Angel Garcia

Phosphorylated 4E Binding Protein 1: A Hallmark of Cell Signaling That Correlates With Survival in Ovarian Cancer

Growth factor receptors and cell signaling factors play a crucial role in human carcinomas and have been studied in ovarian tumors with varying results. Cell signaling involves multiple pathways and a myriad of factors that can be mutated or amplified. Cell signaling is driven through the mammalian target of rapamycin (mTOR) and extracellular regulated kinase (ERK) pathways and by some downstream molecules, such as 4E binding protein 1 (4EBP1), eukaryotic initiation factor 4E, and p70 ribosomal protein S6 kinase (p70S6K). The objectives of this study were to analyze the real role that these pathways play in ovarian cancer, to correlate them with clinicopathologic characteristics, and to identify the factors that transmit individual proliferation signals and are associated with pathologic grade and prognosis, regardless specific oncogenic alterations upstream.

Idiopathic chondrolysis of the hip : Long-term evolution

Idiopathic chondrolysis of the hip is characterized by the destruction of the articular cartilage due to an unknown cause, principally affecting women during adolescence and producing premature degeneration of the hip. Twelve cases (11 patients) were reviewed at our hospital, with an average follow-up period of 13.2 years, during which a clinical and radiologic study was performed. Despite the treatment implemented, idiopathic chondrolysis of the hip causes progressive degeneration of the joint with the appearance of almost constant pain, stiffness, and anomalous positions. Radiologic studies show concentric narrowing of the articular space, decrease in the width of the femoral head and neck, and shortening of the affected member due to alteration in the growth physis of the upper extremity of the femur.

Risk of recurrence during follow-up for optimally treated advanced epithelial ovarian cancer (EOC) with a low-level increase of serum CA-125 levels

BACKGROUND Our group evaluated the risk of recurrence for optimally treated advanced epithelial ovarian cancer (adEOC) in patients with a low-level rising serum CA-125 concentration within the normal range (0-35 kU/l). In addition, we tested the new proposed early CA-125 signal of progressive disease (EPD) criterion in the same study population. PATIENTS AND METHODS Patients treated from 1998 to 2006 for adEOC were identified at our institution. Inclusion criteria were as follows: CA-125 at time of diagnosis (>35 kU/l); International Federation of Gynecology and Obstetrics stages III-IV treated with optimal primary treatment; and complete response (CR) to primary treatment with normalization of CA-125. RESULTS Median progression-free survival and overall survival for the recurrence group (n = 60) were 17.7 and 38.2 months, respectively. The median follow-up time from CR to last contact was 40.2 months for patients in the nonrecurrence group (n = 36). An absolute increase in serum CA-125 levels of >or=5 kU/l compared with baseline CA-125 nadir values was significantly predictive of recurrence (odds ratio for recurrence = 402.98, P < 0.0001). The progression date was predated by the EPD criterion in 77% of patients with known progressive disease (median, 58 days early) with a sensitivity of 90%, a positive predictive value of 96.4%, and a false-positive rate of 5.6%. CONCLUSIONS Among patients with optimally treated adEOC in complete remission, a low-level increase in serum CA-125 concentration within the normal range is a strong independent predictive factor for disease recurrence. In this patient population, future prospective randomized trials should consider the evaluation of the EPD criterion.

Overexpression of Phosphorylated 4E-BP1 Predicts for Tumor Recurrence and Reduced Survival in Cervical Carcinoma Treated With Postoperative Radiotherapy

PURPOSE To examine the prognostic value of the 4E-BP1 activation state and related upstream/downstream signaling proteins on the clinical outcome of patients with intermediate- or high-risk early-stage cervical carcinoma treated with postoperative radiotherapy and to determine the optimal treatment of early-stage cervical carcinoma. METHODS AND MATERIALS Immunohistochemical staining was performed on 64 formalin-fixed, paraffin-embedded cervical carcinoma surgical specimens for each protein of the panel (p4E-BP1, phosphorylated mitogen-activated protein kinase, pAkt, vascular endothelial growth factor, KDR, Bcl-2, TP53, receptor for activated C-kinase 1). The expression patterns were related to the clinical data. All patients received postoperative radiotherapy. Concurrent chemotherapy was added if high-risk features were present. The median follow-up was 40 months. RESULTS Of the 64 patients, 13 received concomitant chemotherapy. p4E-BP1 overexpression in moderate/high-risk early-stage cervical carcinoma correlated significantly with disease-free survival (hazard ratio, 4.39; p = .009) and overall survival (hazard ratio, 4.88; p = .005). Vascular endothelial growth factor, and its receptor KDR, had positive immunoreactivity in all tumor samples. No correlation with clinical outcome was found for the remaining proteins evaluated. CONCLUSION In this study, moderate/high-risk early-stage cervical carcinoma with low p4E-BP1 expression was highly curable with the current postoperative treatments. For tumors with p4E-BP1 overexpression, new investigational strategies are needed.

Activated leukocyte cell adhesion molecule (ALCAM) is a marker of recurrence and promotes cell migration, invasion and metastasis in early stage endometrioid endometrial cancer.

Endometrial cancer is the most common gynaecological cancer in western countries, being the most common subtype of endometrioid tumours. Most patients are diagnosed at an early stage and present an excellent prognosis. However, a number of those continue to suffer recurrence, without means of identification by risk classification systems. Thus, finding a reliable marker to predict recurrence becomes an important unmet clinical issue. ALCAM is a cell–cell adhesion molecule and member of the immunoglobulin superfamily that has been associated with the genesis of many cancers. Here, we first determined the value of ALCAM as a marker of recurrence in endometrioid endometrial cancer by conducting a retrospective multicentre study of 174 primary tumours. In early‐stage patients (N = 134), recurrence‐free survival was poorer in patients with ALCAM‐positive compared to ALCAM‐negative tumours (HR 4.237; 95% CI 1.01–17.76). This difference was more significant in patients with early‐stage moderately–poorly differentiated tumours (HR 9.259; 95% CI 2.12–53.47). In multivariate analysis, ALCAM positivity was an independent prognostic factor in early‐stage disease (HR 6.027; 95% CI 1.41–25.74). Then we demonstrated in vitro a role for ALCAM in cell migration and invasion by using a loss‐of‐function model in two endometrial cancer cell lines. ALCAM depletion resulted in a reduced primary tumour size and reduced metastatic local spread in an orthotopic murine model. Gene expression analysis of ALCAM‐depleted cell lines pointed to motility, invasiveness, cellular assembly, and organization as the most deregulated functions. Finally, we assessed some of the downstream effector genes that are involved in ALCAM‐mediated cell migration; specifically FLNB, TXNRD1, and LAMC2 were validated at the mRNA and protein level. In conclusion, our results highlight the potential of ALCAM as a recurrent biomarker in early‐stage endometrioid endometrial cancer and point to ALCAM as an important molecule in endometrial cancer dissemination by regulating cell migration, invasion, and metastasis. Copyright

Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma.

In developed countries, endometrial carcinoma is the most common cancer that affects the female genital tract. Endometrial carcinoma is divided into two main histological types, type I or endometrioid and type II or non‐endometrioid, each of which have characteristic, although not exclusive, molecular alterations and mutational profiles. Nevertheless, information about the implication and relevance of some of these genes in this disease is lacking. We sought here to identify new recurrently mutated genes in endometrioid cancers that play a role in tumourigenesis and that influence the clinical outcome. We focused on low‐grade, non‐ultramutated tumours as these tumours have a worse prognosis than the ultramutated POLE‐positive endometrioid endometrial carcinomas (EECs). We performed exome‐sequencing of 11 EECs with matched normal tissue and subsequently validated 15 candidate genes in 76 samples. For the first time, we show that mutations in chromatin remodelling‐related genes (KMT2D, KMT2C, SETD1B and BCOR) and in DNA‐repair‐related genes (BRCA1, BRCA2, RAD50 and CHD4) are frequent in this subtype of endometrial cancer. The alterations to these genes occurred with frequencies ranging from 35.5% for KMT2D to 10.5% for BRCA1 and BCOR, with some showing a tendency toward co‐occurrence (RAD50‐KMT2D and RAD50‐SETD1B). All these genes harboured specific mutational hotspots. In addition, the mutational status of KMT2C, KMT2D and SETD1B helps to predict the degree of myometrial invasion, a critical prognostic feature. These results highlight the possible implication of these genes in this disease, creating opportunities for new therapeutic approaches.

Challenges in the management of neuroendocrine cervical cancer during pregnancy: A case report

Large-cell neuroendocrine carcinoma (LCNEC) is an uncommon histological subtype of cervical cancer that is associated with poor survival and its occurrence during pregnancy is particularly rare. We herein present the case of a female patient who was diagnosed with cervical LCNEC during pregnancy. The patient declined pregnancy termination and was treated with neoadjuvant chemotherapy with cisplatin and etoposide, without associated toxicity and with good fetal development. At 31.4 weeks of gestation, the fetus was delivered by caesarean section, and the patient underwent radical nerve-sparing hysterectomy with bilateral adnexectomy, along with pelvic and inframesenteric para-aortic lymphadenectomy. The patient received adjuvant chemoradiotherapy and there was no evidence of recurrence or metastasis at 38 months postoperatively. The baby has also been followed up, without any signs of neurodevelopmental disorders. To the best of our knowledge, the present report describes the first case of LCNEC with pregnancy-preserving management in the literature to date.

The genetic landscape of 87 ovarian germ cell tumors

BACKGROUND Ovarian germ cell tumors (OGCT) are rare gynecological neoplasms, mostly affecting children and young women. The underlying molecular genetic background of these tumors is poorly characterized. METHODS We analyzed somatic copy number aberration (CNA) profiles in 87 OGCT tumors and performed whole exome sequencing (WES) on 24 OGCT tumor and matched germline samples to further elucidate their molecular genetic landscape. RESULTS The overall mutation rate was very low in OGCT compared to other human cancers, with an average of 0.05 mutations per Mb, consistent with their embryological origin. We identified recurrent mutations in KIT and KRAS, while CNA profiling revealed frequent focal amplifications affecting PIK3CA and AKT1 in yolk sac tumors, recurrent focal deletions affecting chromosomal regions 1p36.32, 2q11.1, 4q28.1, 5p15.33, 5q11.1 and 6q27, as well as gains in chromosome 12p that were present in all tumors, except for pure immature teratomas. CONCLUSION We here present the first whole exome sequencing data and to our knowledge the largest CNA study in OGCT. We confirmed that earlier reported KIT mutations were frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas. We detected recurrent KRAS mutations, recurrent focal deletions and an enrichment in the PI3K/AKT/PTEN pathway in yolk sac tumors. Several of these aberrations involve targetable pathways, offering novel treatment modalities for OGCT.

Metabolomic and Lipidomic Profiling Identifies The Role of the RNA Editing Pathway in Endometrial Carcinogenesis

Endometrial cancer (EC) remains the most common malignancy of the genital tract among women in developed countries. Although much research has been performed at genomic, transcriptomic and proteomic level, there is still a significant gap in the metabolomic studies of EC. In order to gain insights into altered metabolic pathways in the onset and progression of EC carcinogenesis, we used high resolution mass spectrometry to characterize the metabolomic and lipidomic profile of 39 human EC and 17 healthy endometrial tissue samples. Several pathways including lipids, Kynurenine pathway, endocannabinoids signaling pathway and the RNA editing pathway were found to be dysregulated in EC. The dysregulation of the RNA editing pathway was further investigated in an independent set of 183 human EC tissues and matched controls, using orthogonal approaches. We found that ADAR2 is overexpressed in EC and that the increase in expression positively correlates with the aggressiveness of the tumor. Furthermore, silencing of ADAR2 in three EC cell lines resulted in a decreased proliferation rate, increased apoptosis, and reduced migration capabilities in vitro. Taken together, our results suggest that ADAR2 functions as an oncogene in endometrial carcinogenesis and could be a potential target for improving EC treatment strategies.

Abstract A56: Identification of a micro RNA profile to predict response to therapy and improve patient survival in ovarian cancer

Introduction & Objectives: Ovarian cancer (OC) is the leading cause of death among gynecological malignancies in developed countries. The standard treatment is surgery plus platinum-paclitaxel (CP/TX) chemotherapy. Nevertheless, 70% of these patients are diagnosed in advanced stages, and, among those, 75% will recur, become resistant to therapies and die. We believe that an improvement in OC survival might be related with an early identification of those patients, since long survival (SV) is related to chemosensitivity. Our aim is to identify an expression profile of micro RNAs (miRNAs) associated with SV of patients with advanced OC. Material & Methods: Formalin-fixed paraffin-embedded (FFPE) primary tumor tissues from late stage (III/IV) OC patients were collected at the time of surgery for the study. All patients were treated with optimal surgery and standard chemotherapy (CP/TX; after surgery). Samples were divided into two groups; (a) patients with “long SV” (SV>10 years after diagnosis) and (b) patients with “short SV”. The identification of miRNAs associated with each profile of SV was performed using TaqMan Array MicroRNA microfluidic cards in 30 patients. Results: The identification phase has shown that the majority of the miRNAs appeared to be down-regulated in the group of “short SV” versus the “long SV”. A validation phase in a new group of tumor tissue samples is ready to validate the promising miRNA candidates that seem to be associated with the resistant (short SV) and the sensitive (long SV) profiles. Conclusions: The ability to identify markers associated with “long SV” in patients with advanced OC could allow transforming the impact of the disease through the reduction of chemotherapy treatments and the reduction of unnecessary health care costs. Moreover, it could permit the generation of knowledge applicable to the future development of new therapies for the “short SV” since they are supposed to be resistant to the therapy. Citation Format: Marina Rigau, Blanca Majem, Tatiana Altadill, Lucia Lanau, Jose-Luis Sanchez-Iglesias, Josep Castellvi, Assumpcio Perez-Benavente, Silvia Cabrera, Angel Garcia, Jordi Xercavins, Francesc Alameda, Xavier Matias-Guiu, Antonio Gil-Moreno, Josep-Maria Del Campo, Marta Llaurado, Jaume Reventos. Identification of a micro RNA profile to predict response to therapy and improve patient survival in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A56.