Update on rare epithelial ovarian cancers: based on the Rare Ovarian Tumors Young Investigator Conference

There has been significant progress in the understanding of the pathology and molecular biology of rare ovarian cancers, which has helped both diagnosis and treatment. This paper provides an update on recent advances in the knowledge and treatment of rare ovarian cancers and identifies gaps that need to be addressed by further clinical research. The topics covered include: low-grade serous, mucinous, and clear cell carcinomas of the ovary. Given the molecular heterogeneity and the histopathological rarity of these ovarian cancers, the importance of designing adequately powered trials or finding statistically innovative ways to approach the treatment of these rare tumors has been emphasized. This paper is based on the Rare Ovarian Tumors Conference for Young Investigators which was presented in Tokyo 2015 prior to the 5th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG)

Automatsko proširenje i primjena računalnog grozda korištenjem dual-boot principa

The paper presents an innovative and simple way of creating computer clustering and obtaining HPC clusters using computers in the classroom, Ethernet facilities and open source software. Automatic enlarge of a computer cluster is a cost-effective way to increase available computing power. This is achieved by forming a computer cluster from the computers in the classroom. The main aim of this paper is to present a solution that will use existing resources in the computer classroom, for applying complex computer services/jobs under the Linux operating system. The execution of these services/jobs programs is performed at the time when the computing resources are not in used in learning under the Windows operating system. A real-life example of applying computers in dual-boot Windows/Linux work mode along with the developed software application support is presented in a teaching environment. The implementation also includes logistics and support for automatic computer clustering and for service/job programs execution. The primary goal is to use existing resources for useful applications in education in the image programming, simulations and volume rendering.U radu je prikazan inovativan i jednostavan način stvaranja računalnih klastera i dobivanja HPC klastera korištenjem postojećih računala u učionici, Ethernet objekata, i open source softvera. Automatsko oblikovanje računalnog klastera je ekonomičan način da se poveća raspoloživa računalna snaga. To se postiže formiranjem računalnog klastera od postojećih računala u učionici. Glavni cilj ovog rada je prikazati rješenje koja će koristiti postojeće resurse u okruženju računalne učionice za izvođenje složenih računalnih poslova koji zahtjevaju vec´u računalnu snagu pod Linux operativnim sustavom. Izvršenje tih poslova se obavlja u vrijeme kada se računalni resursi ne koriste za obrazovanje pod Windows operativnim sustavom. Prikazan je primjer primjene računala u dual-boot Windows/Linux modu rada uz razvijene originalne programske podrške za aplikacije u obrazovnom okruženju. Provedba također uključuje logistiku i podršku za automatsko klasteriranje računala i izvršavanje poslova. Primarni cilj je iskorištavanje postojećih resursa za korisne aplikacije u obrazovanju primarno u području programiranja slike, simulacije i renderiranja. Rezultati provedenog principa su prikazani

Multi-Gene Expression Predictors of Single Drug Responses to Adjuvant Chemotherapy in Ovarian Carcinoma: Predicting Platinum Resistance

Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Standard therapy includes treatment with platinum-based combination chemotherapies yet there is no biomarker model to predict their responses to these agents. We here have developed and independently tested our multi-gene molecular predictors for forecasting patients' responses to individual drugs on a cohort of 55 ovarian cancer patients. To independently validate these molecular predictors, we performed microarray profiling on FFPE tumor samples of 55 ovarian cancer patients (UVA-55) treated with platinum-based adjuvant chemotherapy. Genome-wide chemosensitivity biomarkers were initially discovered from the in vitro drug activities and genomic expression data for carboplatin and paclitaxel, respectively. Multivariate predictors were trained with the cell line data and then evaluated with a historical patient cohort. For the UVA-55 cohort, the carboplatin, taxol, and combination predictors significantly stratified responder patients and non-responder patients (p = 0.019, 0.04, 0.014) with sensitivity = 91%, 96%, 93 and NPV = 57%, 67%, 67% in pathologic clinical response. The combination predictor also demonstrated a significant survival difference between predicted responders and non-responders with a median survival of 55.4 months vs. 32.1 months. Thus, COXEN single- and combination-drug predictors successfully stratified platinum resistance and taxane response in an independent cohort of ovarian cancer patients based on their FFPE tumor samples

Carboplatin-induced gene expression changes in vitro are prognostic of survival in epithelial ovarian cancer

<p>Abstract</p> <p>Background</p> <p>We performed a time-course microarray experiment to define the transcriptional response to carboplatin <it>in vitro</it>, and to correlate this with clinical outcome in epithelial ovarian cancer (EOC). RNA was isolated from carboplatin and control-treated 36M2 ovarian cancer cells at several time points, followed by oligonucleotide microarray hybridization. Carboplatin induced changes in gene expression were assessed at the single gene as well as at the pathway level. Clinical validation was performed in publicly available microarray datasets using disease free and overall survival endpoints.</p> <p>Results</p> <p>Time-course and pathway analyses identified 317 genes and 40 pathways (designated time-course and pathway signatures) deregulated following carboplatin exposure. Both types of signatures were validated in two separate platinum-treated ovarian and NSCLC cell lines using published microarray data. Expression of time-course and pathway signature genes distinguished between patients with unfavorable and favorable survival in two independent ovarian cancer datasets. Among the pathways most highly induced by carboplatin <it>in vitro</it>, the NRF2, NF-kB, and cytokine and inflammatory response pathways were also found to be upregulated prior to chemotherapy exposure in poor prognosis tumors.</p> <p>Conclusion</p> <p>Dynamic assessment of gene expression following carboplatin exposure <it>in vitro </it>can identify both genes and pathways that are correlated with clinical outcome. The functional relevance of this observation for better understanding the mechanisms of drug resistance in EOC will require further evaluation.</p

HER2 expression in cervical cancer as a potential therapeutic target

BACKGROUND: Trastuzumab, a humanized monoclonal antibody against the HER2 receptor is currently being used in breast and other tumor types. Early studies have shown that a variable proportion of cervical carcinoma tumors overexpress the HER2 receptor as evaluated by diverse techniques and antibodies. Currently it is known that a tumor response to trastuzumab strongly correlates with the level of HER2 expression evaluated by the Hercep Test, thus, it seems desirable to evaluate the status of expression of this receptor using the FDA-approved Hercep Test and grading system to gain insight in the feasibility of using trastuzumab in cervical cancer patients. METHODS: We analyzed a series of cervical cancer cell lines, the primary tumors of 35 cases of cervical cancer patients and four recurrent cases, with the Hercep Test in order to establish whether this tumor type overexpress HER2 at level of 2+/3+ as trastuzumab is currently approved for breast cancer having such level of expression. RESULTS: The results indicate that only 1 out of 35 primary tumors cases overexpress the receptor at this level, however, two out of four recurrent tumors that tested negative at diagnosis shifted to Hercep Test 2+ and 3+ respectively. CONCLUSIONS: The low frequency of expression in primary cases suggests that trastuzumab could have a limited value for the primary management of cervical cancer patients, however, the finding of "conversion" to Hercep Test 2+ and 3+ of recurrent tumors indicates the need to further evaluate the expression of HER2 in the metastatic and recurrent cases

Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer delays third-line chemotherapy and prolongs the platinum-free interval

Background: OVA-301 is a large randomized trial that showed superiority of trabectedin plus pegylated liposomal doxorubicin (PLD; CentoCor Ortho Biotech Products L.P., Raritan, NJ, USA). over single-agent PLD in 672 patients with relapsed ovarian cancer, particularly in the partially platinum-sensitive subgroup [platinum-free interval (PFI) of 6–12 months]. This superiority has been suggested to be due to the differential impact of subsequent (platinum) therapy

Efficacy assessment of sustained intraperitoneal paclitaxel therapy in a murine model of ovarian cancer using bioluminescent imaging

We evaluated the pre-clinical efficacy of a novel intraperitoneal (i.p.) sustained-release paclitaxel formulation (PTXePC) using bioluminescent imaging (BLI) in the treatment of ovarian cancer. Human ovarian carcinoma cells stably expressing the firefly luciferase gene (SKOV3Luc) were injected i.p. into SCID mice. Tumour growth was evaluated during sustained or intermittent courses of i.p. treatment with paclitaxel (PTX). In vitro bioluminescence strongly correlated with cell survival and cytotoxicity. Bioluminescent imaging detected tumours before their macroscopic appearance and strongly correlated with tumour weight and survival. As compared with intermittent therapy with Taxol®, sustained PTXePC therapy resulted in significant reduction of tumour proliferation, weight and BLI signal intensity, enhanced apoptosis and increased survival times. Our results demonstrate that BLI is a useful tool in the pre-clinical evaluation of therapeutic interventions for ovarian cancer. Moreover, these results provide evidence of enhanced therapeutic efficacy with the sustained PTXePC implant system, which could potentially translate into successful clinical outcomes

Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886]

BACKGROUND: Topical NSAIDs have been proven to relieve the symptoms of osteoarthritis (OA) in short-term studies (2 weeks). To justify its chronic use, efficacy of a topical NSAID over a longer term of study should be demonstrated. The efficacy and safety of a topical diclofenac solution over a 6-week treatment course in symptomatic primary OA of the knee was investigated. METHODS: 216 men and women, age 40–85 years, with radiologically confirmed primary OA of the knee and a flare of pain at baseline following discontinuation of prior therapy were enrolled into this double-blind study. Participants applied either a topical diclofenac solution (Pennsaid(®)) or vehicle control solution (carrier with no diclofenac); 40 drops 4 times daily directly to the painful knee(s), without massage, for 6 weeks. Pre-planned primary efficacy outcome measures included the core continuous variables pain relief and improved physical function measured by the Western Ontario and McMaster Universities (WOMAC) LK3.1 OA Index, and improved patient global assessment (PGA). Secondary efficacy measure was reduced stiffness. Safety assessments included adverse events and vital signs. RESULTS: The topical diclofenac group had a significantly greater mean change in score (final minus baseline) compared to the vehicle control group for pain (-5.2 vs. -3.3, p = 0.003), physical function (-13.4 vs. -6.9, p = 0.001), PGA (-1.3 vs. -0.7, p = 0.0001) and stiffness (-1.8 vs. -0.9, p = 0.002). The mean difference between treatment arms (95% confidence interval [CI]) was 1.9 (0.7 to 3.2), 6.5 (2.5 to 10.5), 0.6 (0.2 to 0.9), and 0.9 (0.3 to 1.4), respectively. Safety analyses showed that topical diclofenac caused skin irritation, mostly minor local skin dryness, in 42/107 (39%), leading to discontinuation of treatment in 5/107 (5%) participants. CONCLUSION: This topical diclofenac solution demonstrated relief at 6 weeks of the symptoms of primary osteoarthritis of the knee