Clear Cell Cancer of the Uterine Corpus: The Association of Clinicopathologic Parameters and Treatment on Disease Progression

This paper presents a single-institution experience regarding the clinicopathologic features and treatment strategies used in uterine clear cell cancer (UCC), a rare, aggressive histologic subtype of uterine cancer with poor prognosis and discusses parameters associated with progression-free survival (PFS) and overall survival (OS). A retrospective chart review was performed on all patients (n = 80) diagnosed with UCC and treated between 1994 and 2009 at a single academic institution. Data on demographics, FIGO stage, treatment regimens, and recurrences were collected. Patients with early-stage UCC had an excellent survival regardless of adjuvant therapy. Advanced-stage patients had a worse survival. Vaginal apex brachytherapy was associated with an increased OS (P = 0.02) but not PFS (P = 0.10). The use of platinum-based chemotherapy in combination with vaginal apex brachytherapy did not significantly improve survival. Innovative therapies still need to be identified for this uncommon uterine cancer

An approach to shortening the timeframe between the emergence of new compounds on the drugs market and the availability of reference standards: the microscale syntheses of nitrazolam and clonazolam, for use as reference materials, utilizing polymer supported reagents

Nitrazolam and clonazolam are two designer benzodiazepines that are available from internet retailers and there is growing evidence suggesting that such compounds have the potential to cause severe adverse events. Information about tolerability in humans is scarce but typically, low doses can be difficult to administer for users when handling bulk material and variability of the active ingredient in tablet formulations can also be of a concern. Customs, toxicology and forensic laboratories are increasingly encountering designer benzodiazepines, both in tablet and powdered forms, and the unavailability of reference standards can impact on the ability to identify these compounds. Therefore, the need arises for exploring in-house approaches to the preparation of NPS that can be carried out in a timely manner. The present study was triggered when samples of clonazolam were received in powdered and tablet form at a time when reference material for this drug was commercially unavailable. Therefore, microscale syntheses of clonazolam and its deschloro analogue nitrazolam were developed utilizing polymer supported-reagents starting from 2-amino-5-chlorobenzophenone (clonazolam) and 2-amino-5-nitrobenzophenone (nitrazolam). The final reaction step forming the 1,2,4-triazole ring moiety was performed within the GC-MS injector. A comparison with a preparative scale synthesis of both benzodiazepine derivatives showed that microscale synthesis might be an attractive option for a forensic laboratory in terms of time and cost savings when compared with traditional methods of synthesis and when qualitative identifications are needed to direct forensic casework. The reaction by-product profiles for both the micro and preparative scale syntheses are also presented

Expression of Tissue factor in Adenocarcinoma and Squamous Cell Carcinoma of the Uterine Cervix: Implications for immunotherapy with hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor

<p>Abstract</p> <p>Background</p> <p>Cervical cancer continues to be an important worldwide health problem for women. Up to 35% of patients who are diagnosed with and appropriately treated for cervical cancer will recur and treatment results are poor for recurrent disease. Given these sobering statistics, development of novel therapies for cervical cancer remains a high priority. We evaluated the expression of Tissue Factor (TF) in cervical cancer and the potential of hI-con1, an antibody-like-molecule targeted against TF, as a novel form of immunotherapy against multiple primary cervical carcinoma cell lines with squamous- and adenocarcinoma histology.</p> <p>Methods</p> <p>Because TF is a transmembrane receptor for coagulation factor VII/VIIa (fVII), in this study we evaluated the <it>in vitro </it>expression of TF in cervical carcinoma cell lines by immunohistochemistry (IHC), real time-PCR (qRT-PCR) and flow cytometry. Sensitivity to hI-con1-dependent cell-mediated-cytotoxicity (IDCC) was evaluated in 5-hrs-⁵¹chromium-release-assays against cervical cancer cell lines <it>in vitro</it>.</p> <p>Results</p> <p>Cytoplasmic and/or membrane TF expression was observed in 8 out of 8 (100%) of the tumor tissues tested by IHC and in 100% (11 out of 11) of the cervical carcinoma cell lines tested by real-time-PCR and flow cytometry but not in normal cervical keratinocytes (<it>p </it>= 0.0023 qRT-PCR; <it>p </it>= 0.0042 flow cytometry). All primary cervical cancer cell lines tested overexpressing TF, regardless of their histology, were highly sensitive to IDCC (mean killing ± SD, 56.2% ± 15.9%, range, 32.4%-76.9%, <it>p </it>< 0.001), while negligible cytotoxicity was seen in the absence of hI-con1 or in the presence of rituximab-control-antibody. Low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (<it>p </it>= 0.025) while human serum did not significantly decrease IDCC against cervical cancer cell lines (<it>p </it>= 0.597).</p> <p>Conclusions</p> <p>TF is highly expressed in squamous and adenocarcinoma of the uterine cervix. hI-con1 induces strong cytotoxicity against primary cervical cancer cell lines overexpressing TF and may represent a novel therapeutic agent for the treatment of cervical cancer refractory to standard treatment modalities.</p

The Role of Voltage-Dependent Anion Channel in Mitochondrial Dysfunction and Human Disease

The voltage-dependent anion channel (VDAC) is a β-barrel membrane protein located in the outer mitochondrial membrane (OMM). VDAC has two conductance states: an open anion selective state, and a closed and slightly cation-selective state. VDAC conductance states play major roles in regulating permeability of ATP/ADP, regulation of calcium homeostasis, calcium flux within ER-mitochondria contact sites, and apoptotic signaling events. Three reported structures of VDAC provide information on the VDAC open state via X-ray crystallography and nuclear magnetic resonance (NMR). Together, these structures provide insight on how VDAC aids metabolite transport. The interaction partners of VDAC, together with the permeability of the pore, affect the molecular pathology of diseases including Parkinson’s disease (PD), Friedreich’s ataxia (FA), lupus, and cancer. To fully address the molecular role of VDAC in disease pathology, major questions must be answered on the structural conformers of VDAC. For example, further information is needed on the structure of the closed state, how binding partners or membrane potential could lead to the open/closed states, the function and mobility of the N-terminal α-helical domain of VDAC, and the physiological role of VDAC oligomers. This review covers our current understanding of the various states of VDAC, VDAC interaction partners, and the roles they play in mitochondrial regulation pertaining to human diseases

Influence of the labrum on version and diameter of the glenoid: a morphometric study using magnetic resonance images

To use magnetic resonance imaging to determine the influence of the labrum on both the osseous version and effective diameter of the glenoid.This was a retrospective, cross-sectional study of patients with shoulder pain who\ua0underwent MRI between February 2014 and February 2015. The morphology of the glenoid labrum and glenoid was scanned with a 3-T magnetic resonance imaging scanner, and variables were measured by use of IntelliSpace PACS Enterprise. Patients were included if they were aged between 18 and 40\ua0years and the radiologist reported a normal glenohumeral joint or if they were young patients aged less than 30\ua0years with acute traumatic isolated partial- or full-thickness tears of the rotator cuff with a history of symptoms of less than 3\ua0months. A pilot study was conducted with 3 observers and 3 repeated measurements at intervals to determine the interobserver and intraobserver reliability. Data analysis included descriptive statistics of measured variables, as well as paired Student t tests to determine the relative difference between labral and osseous morphometric variables.Excellent inter-rater reliability (0.95-0.96) and intrarater reliability (0.93-0.98) were obtained in the pilot study of 20 patients. The study population was composed of 100 patients with a mean age of 37.3\ua0years (standard deviation [SD], 11.8\ua0years), having a gender distribution of 56 male and 44 female patients; there were 53 right and 47 left shoulders. The glenoid osseous version measured\ua0-5.7° (SD, 5.3°), and the labral version measured\ua0-10° (SD, 5.5°); the glenoid osseous diameter measured 28.0\ua0mm (SD, 3.3\ua0mm), and the labral diameter measured 31.9\ua0mm (SD, 3.2\ua0mm). The labrum significantly increased the version by 4.3° (P\ua0= .001) and significantly increased the diameter by 3.9\ua0mm\ua0(P\ua0= .001).The results of this study showed that the labrum increased the effective glenoid version by 75% (4.3° of retroversion) and the effective glenoid diameter by 14% (3.9\ua0mm).Level IV, prognostic case series

Accuracy in Referrals to Gynecologic Oncologists Based on Clinical Presentation for Ovarian Mass

Ovarian cancer is one of the most lethal gynecological cancers in women due to late diagnosis. Despite technological advancements, experienced physicians have high sensitivities and specificities in subjective assessments when combining ultrasound findings and clinical history in analyzing adnexal masses. This study aims to demonstrate general obstetricians and gynecologists&rsquo; (OB/GYN) appropriateness in gynecologic oncologist referrals for malignant ovarian masses based on history and physical (H&amp;P), imaging, and available tumor markers. Three board certified OB/GYNs were given 148 cases and determined whether or not they would refer them to a gynecologic oncologist. Results showed that OB/GYNs were 81&ndash;85% accurate in diagnosing patients with a benign or malignant disease. Among the malignant cases, reviewers had a high sensitivity ranging from 74&ndash;81% in appropriately referring a malignancy. In our study, OB/GYNs referred between 23&ndash;32% of ovarian masses to a gynecologic oncologist with only 9.5% of cases found to be malignant. Despite the high referral rates, generalists showed a high degree of sensitivity in accurately referring malignant diseases based solely on clinical experience and imaging studies, which could improve survival rates with early intervention by gynecologic oncologists

High-grade, chemotherapy-resistant primary ovarian carcinoma cell lines overexpress human trophoblast cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized monoclonal anti-Trop-2 antibody

We evaluated the expression of human trophoblast cell-surface marker (Trop-2) and the potential of hRS7, a humanized monoclonal anti-Trop-2 antibody, as a therapeutic agent against chemotherapy-resistant ovarian disease