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Minig L.,Italian National Cancer Institute | Minig L.,Hospital Universitario Madrid Sanchinarro | Velez J.I.,Human Genome Research Institutes | Trimble E.L.,U.S. National Institutes of Health | And 3 more authors.
Supportive Care in Cancer | Year: 2013

Purpose: The primary purpose of this study is to evaluate health-related quality of life (HR-QOL) of gynecologic cancer patients undergoing laparotomy. Methods: Women who underwent laparotomy by gynecologic cancer completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of life questionnaires (QLQ-C30 and QLQ-OV28) presurgery and at 1 month. Results: Of the 181 women studied between January 2007 and March 2008, 116 women (64.1 %) had ovarian cancer, 27 (14.9 %) had cervical cancer, and 29 (16.0 %) had endometrial cancer. By 1 month post-surgery, there was a significant decrease in HR-QOL on the global, abdominal/gastrointestinal (GI) score, body image, chemotherapy side effects, and other single items of the OV28 questionnaire, as well as on physical, role and social functioning, fatigue, nausea and vomiting, pain, insomnia, constipation, appetite loss, and financial difficulties items on C30 questionnaires. Emotional functioning on C30 questionnaires was significantly improved 1 month after surgery. The majority of these items persisted 1 month after surgery only in patients with ovarian cancer. Abdominal/GI score on OV28 questionnaires as well as role and physical functioning on C30 questionnaires were significantly lower between baseline and postsurgical HR-QOL in women with other gynecologic malignancies. Conclusion: The results suggest a significant impact of HR-QOL among gynecologic cancer patients 1 month after laparotomy, particularly among those with ovarian cancer. © 2012 Springer-Verlag.


Minig L.,Hospital Universitario Madrid Sanchinarro | Franchi D.,Italian National Cancer Institute | Valero De Bernabe J.,Hospital Universitario Madrid Sanchinarro | Sideri M.,Italian National Cancer Institute
Gynecologic and Obstetric Investigation | Year: 2013

Background: Hysterectomy plus salpingo-oophorectomy represents the standard treatment for patients with well-differentiated endometrial cancer (EC) limited to the endometrium. It is estimated that over 5% of EC are diagnosed in nulliparous women aged 35-44 years. In addition, EC can affect obese women with diabetes, hypertension and other comorbidities increasing the surgical risk. Methods: This article reviews the English literature in PubMed regarding hormonal treatment of EC. Results: Use of hormonal therapies has resulted in complete remission in 60-70%; many of these women were able to achieve full-term pregnancies, and in case of contraindication to surgery, resection could be avoided. Several topics, however, such as patient selection, interobserver histologic evaluation, the type/duration of hormonal treatment, modality of evaluation before treatment and surveillance after treatment, which are still subject to controversy, are therefore discussed in this paper. Conclusion: Uterus-sparing treatment of well-differentiated EC limited to the endometrium is feasible and has acceptable efficacy in women with increased surgical risk or those who wish to preserve their fertility. Although the methods applied to determine disease extent beyond the endometrium are still unsatisfactory, patient selection is a crucial factor determining the outcome of treatment. However, women must be fully informed about the possibility of treatment failure and the necessity of a close follow-up after therapy. Copyright © 2013 S. Karger AG, Basel.


Rodriguez-Nieto S.,Lhospitalet Of Llobregat | Canada A.,Bioinformatics Unit | Pros E.,Lhospitalet Of Llobregat | Pinto A.I.,Lhospitalet Of Llobregat | And 6 more authors.
Human Mutation | Year: 2011

The tumor suppressor gene, SMARCA4 (or BRG1), which encodes the ATPase component of the chromatin remodeling complex SWI/SNF, is commonly inactivated by mutations and deletions in lung cancer cell lines. However, SMARCA4 alterations appear to be rare in lung primary tumors. Ultra-deep sequencing technologies provide a promising alternative to achieve a sensitivity superior to that of current sequencing strategies. Here we used ultra-deep pyrosequencing to screen for mutations over the entire SMARCA4 coding region in 12 lung tumors without detectable BRG1 protein. While automatic-fluorescence-based sequencing detected one somatic mutation (p.K586X), the pyrosequencing revealed additional variants, thus increasing the sensitivity. One of the variants, which affected a consensus splice site, was confirmed by individual cloning of PCR products, ruling out the possibility of PCR or pyrosequencing artifacts. This mutation, confirmed to be somatic, was present at a frequency of ten percent, suggesting normal cell contamination in the tumor. Our analysis also allowed us to determine the sensitivity and to identify some limitations of the technology. In conclusion, in addition to cell lines, SMARCA4 is biallelically inactivated in a significant proportion of lung primary tumors, thereby constituting one of the most important genes contributing to the development of this type of cancer. © 2010 Wiley-Liss, Inc.


Zimmer L.,University of Duisburg - Essen | Barlesi F.,Aix - Marseille University | Martinez-Garcia M.,Hospital del Mar and Cancer Research Program | Dieras V.,University Pierre and Marie Curie | And 15 more authors.
Clinical Cancer Research | Year: 2014

Purpose: This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor. Experimental Design: We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added. Results: Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS /non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications. Conclusions: Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. © 2014 AACR.


Garralda E.,Spanish National Cancer Research Center | Paz K.,Hospital Universitario Madrid Sanchinarro | Lopez-Casas P.P.,Spanish National Cancer Research Center | Jones S.,Hospital Universitario Madrid Sanchinarro | And 14 more authors.
Clinical Cancer Research | Year: 2014

Background: Current technology permits anunbiasedmassive analysis of somatic genetic alterations from tumorDNA aswell as the generation of individualizedmouse xenografts (Avatarmodels). Thiswork aimed to evaluate our experience integrating these two strategies to personalize the treatment of patients with cancer. Methods: We performed whole-exome sequencing analysis of 25 patients with advanced solid tumors to identify putatively actionable tumor-specific genomic alterations. Avatar models were used as an in vivo platform to test proposed treatment strategies. Results: Successful exome sequencing analyses have been obtained for 23 patients. Tumor-specific mutations and copy-number variations were identified. All samples profiled contained relevant genomic alterations. Tumor was implanted to create an Avatar model from 14 patients and 10 succeeded. Occasionally, actionable alterations such as mutations in NF1, PI3KA, and DDR2 failed to provide any benefit when a targeted drug was tested in the Avatar and, accordingly, treatment of the patients with these drugs was not effective. To date, 13 patients have received a personalized treatment and 6 achieved durable partial remissions. Prior testing of candidate treatments in Avatar models correlated with clinical response and helped to select empirical treatments in some patients with no actionable mutations. Conclusion: The use of full genomic analysis for cancer care is encouraging but presents important challenges that will need to be solved for broad clinical application. Avatar models are a promising investigational platform for therapeutic decision making. While limitations still exist, this strategy should be further tested. © 2014 AACR.


Hyman D.M.,Sloan Kettering Cancer Center | Puzanov I.,Vanderbilt University | Subbiah V.,University of Texas M. D. Anderson Cancer Center | Faris J.E.,Massachusetts General Hospital | And 19 more authors.
New England Journal of Medicine | Year: 2015

BACKGROUND BRAF V600 mutations occur in various nonmelanoma cancers. We undertook a histology-independent phase 2 "basket" study of vemurafenib in BRAF V600 mutation- positive nonmelanoma cancers. METHODS We enrolled patients in six prespecified cancer cohorts; patients with all other tumor types were enrolled in a seventh cohort. A total of 122 patients with BRAF V600 mutation-positive cancer were treated, including 27 patients with colorectal cancer who received vemurafenib and cetuximab. The primary end point was the response rate; secondary end points included progression-free and overall survival. RESULTS In the cohort with non-small-cell lung cancer, the response rate was 42% (95% confidence interval [CI], 20 to 67) and median progression-free survival was 7.3 months (95% CI, 3.5 to 10.8). In the cohort with Erdheim-Chester disease or Langerhans'-cell histiocytosis, the response rate was 43% (95% CI, 18 to 71); the median treatment duration was 5.9 months (range, 0.6 to 18.6), and no patients had disease progression during therapy. There were anecdotal responses among patients with pleomorphic xanthoastrocytoma, anaplastic thyroid cancer, cholangiocarcinoma, salivary-duct cancer, ovarian cancer, and clear-cell sarcoma and among patients with colorectal cancer who received vemurafenib and cetuximab. Safety was similar to that in prior studies of vemurafenib for melanoma. CONCLUSIONS BRAF V600 appears to be a targetable oncogene in some, but not all, nonmelanoma cancers. Preliminary vemurafenib activity was observed in non-small-cell lung cancer and in Erdheim-Chester disease and Langerhans'-cell histiocytosis. The histologic context is an important determinant of response in BRAF V600-mutated cancers. Copyright © 2015 Massachusetts Medical Society.


Agullo-Ortuno M.T.,Hospital Universitario 12 Of Octubre | Lopez-Rios F.,Hospital Universitario Madrid Sanchinarro | Paz-Ares L.,Hospital Universitario Virgen Del Rocio
Journal of Thoracic Oncology | Year: 2010

Background: Lung cancer (LC) is the dominant cause of death by cancer in the world, being responsible for more than a million deaths annually. It is a highly lethal common tumor that is frequently diagnosed in advanced stages for which effective alternative therapeutics do not exist. In view of this, there is an urgent need to improve the diagnostic, prognostic, and therapeutic classification systems, currently based on clinicopathological criteria that do not adequately translate the enormous biologic complexity of this disease. Methods: The advent of the human genome sequencing project and the concurrent development of many genomic-based technologies have allowed scientists to explore the possibility of using expression profiles to identify homogenous tumor subtypes, new prognostic factors of human cancer, response to a particular treatment, etc. and thereby select the best possible therapies while decreasing the risk of toxicities for the patients. Therefore, it is becoming increasingly important to identify the complete catalog of genes that are altered in cancer and to discriminate tumors accurately on the basis of their genetic background. Results and Discussion: In this article, we present some of the works that has applied high-throughput technologies to LC research. In addition, we will give an overview of recent results in the field of LC genomics, with their effect on patient care, and discuss challenges and the potential future developments of this area. Copyright © 2010 by the International Association for the Study of Lung Cancer.


Marchetti P.,University of Rome La Sapienza | Voltz R.,University of Cologne | Rubio C.,Hospital Universitario Madrid Sanchinarro | Mayeur D.,Mignot Hospital | Kopf A.,Charité - Medical University of Berlin
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2013

Early initiation of palliative care to address pain and other symptoms offers the potential to improve quality of life for patients with cancer. The approaches to implementing and delivering palliative care and pain management services vary depending on patient needs, available resources, provider training, and clinical setting. This article describes the experiences in developing programs in which the need for early palliative care or pain management services for patients with cancer was recognized. In each case, collaborative efforts, careful planning, administrative support, and ample time were needed to implement such services. To tailor services based on the available resources, different approaches were taken, including structuring of services within oncology units; creation of an integrated partnership between oncology and palliative care departments; establishment of a multidisciplinary comprehensive service; and incorporation of nurse-based pain services to address acute, chronic, and cancer pain. These examples offer insights into how to optimize delivery of services in a variety of settings with varying resources. Copyright © 2013 by the National Comprehensive Cancer Network. All rights reserved.


Castillo S.D.,Bellvitge Biomedical Research Institute IDIBELL | Matheu A.,UK National Institute for Medical Research | Mariani N.,Bellvitge Biomedical Research Institute IDIBELL | Carretero J.,University of Valencia | And 3 more authors.
Cancer Research | Year: 2012

The HMG box transcription factor SOX4 involved in neuronal development is amplified and overexpressed in a subset of lung cancers, suggesting that it may be a driver oncogene. In this study, we sought to develop this hypothesis including by defining targets of SOX4 that may mediate its involvement in lung cancer. Ablating SOX4 expression in SOX4-amplified lung cancer cells revealed a gene expression signature that included genes involved in neuronal development such as PCDHB, MYB, RBP1, and TEAD2. Direct recruitment of SOX4 to gene promoters was associated with their upregulation upon ectopic overexpression of SOX4. We confirmed upregulation of the SOX4 expression signature in a panel of primary lung tumors, validating their specific response by a comparison using embryonic fibroblasts from Sox4-deficient mice. Interestingly, we found that small cell lung cancer (SCLC), a subtype of lung cancer with neuroendocrine characteristics, was generally characterized by high levels of SOX2, SOX4, and SOX11 along with the SOX4-specific gene expression signature identified. Taken together, our findings identify a functional role for SOX genes in SCLC, particularly for SOX4 and several novel targets defined in this study. ©2011 AACR.


Minig L.,Hospital Universitario Madrid Sanchinarro | Otano L.,Hospital Italiano Of Buenos Aires | Diaz-Padilla I.,Hospital Universitario Madrid Sanchinarro | Alvarez Gallego R.,Hospital Universitario Madrid Sanchinarro | And 2 more authors.
Clinical and Translational Oncology | Year: 2013

Epithelial ovarian cancer (EOC) during pregnancy is a rare condition. The diagnosis and treatment strategies are therefore not well defined. The evidence is scarce and limited to small case reports or case series. In this review we describe the safety, utility and limitations of each diagnostic tool and surgical procedure in pregnant women with ovarian cancer. We also discuss the role of chemotherapy for ovarian cancer during pregnancy. Finally, we delineate different strategies of treatment according to the stage of the disease at diagnosis and gestational age. Due to the complexity of the management of EOC during pregnancy, patients should be referred to specialized centers. Gestational age at diagnosis, the initial surgical procedure, disease stage and patient's preferences are the key factors in the decision-making process to establish the best treatment strategy for each individual case. © 2012 Federación de Sociedades Españolas de Oncología (FESEO).

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