An evaluation of progression free survival and overall survival of ovarian cancer patients with clear cell carcinoma versus serous carcinoma treated with platinum therapy: An NRG Oncology/Gynecologic Oncology Group experience.

PURPOSE: We examined disparities in prognosis between patients with ovarian clear cell carcinoma (OCCC) and serous epithelial ovarian cancer (SOC). METHODS: We reviewed data from FIGO stage I-IV epithelial ovarian cancer patients who participated in 12 prospective randomized GOG protocols. Proportional hazards models were used to compare progression-free survival (PFS) and overall survival (OS) by cell type (clear cell versus serous). RESULTS: There were 10,803 patients enrolled, 9531 were eligible, evaluable and treated with platinum, of whom 544 (6%) had OCCC, 7054 (74%) had SOC, and 1933 (20%) had other histologies and are not included further. In early stage (I-II) patients, PFS was significantly better in OCCC than in SOC patients. For late stage (III, IV) patients, OCCC had worse PFS and OS compared to SOC, OS HR=1.66 (1.43, 1.91; p<0.001). After adjusting for age and stratifying by protocol and treatment arm, stage, performance status, and race, OCCC had a significantly decreased OS, HR=1.53 (1.33, 1.76; p<0.001). In early stage cases, there was a significantly decreased treatment effect on PFS for consolidative therapy with weekly Paclitaxel versus observation in OCCC compared to SOC (p=0.048). CONCLUSIONS: This is one of the largest analyses to date of OCCC treated on multiple cooperative group trials. OCCC histology is more common than SOC in early stage disease. When adjusted for prognostic factors, in early stage patients, PFS was better for OCCC than for SOC; however, in late-stage patients, OCCC was significantly associated with decreased OS. Finally, treatment effect was influenced by histology.

Establishment and characterization of a platinum- and paclitaxel-resistant high grade serous ovarian carcinoma cell line.

High grade serous ovarian cancer (HGSOC) patients have a high recurrence rate after surgery and adjuvant chemotherapy due to inherent or acquired drug resistance. Cell lines derived from HGSOC tumors that are resistant to chemotherapeutic agents represent useful pre-clinical models for drug discovery. Here, we describe establishment of a human ovarian carcinoma cell line, which we term WHIRC01, from a patient-derived mouse xenograft established from a chemorefractory HGSOC patient who did not respond to carboplatin and paclitaxel therapy. This newly derived cell line is platinum- and paclitaxel-resistant with cisplatin, carboplatin, and paclitaxel half-maximal lethal doses of 15, 130, and 20 µM, respectively. Molecular characterization of this cell line was performed using targeted DNA exome sequencing, transcriptomics (RNA-seq), and mass spectrometry-based proteomic analyses. Results from exomic sequencing revealed mutations in TP53 consistent with HGSOC. Transcriptomic and proteomic analyses of WHIRC01 showed high level of alpha-enolase and vimentin, which are associated with cell migration and epithelial-mesenchymal transition. WHIRC01 represents a chemorefractory human HGSOC cell line model with a comprehensive molecular profile to aid future investigations of drug resistance mechanisms and screening of chemotherapeutic agents.

Survival advantage of marriage in uterine cancer patients contrasts poor outcome for widows: a Surveillance, Epidemiology and End Results study.

BACKGROUND: Marriage confers a survival advantage for many cancers but has yet to be evaluated in uterine cancer patients. We sought to determine whether uterine cancer survival varied by self-reported relationship status. METHODS: Data were downloaded from the Surveillance, Epidemiology, and End Results program for women diagnosed with uterine cancer (between 1991 and 2010 in nine geographic regions). Patients with complete clinical data for analysis were categorized as married, single, widowed or other (divorced or separated). Differences in distributions were evaluated using Chi-square, exact and/or Mantel-Haenszel test. Uterine cancer survival was analyzed by Kaplan-Meier method with log-rank test and multivariate Cox regression analysis. RESULTS: Of 47,420 eligible patients, 56% were married, 15% were single and 19% were widows. Married vs. non-married women had a higher likelihood of having low risk (grade 1/2 endometrioid) endometrial cancer and local disease (p<0.0001), and a reduced risk of cancer death (HR=0.8, 95% CI=0.77-0.84). Multivariate evaluation of uterine cancer survival by relationship type indicated that widows consistently had significantly worse uterine cancer survival than single, married and other women in all patients and subset analyses (p<0.0001). CONCLUSION: While marital status is associated with differential uterine cancer survival, evaluation of self-reported relationship by type indicated that the poor outcome observed in widows explained most of the benefit attributed to marriage. This report identifies widows as a new high-risk subpopulation with significantly inferior outcomes potentially benefiting from personalized care and social support.

MEK1/2 inhibitors in the treatment of gynecologic malignancies.

Mitogen-activated protein kinases (MAPKs) are a family of ubiquitous eukaryotic signal transduction enzymes which link extracellular stimuli to intracellular gene expression pathways. While several three-tiered MAPK cascades have been elucidated in mammals, the prototypical pathway involves a network of proteins and kinases including the Rat sarcoma protein (Ras), mitogen-activated protein kinase kinase kinase (Raf or MAP3K), mitogen-activated protein kinase kinase (MEK or MAP2K), and extracellular signal regulated protein kinase (ERK or MAPK). This MAPK cascade (the Ras/Raf/MEK/ERK pathway) is a receptor tyrosine kinase mediated signaling pathway that regulates cell proliferation, cell cycle progression, and cell migration. There are multiple molecular mechanisms of interaction and activation between the upstream nodes of the Ras/Raf/MEK/ERK cascade and other cell signaling pathways, all ultimately leading to the activation of the nuclear transcription factor ERK. Important downstream targets include MEK1/2, which comprise the final step leading to ERK transcription factor activation. While multiple conduits exist to activate ERK upstream of MEK, there is little redundancy downstream. Located at this pivotal intersection between a limited number of upstream activators and its exclusive downstream targets, MEK is an appealing molecular target of novel cancer therapies. MEK inhibitors are small molecules that inhibit MEK phosphorylation by binding to a pocket adjacent to the ATP binding site, decreasing both the amount of MEK activity, and the quantity of activated ERK in the cell. Unique allosteric noncompetitive binding sites of MEK inhibitors allow specific targeting of MEK enzymes and prevent cross-activation of other serine/threonine protein kinases through the conserved ATP binding site. This paper reviews the translational evidence in favor of MEK inhibitors in cancer, their role in gynecologic malignancies, and details regarding the status of the fourteen MEK inhibitors currently being clinically tested: trametinib, selumetinib, pimasertib, refametinib, PD-0325901, MEK162, TAK733, RO5126766, WX-554, RO4987655, cobimetinib, AZD8330, MSC2015103B, and ARRY-300.

Spontaneous Resolution of Mirror Syndrome following Demise of Hydropic Twin.

Maternal mirror syndrome is a rare consequence of fetal hydrops. By convention, delivery is recommended in pregnancies complicated by mirror syndrome due to grave fetal prognosis. We describe a case of a dichorionic, diamniotic twin gestation complicated by hydrops fetalis of twin B. The patient declined selective feticide. Two weeks later, intrauterine fetal demise of fetus B was diagnosed and complete resolution of mirror syndrome followed. Unaddressed, mirror syndrome can lead to significant maternal and fetal complications. This case illustrates resolution of mirror syndrome following spontaneous intrauterine demise of the hydropic fetus.

Innovation in hospital quality improvement activities--acute postoperative pain management (APOP) self-help toolkit audits as an example.

It is often difficult to maintain quality improvement change. Many behavioral strategies have been used to improve uptake of new practices and knowledge. One effective way of changing medication prescribing is audit and feedback with specific educational feedback. The challenge however is to maintain ongoing quality improvement activities. In Australia, unique downloadable "toolkits" are now available to assist hospitals to maintain prescribing quality improvement activities. The first designed to improve the management of acute postoperative pain (APOP toolkit) has been piloted. The toolkit includes data collection and educational tools, an automated feedback report on key indicators, with complete instructions for use. The APOP toolkit has been used in 73 hospitals, in two facilitated "snapshot" audits. There was continued improvement in performance, assessed by increases in the percentage of patients with measured pain and sedation scores and in those with documented pain management plans at discharge, compared with earlier APOP project audits. Using this example of the APOP toolkit and "snapshot" audits, we have now demonstrated that hospitals nationwide are able to undertake quality improvement activities voluntarily to maintain optimal performance. Encouragement, guidance, and availability of ready-made tools developed by a national team facilitate opportunities for ongoing quality improvements.

Standardization of a sample preparation and analytical workflow for proteomics of archival endometrial cancer tissue.

The goal of the present study was to establish a standard operating procedure for mass spectrometry (MS)-based proteomic analysis of laser microdissected (LMD) formalin-fixed, paraffin-embedded (FFPE) uterine tissue. High resolution bioimage analysis of a large endometrial cancer tissue microarray immunostained for the breast cancer type 1 susceptibility protein enabled precise counting of cells to establish that there is an average of 600 cells/nL of endometrial cancer tissue. We sought to characterize the peptide recovery from various volumes of tissue gathered by LMD and processed/digested using the present methodology. We observed a nearly linear increase in peptide recovery amount with increasing tissue volume dissected. There was little discernible difference in the peptide recovery from stromal versus malignant epithelium, and there was no apparent difference in the day-to-day recovery. This methodology reproducibly results in 100 ng of digested peptides per nL of endometrial tissue, or ∼25 pg peptides/endometrial cancer cell. Results from liquid chromatography (LC)-MS/MS experiments to assess the impact of total peptide load on column on the total number of peptides and proteins identified from FFPE tissue digests prepared with the present methodology indicate a demonstrable increase in the total number of peptides identified up to 1000 ng, beyond which diminishing returns were observed. Furthermore, we observed no impact on the peptide identification rates from analyses of equivalent peptide amounts derived from lower volume LMD samples. These results show that this single-tube collection-to-injection proteomics (CTIP) workflow represents a straightforward, scalable, and highly reliable methodology for sample preparation to enable high throughput LMD-MS analysis of tissues derived from biopsy or surgery.

Racial disparities in histopathologic characteristics of uterine cancer are present in older, not younger blacks in an equal-access environment.

OBJECTIVE: We sought to determine whether racial disparities in tumor characteristics among uterine cancer patients persisted, and varied by age, in an equal-access healthcare population. METHODS: The distributions of tumor histology, stage and grade by race were compared for uterine cancers diagnosed from 1990 to 2003 using data from the U.S. Department of Defense's Automated Central Tumor Registry. Comparisons were conducted overall and stratified by age (<50, ≥50) using the Chi-square test. RESULTS: Of 2582 uterine tumors identified, 2057 (79.7%) were diagnosed among White women and 183 (7.1%) among Black women. Among all women analyzed, Blacks were more likely than Whites to present with non-endometrioid tumors (47.7% vs 23.5%, p<0.01), non-localized tumors (31.8% vs 24.5%, p=0.02), and poorly differentiated tumors (20.5% vs 15.0%, p<0.01). Among women 50 years and older, similar significant racial disparities were observed. However, no significant racial differences were observed among young patients. When comparisons were restricted to endometrioid histology adenocarcinomas, trends in age-specific disparities for older women were observed. CONCLUSIONS: Our study suggests that racial disparities in uterine cancers persist between Blacks and Whites in an equal-access population. Blacks endure higher stage and grade tumors, and more aggressive histologies. This disparity in clinicopathologic factors is confined to women older than 50 years. Multiple factors such as racial variation in age-related health knowledge/behavior and estrogen metabolism may be related to the racial disparity.

A phase I trial of gemcitabine in combination with patupilone in patients with advanced solid tumors.

INTRODUCTION: Chemotherapy regimens including gemcitabine in combination with microtubule inhibitors such as docetaxel and paclitaxel have wide clinical application. Patupilone is a novel tubulin-polymerizing agent with activity against paclitaxel-resistant cell lines. We conducted a phase I trial to assess the maximum tolerated dose, dose limiting toxicity (DLT) and antitumor activity of gemcitabine and patupilone. METHODS: Patients with refractory solid tumors enrolled in cohorts of three. Cohorts received fixed doses of gemcitabine (1,000 or 750 mg/m(2)) along with escalating doses of patupilone (1.5-3 mg/m(2)) on days 1 and 8 of a 21-day cycle. RESULTS: Twenty-seven patients received a total of 99 courses of treatment on study. Hematologic toxicity in the first cohort required a modification of the protocol to decrease the gemcitabine dose. Subsequent patients received gemcitabine 750 mg/m(2) and escalating doses of patupilone from 1.5 to 3 mg/m(2). DLTs were grade 3 asthenia and grade 3 dehydration. There was also one treatment-related death due to neutropenic infection. Other clinically significant toxicities were persistent asthenia and persistent nausea. Four patients, one each with pancreatic cancer, esophageal carcinoma, cholangiocarcinoma and gallbladder carcinoma, experienced a partial response. CONCLUSIONS: The dose-limiting toxicities of gemcitabine and patupilone were asthenia and dehydration. Dose reductions also occurred due to persistent fatigue that was not dose-limiting. However, patients with advanced malignancies were able to tolerate gemcitabine and patupilone at doses that resulted in clinical benefit. The recommended phase II dose for this schedule is gemcitabine 750 mg/m(2) and patupilone 1.5 mg/m(2) on days 1 and 8 of a 21-day cycle.

Effect of atorvastatin on cognitive function in patients from the Lipid Lowering and Onset of Renal Disease (LORD) trial.

STUDY OBJECTIVE: To examine the effect of atorvastatin on cognitive function by testing two hypotheses: that atorvastatin 10 mg/day would impair cognitive function, and that other biochemical and demographic measures would better predict cognitive performance than atorvastatin alone. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Two primary acute care settings in the north and northwest of Tasmania, Australia. PATIENTS: Fifty-seven patients from the Lipid Lowering and Onset of Renal Disease (LORD) trial. INTERVENTION: Participants were randomly assigned to receive either atorvastatin 10 mg/day or matching placebo. Cognitive testing was performed in two sessions occurring 12 weeks apart and involved three repeated measures of attention and concentration. MEASUREMENTS AND MAIN RESULTS: Performance was measured using three standard neuropsychological tests: Digit Symbol Coding subtest, Trail Making Test, and Stroop Color-Word Reading Test. Patients received atorvastatin for a mean of 72.93 weeks and placebo for a mean of 68.85 weeks. Repeated-measures multivariate analysis of variance failed to identify any significant differences between the two groups on any of the three cognitive measures. Multiple regression analyses identified no single factor or combination of plasma cholesterol levels, renal function, liver function, or age that predicted cognitive performance in either the atorvastatin or placebo group on the three measures at either testing session. CONCLUSION: Atorvastatin 10 mg/day did not produce decrements to cognitive performance. In addition, biochemical and demographic measures and the receipt of atorvastatin versus placebo did not individually or in combination predict cognitive performance on measures of attention and concentration.

OR expansion--a journey into the unknown.

WATCHING A CONSTRUCTION PROJECT mature from concept to culmination is a journey of both professional and personal growth. EFFECTIVE PLANNING and communication are essential for a project to be successful. SUCCESSES AND FAILURES provide learning experiences.