Effects of web-based instruction and patient preferences on patient-reported outcomes and learning for women with advanced ovarian cancer: A randomized controlled trial.

A randomized controlled trial was conducted of a web-based intervention to improve advanced care planning in women with ovarian cancer. A secondary analysis of 35 randomized women focused on changes in distress and knowledge about ovarian cancer through distress monitoring and information tailored to patients' cognitive coping style (monitoring, blunting). Pre-/postresults indicated the Intervention group demonstrated lower distress (p = 0.06); blunting was associated with lower depression (p = 0.04); knowledge in both groups was unchanged. Women in the Intervention vs. Control group reported their family was less likely to be upset by cancer information (p = 0.0004). This intervention reduced distress while incorporating patient preferences.

Excess Cost of Cervical Cancer Screening Beyond Recommended Screening Ages or After Hysterectomy in a Single Institution.

OBJECTIVE: The aim of the study was to estimate the excess cost of guideline nonadherent cervical cancer screening in women beyond the recommended screening ages or posthysterectomy in a single healthcare system. MATERIALS AND METHODS: All Pap tests performed between September 1, 2012, and August 31, 2014, in women younger than 21 years, older than 65 years, or after hysterectomy, were coded as guideline adherent or nonadherent per the 2012 America Society of Colposcopy and Clinical Pathology guidelines. We assumed management of abnormal results per the 2013 America Society of Colposcopy and Clinical Pathology management guidelines. Costs were obtained from a literature review and Center for Medicare and Medicaid Services data and applied to nonadherent screening and subsequent diagnostic tests. RESULTS: During this period, 1,398 guideline nonadherent Pap tests were performed (257 in women <21 years, 536 in women >65 years, and 605 after hysterectomy), with 88 abnormal results: 35 (13.5%) in women younger than 21 years, 14 (2.6%) in women older than 65 years, and 39 (6.5%) in women after hysterectomy. The excess cost for initial screening, diagnostic tests, and follow-up was US $35,337 for 2 years in women younger than 21 years, US $54,378 for 5 years in women older than 65 years, and US $77,340 for 5 years in women after hysterectomy, resulting in a total excess cost of US $166,100 for 5 years. Of the 1,398 women who underwent guideline nonadherent screening, there were only 2 (0.1%) diagnoses of high-grade dysplasia (VaIN3). CONCLUSIONS: Guideline nonadherent cervical cancer screening in women beyond the recommended screening ages and posthysterectomy resulted in costs exceeding US $160,000 for screening, diagnostic tests, and follow-up with minimal improvement in detection of high-grade dysplasia.

Single Health System Adherence to 2012 Cervical Cancer Screening Guidelines at Extremes of Age and Posthysterectomy.

OBJECTIVE: To estimate the proportion of guideline nonadherent Pap tests in women aged younger than 21 years and older than 65 years and posthysterectomy in a single large health system. Secondary objectives were to describe temporal trends and patient and health care provider characteristics associated with screening in these groups. METHODS: A retrospective cross-sectional chart review was performed at Fairview Health Services and University of Minnesota Physicians. Reasons for testing and patient and health care provider information were collected. Tests were designated as indicated or nonindicated per the 2012 cervical cancer screening guidelines. Point estimates and descriptive statistics were calculated. Patient and health care provider characteristics were compared between indicated and nonindicated groups using χ and Wilcoxon rank-sum tests. RESULTS: A total of 3,920 Pap tests were performed between September 9, 2012, and August 31, 2014. A total of 257 (51%; 95% confidence interval [CI] 46.1-54.9%) of tests in the younger than 21 years group, 536 (40%; 95% CI 37.7-43.1%) in the older than 65 years group, and 605 (29%; 95% CI 27.1-31.0%) in the posthysterectomy group were not indicated. White race in the older than 65 years group was the only patient characteristic associated with receipt of a nonindicated Pap test (P=.007). Health care provider characteristics associated with nonindicated Pap tests varied by screening group. Temporal trends showed a decrease in the proportion of nonindicated tests in the younger than 21 years group but an increase in the posthysterectomy group. CONCLUSION: For women aged younger than 21 years and older than 65 years and posthysterectomy, 35% of Pap tests performed in our health system were not guideline-adherent. There were no patient or health care provider characteristics associated with guideline nonadherent screening across all groups.

Evaluation of the performance of the ACS NSQIP surgical risk calculator in gynecologic oncology patients undergoing laparotomy.

OBJECTIVE: The objective of this study was to evaluate the ability of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) surgical risk calculator to predict complications in gynecologic oncology patients undergoing laparotomy. METHODS: A chart review of patients who underwent laparotomy on the gynecologic oncology service at a single academic hospital from January 2009 to December 2013 was performed. Preoperative variables were abstracted and NSQIP surgical risk scores were calculated. The risk of any complication, serious complication, death, urinary tract infection, venous thromboembolism, cardiac event, renal complication, pneumonia and surgical site infection were correlated with actual patient outcomes using logistic regression. The c-statistic and Brier score were used to calculate the prediction capability of the risk calculator. RESULTS: Of the 1094 patients reviewed, the majority were <65years old (70.9%), independent (95.2%), ASA class 1-2 (67.3%), and overweight or obese (76.1%). Higher calculated risk scores were associated with an increased risk of the actual complication occurring for all events (p<0.05). The calculator performed best for predicting death (c-statistic=0.851, Brier=0.008), renal failure (c-statistic=0.752, Brier=0.015) and cardiac complications (c-statistic=0.708, Brier=0.011). The calculator did not accurately predict most complications. CONCLUSIONS: The NSQIP surgical risk calculator adequately predicts specific serious complications, such as postoperative death and cardiac complications. However, the overall performance of the calculator was worse for gynecologic oncology patients than reported in general surgery patients. A tailored prediction model may be needed for this patient population.

Association Between Indoor Tanning and Melanoma in Younger Men and Women.

IMPORTANCE: In the United States and Minnesota, melanoma incidence is rising more steeply among women than men younger than 50 years. To our knowledge, no study has examined age- and sex-specific associations between indoor tanning and melanoma to determine if these trends could be due to greater indoor tanning use among younger women. OBJECTIVE: To examine associations between indoor tanning and melanoma among men and women younger than 50 years. DESIGN, SETTING, AND PARTICIPANTS: Population-based case-control study conducted in Minnesota of 681 patients (465 [68.3%] women) diagnosed as having melanoma between 2004 and 2007, and 654 controls (446 [68.2%] women), ages 25 to 49 years. EXPOSURE: Indoor tanning, defined as any use, first age of use, and total sessions. MAIN OUTCOMES AND MEASURES: Crude and adjusted odds ratios (ORs) and 95% CIs were calculated for melanoma in relation to indoor tanning exposure for men and women by diagnosis or reference age (<30, 30-39, 40-49 years). Sex-specific associations for indoor tanning and melanoma by anatomic site were examined. RESULTS: Compared with women aged 40 to 49 years, women younger than 40 years initiated indoor tanning at a younger age (16 vs 25 years, P < .001) and reported more frequent indoor tanning (median number of sessions, 100 vs 40, P < .001). Women younger than 30 years were 6 times more likely to be in the case than the control group if they tanned indoors (crude OR, 6.0; 95% CI, 1.3-28.5). Odds ratios were also significantly elevated among women, ages 30 to 49 years (adjusted OR, 3.5; 95% CI, 1.2-9.7 for women 30-39 years; adjusted OR, 2.3; 95% CI, 1.4-3.6 for women 40-49 years); a dose response was observed among women regardless of age. Among men, results by age were inconsistent. The strongest OR for indoor tanning by anatomic site was for melanomas arising on the trunk of women (adjusted OR, 3.7; 95% CI, 1.9-7.2). CONCLUSIONS AND RELEVANCE: Indoor tanning is a likely factor for the steeper increase in melanoma rates in the United States among younger women compared with men, given the timing of when women initiated indoor tanning relative to diagnosis. The melanoma epidemic can be expected to continue unless indoor tanning is restricted and reduced.

UNC-45A Is a Nonmuscle Myosin IIA Chaperone Required for NK Cell Cytotoxicity via Control of Lytic Granule Secretion.

NK cell's killing is a tightly regulated process under the control of specific cytoskeletal proteins. This includes Wiskott-Aldrich syndrome protein, Wiskott-Aldrich syndrome protein-interacting protein, cofilin, Munc13-4, and nonmuscle myosin IIA (NMIIA). These proteins play a key role in controlling NK-mediated cytotoxicity either via regulating the attachment of lytic granules to the actin-based cytoskeleton or via promoting the cytoskeletal reorganization that is requisite for lytic granule release. UNC-45A is a highly conserved member of the UNC-45/CRO1/She4p family of proteins that act as chaperones for both conventional and nonconventional myosin. Although we and others have shown that in lower organisms and in mammalian cells NMIIA-associated functions, such as cytokinesis, cell motility, and organelle trafficking, are dependent upon the presence of UNC-45A, its role in NK-mediated functions is largely unknown. In this article, we describe UNC-45A as a key regulator of NK-mediated cell toxicity. Specifically we show that, in human NK cells, UNC-45A localize at the NK cell immunological synapse of activated NK cells and is part of the multiprotein complex formed during NK cell activation. Furthermore, we show that UNC-45A is disposable for NK cell immunological synapse formation and lytic granules reorientation but crucial for lytic granule exocytosis. Lastly, loss of UNC-45A leads to reduced NMIIA binding to actin, suggesting that UNC-45A is a crucial component in regulating human NK cell cytoskeletal dynamics via promoting the formation of actomyosin complexes.

The Candidate Cancer Gene Database: a database of cancer driver genes from forward genetic screens in mice.

Identification of cancer driver gene mutations is crucial for advancing cancer therapeutics. Due to the overwhelming number of passenger mutations in the human tumor genome, it is difficult to pinpoint causative driver genes. Using transposon mutagenesis in mice many laboratories have conducted forward genetic screens and identified thousands of candidate driver genes that are highly relevant to human cancer. Unfortunately, this information is difficult to access and utilize because it is scattered across multiple publications using different mouse genome builds and strength metrics. To improve access to these findings and facilitate meta-analyses, we developed the Candidate Cancer Gene Database (CCGD, http://ccgd-starrlab.oit.umn.edu/). The CCGD is a manually curated database containing a unified description of all identified candidate driver genes and the genomic location of transposon common insertion sites (CISs) from all currently published transposon-based screens. To demonstrate relevance to human cancer, we performed a modified gene set enrichment analysis using KEGG pathways and show that human cancer pathways are highly enriched in the database. We also used hierarchical clustering to identify pathways enriched in blood cancers compared to solid cancers. The CCGD is a novel resource available to scientists interested in the identification of genetic drivers of cancer.

Factors influencing same-day hospital discharge and risk factors for readmission after robotic surgery in the gynecologic oncology patient population.

STUDY OBJECTIVE: To determine the factors that allow for a safe outpatient robotic-assisted minimally invasive gynecologic oncology surgery procedure. DESIGN: Retrospective chart review (Canadian Task Force classification II-1). SETTING: University hospital. PATIENTS: All patients (140) undergoing robotic-assisted minimally invasive surgery with the gynecologic oncology service from January 1, 2013, to December 31, 2013. INTERVENTIONS: Risk factors for unsuccessful discharge within 23 hours of surgery and same-day discharge were assessed using logistic regression models. MEASUREMENTS AND MAIN RESULTS: All patients were initially scheduled for same-day discharge. The outpatient surgery group was defined by discharge within 23 hours of the surgery end time, and a same-day surgery subgroup was defined by discharge before midnight on the day of surgery. One hundred fifteen (82.1%) were successfully discharged within 23 hours of surgery, and 90 (64.3%) were discharged the same day. The median hospital stay was 5.3 hours (range, 1-48 hours). Unsuccessful discharge within 23 hours was associated with a preoperative diagnosis of lung disease and intraoperative complications; unsuccessful same-day discharge was associated with older age and later surgery end time. Only 2 patients (1.4%) were readmitted to the hospital within 30 days of surgery. CONCLUSIONS: Outpatient robotic-assisted minimally invasive surgery is safe and feasible for most gynecologic oncology patients and appears to have a low readmission rate. Older age, preoperative lung disease, and later surgical end time were risk factors for prolonged hospital stay. These patients may benefit from preoperative measures to facilitate earlier discharge.

Adherence to the 2012 national cervical cancer screening guidelines: a pilot study.

OBJECTIVE: The goal of this pilot study was to evaluate adherence to the 2012 cervical cancer screening guidelines among health care providers in a large health maintenance organization. STUDY DESIGN: A cross-sectional survey evaluating knowledge, reported practices, and views of the 2012 cervical cancer screening guidelines was distributed to 325 health care providers within HealthPartners. The survey was divided into 3 sections: (1) provider demographics; (2) knowledge of the 2012 age-specific cancer screening guidelines; and (3) provider practice. Comparisons based on appropriate knowledge and practice of the guidelines were made using Fisher exact tests. RESULTS: The response rate was 42%. Of 124 respondents, 15 (12.1%) reported they were not aware of the 2012 guideline changes. Only 7 (5.7%) respondents answered all the knowledge questions correctly. A majority of respondents reported correct screening practices in the 21-29 year patient age group (65.8%) and in the >65 year patient age group (74.3%). Correct screening intervals in the 30-65 year patient age group varied by modality, with 89.3% correctly screening every 3 years with Pap smear alone, but only 57.4% correctly screening every 5 years with Pap smear + human papillomavirus cotesting. The most frequently cited reasons for not adhering were lack of knowledge of the guidelines and patient demand for a different screening interval. CONCLUSION: Adherence to the 2012 cervical cancer screening guidelines is poor due, in part, to a lack of knowledge of the guidelines. Efforts should focus on improved provider and patient education, and methods that facilitate adherence to the guidelines such as electronic health record order sets.

Evaluation of protein biomarkers of prostate cancer aggressiveness.

BACKGROUND: Prognostic multibiomarker signatures in prostate cancer (PCa) may improve patient management and provide a bridge for developing novel therapeutics and imaging methods. Our objective was to evaluate the association between expression of 33 candidate protein biomarkers and time to biochemical failure (BF) after prostatectomy. METHODS: PCa tissue microarrays were constructed representing 160 patients for whom clinicopathologic features and follow-up data after surgery were available. Immunohistochemistry for each of 33 proteins was quantified using automated digital pathology techniques. Relationships between clinicopathologic features, staining intensity, and time to BF were assessed. Predictive modeling using multiple imputed datasets was performed to identify the top biomarker candidates. RESULTS: In univariate analyses, lymph node positivity, surgical margin positivity, non-localized tumor, age at prostatectomy, and biomarkers CCND1, HMMR, IGF1, MKI67, SIAH2, and SMAD4 in malignant epithelium were significantly associated with time to BF. HMMR, IGF1, and SMAD4 remained significantly associated with BF after adjusting for clinicopathologic features while additional associations were observed for HOXC6 and MAP4K4 following adjustment. In multibiomarker predictive models, 3 proteins including HMMR, SIAH2, and SMAD4 were consistently represented among the top 2, 3, 4, and 5 most predictive biomarkers, and a signature comprised of these proteins best predicted BF at 3 and 5 years. CONCLUSIONS: This study provides rationale for investigation of HMMR, HOXC6, IGF1, MAP4K4, SIAH2, and SMAD4 as biomarkers of PCa aggressiveness in larger cohorts.

Establishment, characterization and downstream application of primary ovarian cancer cells derived from solid tumors.

Ovarian cancer is the deadliest of the gynecological diseases and the fifth cause of cancer death among American women. This is mainly due to the lack of prognostic tools capable of detecting early stages of ovarian cancer and to the high rate of resistance to the current chemotherapeutic regimens. In this scenario the overall 5-year survival rate for ovarian cancer patients diagnosed at late stage is less than 25%. Abnormalities associated with the malignant phenotype and the mechanisms of tumor progression are not clearly understood. In vitro studies are necessary, yet have been hampered due to the limitations accompanied with the use of ovarian cancer cell lines and the heterogeneity of the ovarian cancer cell population derived from ascites fluids. In this study we present a simple, rapid and reproducible method for the isolation and characterization of ovarian cancer cells from solid tumor tissue and show that enzymatic digestion for 30 minutes with dispase II results in the most effective recovery of viable epithelial ovarian cancer (EOC) cells. The resulting cancer (EOC) cell preparations demonstrate a significant yield, high levels of viability and are fibroblast-free. They grow for up to six passages and retain the capacity of forming spheroids-like structures in agarose. In addition, they can be genetically manipulated and used for drug screening, thus rendering them highly suitable for downstream applications. Notably, isolation of ovarian cancer cells from solid specimens using this method has the advantage of allowing for isolation of cancer cells from early stages of ovarian cancer as well as obtaining cells from defined either primary and/or metastatic ovarian cancer sites. Thus, these cells are highly suitable for investigations aimed at understanding ovarian cancer.

Stressing the ubiquitin-proteasome system without 20S proteolytic inhibition selectively kills cervical cancer cells.

Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate, and for specific signaling pathways, notably HPV E6-targeted degradation of p53 and PDZ proteins. Natural compounds with antioxidant properties including flavonoids and triterpenoids hold promise as anticancer agents by interfering with ubiquitin-dependent protein degradation. An increasing body of evidence indicates that their α-ß unsaturated carbonyl system is the molecular determinant for inhibition of ubiquitin-mediated protein degradation up-stream of the catalytic sites of the 20S proteasome. Herein we report the identification and characterization of a new class of chalcone-based, potent and cell permeable chemical inhibitors of ubiquitin-dependent protein degradation, and a lead compound RAMB1. RAMB1 inhibits ubiquitin-dependent protein degradation without compromising the catalytic activities of the 20S proteasome, a mechanism distinct from that of Bortezomib. Treatment of cervical cancer cells with RAMB1 triggers unfolded protein responses, including aggresome formation and Hsp90 stabilization, and increases p53 steady state levels. RAMB1 treatment results in activation of lysosomal-dependent degradation pathways as a mechanism to compensate for increasing levels of poly-ubiquitin enriched toxic aggregates. Importantly, RAMB1 synergistically triggers cell death of cervical cancer cells when combined with the lysosome inhibitor Chloroquine.

α,ß-Unsaturated carbonyl system of chalcone-based derivatives is responsible for broad inhibition of proteasomal activity and preferential killing of human papilloma virus (HPV) positive cervical cancer cells.

Proteasome inhibitors have potential for the treatment of cervical cancer. We describe the synthesis and biological characterization of a new series of 1,3-diphenylpropen-1-one (chalcone) based derivatives lacking the boronic acid moieties of the previously reported chalcone-based proteasome inhibitor 3,5-bis(4-boronic acid benzylidene)-1-methylpiperidin-4-one and bearing a variety of amino acid substitutions on the amino group of the 4-piperidone. Our lead compound 2 (RA-1) inhibits proteasomal activity and has improved dose-dependent antiproliferative and proapoptotic properties in cervical cancer cells containing human papillomavirus. Further, it induces synergistic killing of cervical cancer cell lines when tested in combination with an FDA approved proteasome inhibitor. Exploration of the potential mechanism of proteasomal inhibition by our lead compound using in silico docking studies suggests that the carbonyl group of its oxopiperidine moiety is susceptible to nucleophilic attack by the γ-hydroxythreonine side chain within the catalytic sites of the proteasome.

MT103 inhibits tumor growth with minimal toxicity in murine model of lung carcinoma via induction of apoptosis.

Molecular topology (MT) was used to develop quantitative structure-activity relationship (QSAR) models to screen databases for new anticancer compounds. One of the selected compounds was MT103, an isoborneol derivative, with a promising profile predicted to slow tumor growth through pro-apoptotic signaling and protein kinase C inhibition. We found that MT103 inhibited the growth of a wide variety of cancer cell types as verified by the NCI-60 cancer cell line panel. MTT cell viability assay showed that MT103 inhibited 50% of the growth of HOP-92, ACHN, NCI-H226, MCF-7, and A549 cancer cell lines at much lower concentrations than that required for HUVECs and human fibroblasts. MT103 stimulated apoptosis in NCI-H226 lung carcinoma cells as measured by oligonucleosomal DNA fragmentation. However, protein kinase C was not targeted by MT103, as predicted by in silico modeling. MT103 slowed in vivo tumor growth and metastatic spread of NCI-H226 cells injected subcutaneously into NOD/SCID mice, without eliciting any severe adverse events as monitored by animal survival, blood serum analysis, and histological analysis of organs. Oral administration of MT103 nanoparticles (200 nm in diameter), which were generated with ElectroNanospray™ technology, inhibited in vivo growth of HOP-92 lung carcinoma cells almost as effectively as intraperitoneal injections of cisplatin. Taken together, our study of a novel anti-cancer drug identified using a molecular topology-based approach to drug discovery demonstrates that MT103 has anti-tumor activity in vitro and in vivo, although additional studies are needed to elucidate its mechanism of action.

A single institution experience using sequential multi-modality adjuvant chemotherapy and radiation in the "sandwich" method for high risk endometrial carcinoma.

OBJECTIVE: We sought to evaluate the outcomes and feasibility associated with delivering sequential chemotherapy and radiation in advanced stage endometrial cancer. METHODS: We conducted a retrospective analysis of patients treated at the University of Minnesota with sequential chemotherapy and radiation for advanced stage endometrial cancer from 1999 to 2007. Inclusion criteria were endometrial cancer patients treated with comprehensive surgical staging followed by adjuvant therapy consisting of sequential chemotherapy, radiation, and consolidation chemotherapy in a "sandwich" fashion. Progression free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier (KM) method. RESULTS: Twenty-three patients met entry criteria and were included in the analysis. The median age was 57 years (range 28-78). The majority of patients were stage III (78%) and the most common histologic type was serous (52%). The combination of a taxane and carboplatin was administered in 100% of cases. All planned cycles of chemotherapy were completed (100%) with the majority being prescribed six cycles (82%). Of the 23 patients, 5 progressed of which 3 died during the follow up period. The KM estimate of 1, 3, and 5 year PFS is 100%, 80%, and 74%, respectively. The KM estimate for 1, 3, and 5 year OS is 100%, 88% and 79%, respectively. CONCLUSION: Adjuvant therapy delivered in a "sandwich" fashion was feasible, well-tolerated and resulted in excellent long-term progression free and overall survival. A prospective study is currently ongoing at our institution.