KRAS mutation analysis in ovarian samples using a high sensitivity biochip assay

<p>Abstract</p> <p>Background</p> <p>Mutations in the <it>KRAS </it>gene are one of the most frequent genetic abnormalities in ovarian carcinoma. They are of renewed interest as new epidermal growth factor receptor (EGFR)-targeted therapies are being investigated for use in ovarian carcinoma. As <it>KRAS </it>mutations are associated with poor response and resistance to EGFR-targeting drugs, this study was conducted to obtain more information on the spectrum of <it>KRAS </it>mutations in ovarian carcinoma.</p> <p>Methods</p> <p>The presence of <it>KRAS </it>mutations in codon 12 and 13 was analyzed in frozen and formalin-fixed paraffin-embedded (FFPE) tissue with a low density biochip platform. 381 malignant (29 borderline malignancy, 270 primary carcinomas, and 82 recurrent carcinomas) and 22 benign tissue samples from a total of 394 patients were examined. <it>KRAS </it>mutational status of each sample was correlated with dignity, FIGO stage, grade, histology, and survival.</p> <p>Results</p> <p><it>KRAS </it>mutations were found in 60 (15%) samples with 58 samples deriving from malignant tissue and 2 samples deriving from benign tissue. In 55 (92%) samples codon 12 was found to be mutated. Frozen and FFPE samples concurred with respect to <it>KRAS </it>mutation status.</p> <p>Conclusion</p> <p><it>KRAS </it>mutation is a common event in ovarian cancer primarily in carcinomas of lower grade, lower FIGO stage, and mucinous histotype. The <it>KRAS </it>mutational status is no prognostic factor for patients treated with standard therapy. However, in line with experience from colorectal cancer and non-small-cell-lung cancer (NSCLC), it may be important for prediction of response to EGFR-targeted therapies.</p

Tumor Growth Rate Estimates Are Independently Predictive of Therapy Response and Survival in Recurrent High-Grade Serous Ovarian Cancer Patients

This study aimed to assess the predictive value of tumor growth rate estimates based on serial cancer antigen-125 (CA-125) levels on therapy response and survival of patients with recurrent high-grade serous ovarian cancer (HGSOC). In total, 301 consecutive patients with advanced HGSOC (exploratory cohort: n = 155, treated at the Medical University of Vienna; external validation cohort: n = 146, from the Ovarian Cancer Therapy–Innovative Models Prolong Survival (OCTIPS) consortium) were enrolled. Tumor growth estimates were obtained using a validated two-phase equation model involving serial CA-125 levels, and their predictive value with respect to treatment response to the next chemotherapy and the prognostic value with respect to disease-specific survival and overall survival were assessed. Tumor growth estimates were an independent predictor for response to second-line chemotherapy and an independent prognostic factor for second-line chemotherapy use in both univariate and multivariable analyses, outperforming both the predictive (second line: p = 0.003, HR 5.19 [1.73–15.58] vs. p = 0.453, HR 1.95 [0.34–11.17]) and prognostic values (second line: p = 0.042, HR 1.53 [1.02–2.31] vs. p = 0.331, HR 1.39 [0.71–2.27]) of a therapy-free interval (TFI) &lt; 6 months. Tumor growth estimates were a predictive factor for response to third- and fourth-line chemotherapy and a prognostic factor for third- and fourth-line chemotherapy use in the univariate analysis. The CA-125-derived tumor growth rate estimate may be a quantifiable and easily assessable surrogate to TFI in treatment decision making for patients with recurrent HGSOC

The presence of postmenopausal bleeding as prognostic parameter in patients with endometrial cancer: a retrospective multi-center study

Abstract Background To date, there is no consensus on the utility of screening procedures for the early detection of endometrial cancer. The value of transvaginal ultrasound for screening of asymptomatic endometrial cancer has been discussed controversially. This study was conducted to evaluate whether asymptomatic patients with endometrial cancer have a better prognosis than symptomatic patients with endometrial cancer diagnosed after postmenopausal bleeding. Methods In the present multi-center study, the effect of the presence of postmenopausal bleeding on prognosis was evaluated retrospectively in 605 patients with endometrial cancer using patients' files. 543 patients (133 patients were asymptomatic, 410 patients were symptomatic) with endometrioid endometrial cancer were enrolled in all further analysis. Student's t-test, Cox regression analysis and Kaplan-Meier analysis were used were appropriate. Results Presence/absence of a postmenopausal bleeding was not associated with tumor stage (p = 0.2) and age at diagnosis (p = 0.5). Asymptomatic patients with endometrial cancer had a significantly higher rate of well and moderate-differentiated tumors compared to symptomatic patients (p = 0.008). In univariable and multivariable survival analysis, tumor stage, tumor grade, and patients' age at diagnosis, but not presence/absence of a postmenopausal bleeding, were associated with disease free and overall survival. Conclusion Asymptomatic patients with endometrial cancer have a higher rate of well differentiated tumors compared to patients with a postmenopausal bleeding prior to diagnosis. The prognosis of both groups of patients was similar.</p

Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer

Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of mutation status is unknown. We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death. Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab. In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.)

The prognostic value of four interleukin-1 gene polymorphisms in caucasian women with breast cancer – a multicenter study

<p>Abstract</p> <p>Background</p> <p>The proinflammatory cytokine interleukin-1 (IL-1) is known to play an important role in the carcinogenesis of breast cancer. Although IL-1 gene polymorphisms were reported to be associated with increased risk of breast cancer, their influence on survival of Caucasian breast cancer patients remains to be shown.</p> <p>Methods</p> <p>We studied the influence of four common gene polymorphisms (<it>IL1A </it>-889C/T, <it>IL1B </it>-511C/T, <it>IL1B </it>+3953E1/E2, and <it>IL1RN </it>long/2) of the IL-1 family on survival in 262 Caucasian patients with breast cancer by univariate and multivariate survival analysis. The combined effect of the four gene polymorphisms on overall survival was studied by haplotype analysis.</p> <p>Results</p> <p>In the present study 38 cases of cancer related death and a median time of follow-up (range) of 55.3 (0.4–175.8) months was observed. <it>IL1RN </it>2/2 (homozygous mutant) gene polymorphism was associated with shortened disease free and overall survival in a univariate (p = 0.001 and p = 0.01, respectively) and multivariate analysis (p = 0.002, Odds Ratio [95% Confidence Interval] = 3.6 [1.6–8.0] and p = 0.05, Odds Ratio = 3.0 [1.1–9.3], respectively). Presence of the homozygous mutant genotype of the <it>IL1A </it>-889 and <it>IL1B </it>+3953 gene polymorphism was associated with overall survival in the univariate (p = 0.004 and p = 0.002, respectively), but not in the multivariate analysis. No association was observed between all possible haplotype combinations and overall survival.</p> <p>Conclusion</p> <p>Carriage of the mutant alleles of <it>IL1RN </it>was independently associated with shortened disease free and overall survival rates in Caucasian patients with breast cancer.</p

Assessment of a six gene panel for the molecular detection of circulating tumor cells in the blood of female cancer patients

<p>Abstract</p> <p>Background</p> <p>The presence of circulating tumor cells (CTC) in the peripheral blood of cancer patients has been described for various solid tumors and their clinical relevance has been shown. CTC detection based on the analysis of epithelial antigens might be hampered by the genetic heterogeneity of the primary tumor and loss of epithelial antigens. Therefore, we aimed to identify new gene markers for the PCR-based detection of CTC in female cancer patients.</p> <p>Methods</p> <p>Gene expression of 38 cancer cell lines (breast, ovarian, cervical and endometrial) and of 10 peripheral blood mononuclear cell (PBMC) samples from healthy female donors was measured using microarray technology (Applied Biosystems). Differentially expressed genes were identified using the maxT test and the 50% one-sided trimmed maxT-test. Confirmatory RT-qPCR was performed for 380 gene targets using the AB TaqMan^®Low Density Arrays. Then, 93 gene targets were analyzed using the same RT-qPCR platform in tumor tissues of 126 patients with primary breast, ovarian or endometrial cancer. Finally, blood samples from 26 healthy women and from 125 patients (primary breast, ovarian, cervical, or endometrial cancer, and advanced breast cancer) were analyzed following OncoQuick enrichment and RNA pre-amplification. Likewise, <it>hMAM </it>and <it>EpCAM </it>gene expression was analyzed in the blood of breast and ovarian cancer patients. For each gene, a cut-off threshold value was set at three standard deviations from the mean expression level of the healthy controls to identify potential markers for CTC detection.</p> <p>Results</p> <p>Six genes were over-expressed in blood samples from 81% of patients with advanced and 29% of patients with primary breast cancer. <it>EpCAM </it>gene expression was detected in 19% and 5% of patients, respectively, whereas <it>hMAM </it>gene expression was observed in the advanced group (39%) only. Multimarker analysis using the new six gene panel positively identified 44% of the cervical, 64% of the endometrial and 19% of the ovarian cancer patients.</p> <p>Conclusions</p> <p>The panel of six genes was found superior to <it>EpCAM </it>and <it>hMAM </it>for the detection of circulating tumor cells in the blood of breast cancer, and they may serve as potential markers for CTC derived from endometrial, cervical, and ovarian cancers.</p

memo - Magazine of European Medical Oncology / Antiangiogenic therapies in ovarian cancer

Angiogenesis plays a pivotal role in normal ovarian physiology as well as in the formation and progression of ovarian cancer. Several well-designed phase II and III trials studied the efficacy of antiangiogenic agents in advanced ovarian cancer. The results of these trials demonstrated significantly prolonged progression-free survival when antiangiogenic agents were used as a maintenance therapy. To date, no effect on overall survival could be ascertained. The most widely studied antiangiogenic agent, bevacizumab a monoclonal humanized antibody against vascular endothelial growth factor was effective in all phases of the disease (first-line therapy, platinum-sensitive and platinum-resistant recurrence). These results led to regulatory approval in many countries including the European Union. Other anti-VEGF agents such as tyrosine kinase inhibitors have not shown increased activity but increased toxicity relative to bevacizumab. Agents targeting angiopoietin-1 and -2 are in development and new combinations with PARP inhibitors and immune checkpoint inhibitors are studied. This review summarizes the current data and knowledge on the clinical use of antiangiogenic agents in advanced ovarian cancer.(VLID)365877

Implementierung des Intensivtagebuchs anhand des IOWA Modells

Abstract Deutsch Die vorliegende Master Thesis zeigt die Notwendigkeit des Intensivtagebuchs in der Pflege von IntensivpatientInnen auf. Zusätzlich wird das Implementierungsverfahren anhand des IOWA Modells vorgestellt. Die Fragestellungen sind, welche Auswirkungen hat das Intensivtagebuch auf Betroffene, Angehörige bzw. Pflegepersonen und wie das Implementierungsverfahren anhand des IOWA Modells umgesetzt werden kann. Die Arbeit beruht auf einer systematischen Literaturanalyse und qualitativen Interviews von zwei Pflegeexperten, welche das Intensivtagebuch erfolgreich implementiert haben. Die Ergebnisse zeigen, dass Auswirkungen des Intensivtagebuchs auf Betroffene sowohl anhand der theoretischen wie auch der empirischen Analysen überwiegend positiv sind. Das Tagebuch hilft, die Lücken der Erinnerung zu schließen, verwirrende traumatisierende Erfahrungen richtig zu zuordnen bzw. zu interpretieren und damit posttraumatische Belastungsstörungen zu verringern. Zusätzlich wird die Unterstützung aller beteiligten Personen, wie vor allem der Angehörigen, als sehr positiv erlebt. Damit gelingt den PatientInnen ein besserer Wiedereinstieg in das Alltagsleben. Die Angehörigen profitieren vor allem dadurch, dass sie sich einen raschen Überblick über die Geschehnisse verschaffen können, die in der Zeit ihrer Abwesenheit erfolgt sind. Zusätzlich bietet das Intensivtagebuch eine Hilfe zur Aufarbeitung der eigenen Belastungserfahrungen. Für eine erfolgreiche Implementierung des Intensivtagebuchs sind seine Auswirkungen für die Pflegepersonen wichtig. Hier zeigen sich Abweichungen zwischen den Ergebnissen der Theorie und jenen der Empirie. Während vor allem die dargelegte Studie des Wagner Jauregg Krankenhauses von erheblichen Widerständen berichtet, konnten die Fallstudien der befragten Experten zeigen, dass anfängliche Ressentiments rasch überwunden werden konnten. Die überwiegende Zahl der Pflegepersonen begann rasch mit der aktiven Führung des Tagebuchs und bewertet die gewonnenen Erfahrungen positiv. Ein entscheidender Aspekt dafür ist der von den Experten berichtete geringe Mehraufwand für das Intensivtagebuch, der nur wenige Minuten pro Eintrag umfasst. Diese Erkenntnis ist zentral für die Fragestellung, wie das Implementierungsverfahren anhand des IOWA Modells umgesetzt werden kann. Das IOWA-Modell, sowie weitergehende theoretische Change Management Verfahren gehen davon aus, dass für eine erfolgreiche Implementation ein strukturierter mehrstufiger Prozess zu durchlaufen ist. Im Gegensatz dazu zeigt die Erfahrung der Experten, dass die Implementation auch informell und ohne Vorgehensmodell erfolgen kann, wenn der Prozess professionell initiiert und begleitet wird, da der geringe Aufwand kein umfassendes Change Management erfordertAbstract English This master's thesis shows the necessity of the intensive care journal in the care of patients. In addition, the implementation process will be presented using the IOWA model. The questions are, what impact the intensive care journal has on affected patients, relatives or caregivers and how the implementation process can be implemented using the IOWA model. The work is based on a theoretical analysis and the interviews of two nursing experts, who have successfully implemented the intensive diary. The results show, that the impact of the intensive care journal on patients are overwhelmingly positive, both on the theoretical as well as on the empirical analyzes. The diary helps to close the gaps in memory, to correctly assign or interpret confusing traumatic experiences and thus to reduce post-traumatic stress disorders. In addition, the support of all persons involved, especially the relatives, is experienced as very positive. Thus, the patients manage a better re-entry into everyday life. The relatives benefit above all from the fact, that they can get a quick overview of the events that took place during their absence. In addition, the intensive diary offers help in processing one's own stress experiences. Important for a successful implementation of the intensive care journal are its implications for the caregivers. Here are differences between the results of the theoretical and those of the empirical analysis. While the presented study of the Wagner Jauregg hospital reported considerable resistance, the case studies of the interviewed experts showed that initial resentments could be overcome quickly. The overwhelming number of caregivers quickly began actively managing the diary and rated the experience gained positively. A crucial aspect of this is the low overhead, reported by the experts for the intensive journal, which only covers a few minutes per entry. This finding is central to the question of how the implementation process can be implemented using the IOWA model. The IOWA model as well as further theoretical change management procedures assume, that a structured multi-stage process has to be completed for a successful implementation. In contrast, the experience of the experts shows, that the implementation can also be made informally and without a procedural model, if the process is professionally initiated and supported, since the low effort does not require comprehensive change managementvorgelegt von: Nikolaus A. ReinthallerWien, FH Campus Wien, Masterarb., 2018(VLID)288336