q12-15, and 6q23-27 constituted a recurrent observation. In this report, a pseudotetraploidy tumor clone with multiple numerical and structural aberrations involving 6p23 as well as other chromosomal loci was identified in a chondromyxoid fibroma from the metaphysis of the left fibula of an 18-year-old male, which has not been reported. The finding may relate to the atypical-looking large cells often seen in this benign tumor.

Porcine intact and wounded skin responses to atmospheric nonthermal plasma.

Thermal plasma is a valued tool in surgery for its coagulative and ablative properties. We suggested through in vitro studies that nonthermal plasma can sterilize tissues, inactive pathogens, promote coagulation, and potentiate wound healing. The present research was undertaken to study acute toxicity in porcine skin tissues. We demonstrate that floating electrode-discharge barrier discharge (FE-DBD) nonthermal plasma is electrically safe to apply to living organisms for short periods. We investigated the effects of FE-DBD plasma on Yorkshire pigs on intact and wounded skin immediately after treatment or 24h posttreatment. Macroscopic or microscopic histological changes were identified using histological and immunohistochemical techniques. The changes were classified into four groups for intact skin: normal features, minimal changes or congestive changes, epidermal layer damage, and full burn and into three groups for wounded skin: normal, clot or scab, and full burn-like features. Immunohistochemical staining for laminin layer integrity showed compromise over time. A marker for double-stranded DNA breaks, γ-H2AX, increased over plasma-exposure time. These findings identified a threshold for plasma exposure of up to 900s at low power and <120s at high power. Nonthermal FE-DBD plasma can be considered safe for future studies of external use under these threshold conditions for evaluation of sterilization, coagulation, and wound healing.

Decreased cervical epithelial sensitivity to nonoxynol-9 (N-9) after four daily applications in a murine model of topical vaginal microbicide safety.

BACKGROUND: The disappointing clinical failures of five topical vaginal microbicides have provided new insights into factors that impact microbicide safety and efficacy. Specifically, the greater risk for human immunodeficiency virus type 1 (HIV-1) acquisition associated with multiple uses of a nonoxynol-9 (N-9)-containing product has highlighted the importance of application frequency as a variable during pre-clinical microbicide development, particularly in animal model studies. METHODS: To evaluate an association between application frequency and N-9 toxicity, experiments were performed using a mouse model of cervicovaginal microbicide safety. In this model system, changes in cervical and vaginal epithelial integrity, cytokine release, and immune cell infiltration were assessed after single and multiple exposures to N-9. RESULTS: After the initial application of N-9 (aqueous, 1%), considerable damage to the cervical epithelium (but not the vaginal epithelium) was observed as early as 10 min post-exposure and up to 8 h post-exposure. Subsequent daily exposures (up to 4 days) were characterized by diminished cervical toxicity relative to single exposures of like duration. Levels of pro-inflammatory cytokines released into the cervicovaginal lumen and the degree of CD14-positive immune cell infiltration proximal to the cervical epithelium were also dependent on the number of N-9 exposures. CONCLUSIONS: Rather than causing cumulative cervical epithelial damage, repeated applications of N-9 were characterized by decreased sensitivity to N-9-associated toxicity and lower levels of immune cell recruitment. These results provide new insights into the failure of N-9-based microbicides and illustrate the importance of considering multiple exposure protocols in pre-clinical microbicide development strategies.

Breast cancer cell surface annexin II induces cell migration and neoangiogenesis via tPA dependent plasmin generation.

Annexin II, an abundant phospholipids binding cell surface protein, binds tPA and functions as a regulator of fibrinolysis. Annexin II also mediates angiogenesis and enhances tumor growth and metastasis. However, the mechanism supporting this role is not known. Using human breast cancer model we show that invasive human breast cancer cells (MDA-MB231) synthesize annexin II and tissue plasminogen activator (tPA). In vitro both annexin II and tPA interacts which in turn convert zymogen plasminogen to reactive enzyme plasmin. Cell surface produced plasmin inhibited the migration of MDA-MB231 cells. Silencing of annexin II gene in MDA-MB231 cells abolished tPA binding therefore inhibited tPA dependent plasmin generation. These annexin II suppressed MDA-MB231 cells showed reduced motility. Immunohistochemical analysis of prediagnosed clinical specimens showed abundant secretion of tPA and expression of annexin II on the surface of invasive human breast cancer cells which correlates with neovascularization of the tumor. Taken together, these data indicate that annexin II may regulate localized plasmin generation in breast cancer. This may be an early event switching breast cancer from the prevascular phase to the vascular phase and thus contributing to aggressive cancer with the possibility of metastasis. The data provide a mechanism explaining the role of annexin II in breast cancer progression and suggest that annexin II may be an attractive target for therapeutic strategies aimed to inhibit angiogenesis and breast cancer.

Interpreting the histopathology of chronic cough: a prospective, controlled, comparative study.

HYPOTHESIS: Trauma from chronic coughing produces airway inflammation similar to diseases causing cough. DESIGN: Prospective, cross-sectional, controlled, clinicopathologic correlation study in four groups: group 1, cough from intrapulmonary diseases; group 2, cough from extrapulmonary diseases; group 3, cough that was unexplained; and group 4, nonsmoking, asymptomatic control subjects. METHODS: Patients with chronic cough underwent a standardized workup including endobronchial biopsies before treatment. Causes were determined by a favorable response to therapy. Bronchial biopsy samples from control subjects were obtained from surgical specimens. RESULTS: There were 24 adult subjects (13 women and 11 men) with mean cough duration of 8.6 +/- 7.4 years (+/- SD). Thirteen patients had cough due to a specific disease: intrapulmonary diseases in 5 patients, and extrapulmonary diseases in 8 patients. Eleven patients had unexplained cough. Compared to control subjects, there was minimal-to-moderate chronic inflammation in all coughers (p < or = 0.0004), in group 1 (p < or = 0.039), group 2 (p = 0.061), and group 3 (p < or = 0.025) diseases that were not correlated with cough duration. There was no difference in type of inflammation, cough duration, or smoking history between groups, nor were there histologic differences between subjects with explained causes of cough compared with unexplained cough. CONCLUSIONS: Our findings suggest that airway inflammation associated with chronic cough, assessed on morphologic appearance and inflammatory cell counting in hematoxylin-eosin-prepared samples, may be due to the trauma of coughing, and the inflammation may be similar to that seen with diseases putatively thought to cause chronic cough. Investigators must be cautious when attributing pathogenic importance to observed inflammatory changes in airways of coughing subjects.

Angiogenesis-associated protein annexin II in breast cancer: selective expression in invasive breast cancer and contribution to tumor invasion and progression.

Many advanced human tumors including breast cancer overproduce plasmin that is known to promote angiogenesis and metastasis. The mechanism of this effect is poorly understood. Here we report that annexin II, an endothelial co-receptor for tPA (tissue-type plasminogen activator) and plasminogen, was undetectable in normal and hyperplastic ductal epithelial cells and ductal complexes. By contrast, it was consistently expressed in invasive breast cancer and ductal carcinoma in situ (DCIS) indicating its involvement in breast cancer. Using the well established invasive/metastatic MDA-MB231 cell line and the noninvasive/nonmetastatic MCF-7 human breast cancer cell line, we investigated the mechanism by which annexin II regulates breast cancer progression and metastasis. Western and Northern blot analyses demonstrate selective expression of annexin II in MDA-MB231 cells but not in poorly invasive MCF-7 cells suggesting its participation in invasive breast cancer. Since annexin II is a receptor for plasminogen, we tested whether MDA-MB231 cells are capable of producing plasmin in vitro. MDA-MB231 cell membranes induced plasmin generation in a time-dependent manner while those from MCF-7 cells failed to convert plasminogen to plasmin. The generated plasmin is capable of degrading ECM consequently facilitating cell invasion and migration, biological functions required for angiogenesis and metastasis. Plasmin generation and its dependent invasion and migration can be blocked by a monoclonal antibody to annexin II or angiostatin, potent inhibitors of angiogenesis, breast cancer, and metastasis. Our findings indicate that annexin II-dependent localized plasmin generation by human breast cancer cells could contribute to angiogenesis and metastasis. These results suggest that annexin II may be an attractive target for new anti-angiogenic and anti-breast cancer therapies.