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The use of circulating tumor cells (CTCs) as indicators of treatment response in metastatic colorectal cancer (mCRC) needs to be clarified. The objective of this study is to compare the Response Evaluation Criteria in Solid Tumors (RECIST) with the Cytologic Criteria Assessing Response (CyCAR), based on the presence and phenotypic characterization of CTCs, as indicators of FOLFOX–bevacizumab treatment response. We observed a decrease of CTCs (42.8 vs. 18.2%) and VEGFR positivity (69.7% vs. 41.7%) after treatment. According to RECIST, 6.45% of the patients did not show any clinical benefit, whereas 93.55% patients showed a favorable response at 12 weeks. According to CyCAR, 29% had a non-favorable response and 71% patients did not. No significant differences were found between the response assessment by RECIST and CyCAR at 12 or 24 weeks. However, in the multivariate analysis, RECIST at 12 weeks and CyCAR at 24 weeks were independent prognostic factors for OS (HR: 0.1, 95% CI 0.02–0.58 and HR: 0.35, 95% CI 0.12–0.99 respectively). CyCAR results were comparable to RECIST in evaluating the response in mCRC and can be used as an alternative when the limitation of RECIST requires additional response analysis techniques., This work was supported by Roche Spain and a Ph.D. grant from the University of Granada.

Circulating tumor cells (CTCs) have been recently accepted as prognostic markers in metastatic prostate cancer (PCa). However, very few studies have analyzed their role in early-stage PCa. The aim of this research is to study the value of CTCs at the moment of PCa diagnosis and to identify different subpopulations of CTCs. Patients with PSA value > 4 ng/ml and clinical suspicion of PCa were included. Samples were collected immediately before prostatic biopsy. CTCs were isolated by immunomagnetic technique using a multi-CK specific antibody. Molecular expression of EGFR and AR in the tissue was analysed by real-time PCR. Up to eight different SNPs in patients’ blood DNA were studied. In a total of 86 patients, the CTC detection rate was 18.6%. The sensitivity, specificity, positive and negative predictive values of CTCs to detect PCa was 14.2%, 78.4%, 31.2% and 57.4%, respectively. Up to 75% of CTC-positive patients were AR-negative. A direct association was found between the expression of AR in the prostatic tissue and the presence of CTCs in blood (p

Background: Breast cancer patients under neoadjuvant chemotherapy includes a heterogeneous group of patients who eventually develop distal disease, not detectable by current methods. We propose the use of exosomal miRNAs and circulating tumor cells as diagnostic and predictive biomarkers in these patients. Methods: Fifty-three breast cancer women initially diagnosed with localized breast cancer under neoadjuvant chemotherapy were prospectively enrolled in this study. However, six of them were later re-evaluated and diagnosed as metastatic breast cancer patients by PET-CT scan. Additionally, eight healthy donors were included. Circulating tumor cells and serum exosomal miRNAs were isolated from blood samples before and at the middle of neoadjuvant therapy and exosomal miRNA levels analyzed by qPCR. Results: Before neoadjuvant therapy, exosomal miRNA-21 and 105 expression levels were higher in metastatic versus non-metastatic patients and healthy donors. Likewise, higher levels of miRNA-222 were observed in basal-like (p = 0.037) and in luminal B versus luminal A (p = 0.0145) tumor subtypes. Exosomal miRNA-222 levels correlated with clinical and pathological variables such as progesterone receptor status (p = 0.017) and Ki67 (p = 0.05). During neoadjuvant treatment, exosomal miRNA-21 expression levels directly correlated with tumor size (p = 0.039) and inversely with Ki67 expression (p = 0.031). Finally, higher levels of exosomal miRNA-21, miRNA-222, and miRNA-155 were significantly associated with the presence of circulating tumor cells. Conclusion: Liquid biopsies based on exosomal miRNAs and circulating tumor cells can be a complementary clinical tool for improving breast cancer diagnosis and prognosis., This work was supported by “Granada Research of Excellence Initiative on BioHealth (GREIB)”, the PhD grant from the University of Granada and the PhD grant from the Spanish Government (FPU) 2014, REF FPU14/05461

Retrotransposons are a type of transposable element (TE) that have amplified to astonishing numbers in mammalian genomes, comprising more than a third of the human and mouse genomes. Long interspersed element class 1 (LINE-1 or L1) retrotransposons are abundant and currently active retroelements in the human and mouse genomes. Similarly, long terminal repeat (LTR)-containing retrotransposons are abundant in both genomes, although only active in mice. LTR- and LINE-1-retroelements use different mechanisms for retrotransposition, although both involve the reverse transcription of an intermediate retroelement-derived RNA. Retrotransposon activity continues to effect the germline and somatic genomes, generating interindividual variability over evolution and potentially influencing cancer and brain physiology, respectively. However, relatively little is known about the functional consequences of retrotransposition. In this study, we have synthesized and characterized reverse transcriptase inhibitors specific for mammalian LINE-1 retrotransposons, which might help deciphering the functional impact of retrotransposition in vivo.

Retrotransposons comprise over 40 % of the human genome and are a major contributor to genome diversity and evolution. They contribute to human genome variation through both germline and somatic retrotransposition. Over recent years, studies on the biology of cancer have revealed that somatic retrotransposition is a feature of many cancer genomes. The most recent comparison between 200 pairs of tumours and normal tissue, across 11 tumour types, has revealed frequent somatic retrotransposition in particular cancers; lung squamous cell, head and neck squamous cell, colorectal and endometrial carcinomas. Importantly some of these insertions occur in cancer-related genes underlining retrotransposition’s role as a mutagen. It is now clear that retrotransposons contribute to genome instability during cancer progression. However, the exact role of retrotransposons in tumuorigenesis, tumour progression and prognosis still remains a subject of an active discussion in the field of cancer biology.

Circulating Tumor Cells (CTCs) are a valuable prognostic factor in several solid tumors. By understanding the biological characteristics of CTCs we could better understand the biology of metastasis. CTCs usually adopt a dormant state that is believed to be a strategy to survive in extreme conditions. To enter a dormant state, CTCs undergo numerous phenotypic, genetic and functional mutations that significantly affect the efficacy of the therapies used to kill dormant CTCs. Hence, understanding the biological events involved in the dormancy process of CTCs would allow the identification of new therapeutic targets. Some experimental studies or preclinical models have explored these biological events, as well as the molecular factors that contribute to the maintenance of and release from dormancy. However, few studies have assessed the effects of anticancer therapies on dormant cells. This study reviews current the data currently available on cell dormancy mechanisms in prostate cancer, with a special focus on the functional, genetic and phenotypic plasticity of CTCs and their potential implications in the clinical and therapeutic management of prostate cancer.

Recent technological advances have made it possible to detect circulating tumor cells (CTCs) as a prognostic marker in operable breast cancer patients. Whether the presence of CTCs in cancer patients correlates with molecular alterations in the primary tumor has not been widely explored. We identified 14 primary breast cancer specimens with known CTC status, in order to evaluate the presence of differential genetic aberrations by using SNP array assay. There was a global increase of altered genome, CNA, and copy-neutral loss of heterozygosity (cn-LOH) observed in the CTC-positive (CTC(+)) versus CTC-negative (CTC(-)) cases. As the preliminary results showed a higher proportion of copy number alteration (CNA) at 8q24 (MYC loci) and the available evidence supporting the role of MYC in the processes cancer metastases is conflicting, MYC status was determined in tissue microarray sections in a larger series of patients (n = 49) with known CTC status using FISH. MYC was altered in 62% (16/26) CTC(+) patients and in 43% (6/14) CTC(-) patients (p = 0.25). Based on the observation in our study, future studies involving a larger number of patients should be performed in order to definitively define if this correlation exists.

e22025 Background: To develop clinical applications of Circulating Tumor Cells (CTC), their phenotypic and genetic characterization is required. Here, we present the first protocol to detect miRNAs...

An otherwise normal 48-year-old man had malignant large cell calcifying Sertoli cell tumor of the testis. There were lymph node involvement and albugineal invasion at orchiectomy, and pulmonary metastases developed despite radiotherapy and chemotherapy. Our case and, to our knowledge, the only other reported case of malignant large cell calcifying Sertoli cell tumor had clinical and histopathological features related to aggressiveness, such as unusual patient age, large tumor size, cellular pleomorphism, high mitotic rate, necrosis and aneuploid deoxyribonucleic acid. Such characteristics are not found in benign large cell calcifying Sertoli cell tumors. Associated findings included granular change of the epididymal lining, probably due to compression by the large tumor.

This is a case report of a testicular papillary serous carcinoma of ovarian type (PSCOT) diagnosed in a 50-year-old man. The tumor presented in the form of multiple papillary exophytic excrescencies on the visceral tunica vaginalis testis lining the inner surface of a hydrocele sac. The tumor was histologically a papillary serous carcinoma with numerous psammoma bodies, indistinguishable from similar tumors arising on the surface of the ovary. Following the tumor's surgical removal, the patient was treated with the same drugs used to treat ovarian serous carcinomas, and he is alive two years after the initial diagnosis. PSCOT must be distinguished from mesothelioma of the tunica vaginalis testis, a tumor with a most unfavorable prognosis. As shown here, immunohistochemical findings can be useful for formulating the correct diagnosis of PSCOT.

Survival in patients with advanced cervical cancer (stage III B) treated by radical radiotherapy is low. In this study we attempted to assess the efficacy of the cis-diamminedichloroplatinum(II) (CDDP)-ifosfamide combination as neoadjuvant chemotherapy in advanced cervical cancer. The treatment schedule was: 20 mg/m2 CDDP on days 1-5; 1.5 g/m2 ifosfamide on days 1-5; and 900 mg/m2 mesna on days 1-5. Courses were given every 28 days. Radiotherapy was given 15 days after the completion of chemotherapy. A total of 26 patients were entered in this trial. Of the 24 patients evaluable for response, 15 (62.5%) achieved at least a 50% reduction in tumor volume, 6 (25%) showed stable disease, and three (12.5%) had progressive disease. At 38 months (mean follow-up) after completion of radiotherapy, 13 of the 24 (54%) evaluable patients were disease-free; 73% of the patients responding to chemotherapy vs 22% of the nonresponders remained free of disease (Fisher's exact test: P less than 0.02). Major hematologic depression occurred in 2 of the 26 patients evaluable for toxicity. No CNS toxicity was detected. These results are superior to those obtained by radical radiotherapy alone. Future treatment should be directed toward improving response rates as the best way of increasing both local and distant long-term disease control in these patients.

We thank the patients for their participation in the study. We also thank John Pope for excellent editorial assistance. This work was supported by the RETICS, FEDER [RD07/0020/2004]; the FIS [PI08/0334] FEDER and the Consejeria de Salud, Andalusian Regional Government, Spain., Introduction: Increasing evidence supports the view that the detection of circulating tumor cells (CTCs) predicts outcomes of nonmetastatic breast cancer patients. CTCs differ genetically from the primary tumor and may contribute to variations in prognosis and response to therapy. As we start to understand more about the biology of CTCs, we can begin to address how best to treat this form of disease. Methods: Ninety-eight nonmetastatic breast cancer patients were included in this study. CTCs were isolated by immunomagnetic techniques using magnetic beads labelled with a multi-CK-specific antibody (CK3-11D5) and CTC detection through immunocytochemical methods. Estrogen receptor, progesterone receptor and epidermal growth factor receptor (EGFR) were evaluated by immunofluorescence experiments and HER2 and TOP2A by fluorescence in situ hybridization. We aimed to characterize this set of biomarkers in CTCs and correlate it with clinicalpathological characteristics. Results: Baseline detection rate was 46.9% ≥ 1 CTC/30 ml threshold. CTC-positive cells were more frequent in HER2-negative tumors (p = 0.046). In patients younger than 50 years old, HER2-amplified and G1-G2 tumors had a higher possibility of being nondetectable CTCs. Heterogeneous expression of hormonal receptors (HRs) in samples from the same patients was found. Discordances between HR expression, HER2 and TOP2A status in CTCs and their primary tumor were found in the sequential blood samples. Less that 35% of patients switched their CTC status after receiving chemotherapy. EGFR-positive CTCs were associated with Luminal tumors (p = 0.03). Conclusions: This is the largest exploratory CTC biomarker analysis in nonmetastatic BC patients. Our study suggests that CTC biomarkers profiles might be useful as a surrogate marker for therapeutic selection and monitoring since heterogeneity of the biomarker distribution in CTCs and the lack of correlation with the primary tumor biomarker status were found. Further exploration of the association between EGFR-positive CTCs and Luminal tumors is warranted., RETICS, FEDER RD07/0020/2004, European Union (EU) PI08/0334, Consejeria de Salud, Andalusian Regional Government, Spain