Neoplasia In Men Research Articles

New Therapeutic Perspectives in Prostate Cancer: Patient-Derived Organoids and Patient-Derived Xenograft Models in Precision Medicine.

One of the major goals in the advancement of basic cancer research focuses on the development of new anticancer therapies. To understand the molecular mechanisms of cancer progression, acquired drug resistance, and the metastatic process, the use of preclinical in vitro models that faithfully summarize the properties of the tumor in patients is still a necessity. The tumor is represented by a diverse group of cell clones, and in recent years, to reproduce in vitro preclinical tumor models, monolayer cell cultures have been supplanted by patient-derived xenograft (PDX) models and cultured organoids derived from the patient (PDO). These models have proved indispensable for the study of the tumor microenvironment (TME) and its interaction with tumor cells. Prostate cancer (PCa) is the most common neoplasia in men in the world. It is characterized by genomic instability and resistance to conventional therapies. Despite recent advances in diagnosis and treatment, PCa remains a leading cause of cancer death. Here, we review the studies of the last 10 years as the number of papers is growing very fast in the field. We also discuss the discovered limitations and the new challenges in using the organoid culture system and in using PDXs in studying the prostate cancer phenotype, performing drug testing, and developing anticancer molecular therapies.

HB-300, a novel arenavirus-based cancer immunotherapy in patients with metastatic castration-resistant prostate cancer.

TPS5108 Background: Prostate cancer is the most frequent type of malignant neoplasia in men. Immunotherapy targeting self-antigens in prostate cancer is evolving and requires overcoming multiple mechanisms that mediate immune tolerance. Sipuleucel-T, a cell-based therapy recognizing prostatic acid phosphatase (PAP) protein, is approved for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and induced PAP-specific T cell responses correlating with overall survival (OS). Poxvirus vectors encoding prostate-specific antigen (PSA) increased PSA-specific T cell levels and were associated with OS benefit, although not confirmed in a Phase 3 study. Arenaviral vectors used in preclinical tumor models could overcome self-tolerance by inducing strong self-antigen specific CD8 T cell responses. In humans, arenaviral vectors encoding HPV16 E7E6 fusion protein (HB-200) induced unprecedented E6E7-specific CD8 T cell levels in patients with recurrent/metastatic HPV16+ cancers. Preliminary clinical activity and favorable safety and tolerability were observed in these heavily pre-treated, checkpoint inhibitor-resistant patients (ref: Fu et al. ASCO 2022; NCT04180215). It is therefore hypothesized that HB-300, a live-attenuated arenaviral vector therapy encoding the self-antigens PAP and PSA, will induce substantially stronger T cell responses in prostate cancer patients than previously tested active immunization approaches. Methods: This is a Phase 1/2 open-label clinical study of HB-300 in ~ 70 patients with advanced mCRPC. A 3+3 Dose Escalation will be followed by a dose-expansion to confirm the recommended Phase 2 dose (RP2D). HB-300 consists of HB-302 (Pichinde virus based) alternating with HB-301 (LCMV based) vectors, administered IV every 3 weeks (Q3W) for 5 doses then Q6W. The program’s entry into the clinic with a mini dose-escalation was supported by the submission of a data master file along with the HB-300 Investigational New Drug application, based on arenavirus vector platform data collected in the HB-200 program. Trial inclusion criteria include male participants age ≥ 18; documented mCRPC (adenocarcinoma without neuroendocrine or small cell features); receipt of at least 1 androgen deprivation therapy and no prior chemotherapy regimens (docetaxel in the castration-sensitive setting is allowed); ≥1 measurable lesion; ECOG PS 0-1. Exclusions are uncontrolled pain or symptoms; active auto-immune disease; immunosuppression; active central nervous system or liver metastasis; and active infection. Phase 1 primary objectives include safety/tolerability and determination of RP2D, secondary objectives include preliminary efficacy, and exploratory assessments include antigen-specific T cell response and circulating tumor cell analysis. Clinical trial# NCT05553639. Clinical trial information: NCT05553639 .

Long-term effect of cytotoxic treatments on sperm DNA fragmentation in patients affected by testicular germ cell tumor.

Testicular germ cell tumor (TGCT) is the most frequent neoplasia in men of reproductive age, with a 5-year survival rate of 95%. Antineoplastic treatments induce sperm DNA fragmentation (SDF), especially within the first year post-therapy. Data in the literature are heterogeneous concerning longer follow-up periods and the large majority is limited to 2 years. To define the timing for the recovery of sperm DNA damage and the proportion of patients with severe DNA damage (SDD) at 2 and 3 years from the end of therapy. SDF was evaluated in 115 TGCT patients using TUNEL assay coupled with flow cytometry before (T0 ) and 2 (T2 ) and 3 (T3 ) years post-treatment. Patients were divided based on the type of treatment: carboplatin (CP), bleomycin-etoposide-cisplatin (BEP), radiotherapy (RT). For 24 patients paired SDF data were available at all time-points (T0 -T2 -T3 ). 79 cancer-free, fertile normozoospermic men served as controls. SDD was defined as the 95th percentile in controls (SDF = 50%). Comparing patients versus controls we observed: i) no differences at T0 and T3 ; ii) significantly higher SDF levels (p<0.05) at T2 in all treatment groups. Comparing pre and post-therapy in the 115 patients, the median SDF values were higher in all groups at T2 , reaching significance (p<0.05) only in the CP group. While the median SDF values were higher also in the strictly paired cohort at T2 , about 50% of patients returned to baseline. The proportion of SDD in the entire cohort was 23.4% and 4.8% of patients at T2 and T3 , respectively. Currently, TGCT patients are advised to wait two years post-therapy before seeking natural pregnancy. Our results suggest that this period may not be sufficient for all patients. The analysis of SDF may represent a useful biomarker for pre-conception counselling following cancer treatment. This article is protected by copyright. All rights reserved.

Clinical and Novel Biomarkers in Penile Carcinoma: A Prospective Review

Penile carcinoma is a rare urological neoplasia in men compared to other more common tumors, such as prostate, kidney, or bladder tumors. However, this neoplasm continues to affect a large number of patients worldwide, with developing countries presenting the highest incidence and mortality rates. Important risk factors such as the human papilloma virus, a factor affecting a large number of patients, have been described; however, few studies have evaluated screening programs in populations at risk for this disease, which severely affects the quality of life of older men. The management of these patients is usually complex, requiring surgical interventions that are not without risk and that have a great impact on the functionality of the male reproductive system. In addition, in cases of disseminated disease or with significant locoregional involvement, patients are evaluated by multidisciplinary oncological committees that can adjust the application of aggressive neoadjuvant or adjuvant chemotherapy on numerous occasions without clear improvement in survival. Chemotherapy regimens are usually aggressive, and unlike in other urological neoplasms, few advances have been made in the use of immunotherapy in these patients. The study of serological and histological biomarkers may help to better understand the underlying pathophysiology of these tumors and select patients who have a higher risk of metastatic progression. Similarly, the analysis of molecular markers will improve the availability of targeted therapies for the management of patients with disseminated disease that would benefit prognosis. Therefore, the purpose of this article is to summarize the main advances that have occurred in the development of serological and histological markers and their therapeutic implications in patients diagnosed with penile carcinoma, explaining the limitations that have been observed and analyzing future perspectives in the management of this disease.

Lemongrass (Cymbopogon citratus (D.C.) Stapf) Presents Antitumoral Effect and Improves Chemotherapy Activity in Prostate Cancer Cells.

Prostate cancer is the most common visceral neoplasia in men and frequently presents chemotherapy resistance. In this context, lemongrass (Cymbopogon citratus (D.C.) Stapf) has been studied since it presents many important biological activities, such as anticancer. We investigated the antitumor effect of lemongrass and in chemotherapy activity using prostate cancer cells line (DU-145). DU-145 cells were exposed to different concentrations of aqueous extract of lemongrass (30; 100; 300; 500 and 1000 μg/mL), isolated and in combination with docetaxel, during 24 and 72 hours. After, cell viability and proliferation, oxidative metabolism, colony formation and cell cycle analyses were performed. Also, we exposed the African green monkey kidney cell line (VERO) to the same lemongrass concentrations to investigate a possible toxicity of this extract. Our findings suggested that lemongrass presented an antitumor effect and improved docetaxel chemotherapy activity by decreasing cell viability and proliferation as well as colony formation. Moreover, we found an oxidative stress increased and cell cycle arresting in G0 /G1 phase. In addition, this extract presented selectivity action for cancer cells, since it did not cause cytotoxicity in normal cells, ensuring non-toxic therapeutic concentrations. Lemongrass is a promising medicinal plant that could be used during chemotherapeutic treatment, in order to potentiate the antitumor response and decrease the resistance of prostate cancer.

Human papillomavirus 16 L1 gene methylation as a potential biomarker for predicting anal intraepithelial neoplasia in men who have sex with men (MSM).

The human papillomavirus (HPV) 16 early promoter and L1 gene methylation were quantitatively measured using pyrosequencing assay in anal cells collected from men who have sex with men (MSM) to determine potential biomarkers for HPV-related anal cancer. The methylation patterns of HPV16 genes, including the early promoter (CpG 31, 37, 43, 52, and 58) and L1 genes (CpG 5600, 5606, 5609, 5615, 7136, and 7145), were analyzed in 178 anal samples. The samples were diagnosed as normal, anal intraepithelial neoplasia (AIN) 1, AIN2, and AIN3. Low methylation levels of the early promoter (< 10%) and L1 genes (< 20%) were found in all detected normal anal cells. In comparison, medium to high methylation (≥ 20–60%) in the early promoter was found in 1.5% (1/67) and 5% (2/40) of AIN1 and AIN2-3 samples, respectively. Interestingly, slightly increased L1 gene methylation levels (≥ 20–60%), especially at the HPV16 5’L1 regions CpGs 5600 and 5609, were demonstrated in AIN2-3 specimen. Moreover, a negative correlation between high HPV16 L1 gene methylation at CpGs 5600, 5609, 5615, and 7145 and a percentual CD4 count was found in AIN3 HIV positive cases. When comparing the methylation status of AIN2-3 to that of normal/AIN1 lesions, the results indicated the potential of using HPV16 L1 gene methylation as a biomarker for HPV-related cancer screening.

Relationship with Metalloproteinase 13, E-cadherin, Homocysteine and Co Factors Folic Acid and Vitamin B12 in Patients Diagnosed with Prostate Cancer

Introduction:: Prostate cancer (Pc) is the most frequent neoplasia in men and the second cause of death in Brazil. Objective:: To analyze the interactions and biologicals responses of Pc oxidative stress and prostatespecific antigen (PSA), E-cadherin and MMP-13. Demonstrate whether the increase of the amount of the form of E-cadherin found in the plasma of Pc patients, correlates with decrease of the PSA. Methods:: Samples were obtained through peripheral venipuncture to analyse parameters of biomarkers pc as PSA, E-cadherin, MMP-13, Homocysteine, Folic acid, Vitamin B12, Testosterone T and free following the patients diagnosis, 3 and 6 months during their treatment to analyze the biological responses of Pc oxidative stress. Results:: The analysis was performed by using immunoenzymatic assay. Statistical data processed through Excel in Windows Vista and analyzed through the Shapiro-wilk Test, ANOVA, and Spearman Test. An increase in the concentration of E-cadherin (p = 0.02), as a decrease in concentration of PSA (p &lt; 0.001), total testosterone (p &lt; 0.001) and free testosterone (p = 0.02) was observed during the treatment period without significant alterations in the remaining markers for either of the periods. Discussion:: It was found that during treatment of men diagnosed with pc that there was an an increase in the concentration of plasmatic E-cadherin, which was negatively correlated with the concentrations of folic acid (-0,03 (0,87) rs (p). It was observed that the levels of hcy are positively correlated with concentrations of total testosterone and a negative correlation. Vitamins B12 remained within the parameters of normality during the entire study. Conclusion:: P.S.A levels were free and total testosterone levels decreased. In this way, monitoring the folic acid, E-cadherin dosages of patients during the treatment phases can effectively complement in the face of remission, since it would be a way of preventing abnormal cell replications, with a clinical view prudent so that the cell methylation cycle is not affected.

Over-diagnosed prostate cancer in solid organ recipients: lessons from the last 3 decades.

Prostate cancer (PC) is the most common neoplasia in men. With aging of solid organ transplant recipients (SOTR), its incidence is likely to increase. The aim of this study was to analyze PC screening results retrospectively in renal transplant recipients (RTR), hepatic transplant recipients (HTR) and cardiac transplant recipients (CTR). A retrospective monocentric study of PC diagnosed in renal, hepatic or cardiac transplanted patients since 1989 was performed. All the patients were followed annually by digital rectal examination and prostate serum antigen (PSA) dosage. 57 PC were diagnosed in 1565 SOTR male patients (3.6%): 35 RTR, 15 HTR, and 7 CTR. Standard incidence ratio (SIR) was 41.9. Mean age at the time of diagnosis was 64.5 (60.5-69.2). Mean time between transplantation and PC diagnosis was 95.7 (39.0-139.5) months. Median PSA rate was 7.0 (6.2-13) ng/mL. Clinical stages were T1, T2, and T3, respectively, for 29, 22 and 6 patients. Diagnosis was done by screening in 52 patients, after prostatitis in 1 and bone pain in another. Three PC were discovered on prostate chips after transurethral resection. Two patients were treated by active surveillance. 39 (68%) patients (25 RTR, 11 HTR and 3 CTR) were treated by radical prostatectomy. Histological results were 30 pT2 and 9 pT3 tumors, with 7 positive surgical margins. Gleason score was 5, 6, 7, 8 and 9 in, respectively, in 2, 24, 11, 1 and 1 patients. One patient with positive pelvic nodes was treated with hormonal therapy (HT). One had a biochemical relapse at 10months and underwent salvage radiotherapy. Median follow-up was 85.2months (46.1-115.0). 23 (40.4%) patients died. Two (3.6%) RTR and 1 (1.8%) CTR died from their PC. Standard incidence ratio were, respectively, 42.4, 48.2 and 39 in RTR, HTR and CTR. Systematic screening in male SOTR after 50years old could not be recommended. In the last 3 decades, we diagnosed too many low-risk prostate cancers strongly increasing the SIR but failing to decrease prostate cancer related mortality. SOTR should undergo individual screening with prior MRI when PSA rates are high. Management should not be different from that of the general population.

Current therapeutic strategies for erectile function recovery after radical prostatectomy – literature review and meta-analysis

Current therapeutic strategies for erectile function recovery after radical prostatectomy – literature review and meta-analysis

Vaccinations for Anal Squamous Cancer: Current and Emerging Therapies.

Human papillomavirus (HPV) infection is responsible for 4.3% of the global cancer burden. Since 2006, current HPV vaccines have reduced the prevalence of the virus in adolescent girls, reduced the prevalence of genital warts, and been proven to reduce the progression of anal intraepithelial neoplasia in men. Herein, we review the epidemiology, virology, and immunology behind the prophylactic HPV vaccines and current recommendations for its use. We also review future immune therapies being trialed for use against HPV-related cancers including anal cancer.

Submit Manuscript | http://medc rav eonline.co m Introduction Colorectal adenocarcinoma is the third most common malignant neoplasia and the third leading cause of death from cancer in men and women in the United States. Current data show that the incidence of colorectal adenocarcinoma is decreasing in developed countries but increasing in developing countries. 1 The 2018 estimates of the Bra

Introduction Rectal cancer RC is a tumor commonly diagnosed in developing countries accounting to the considerable rates of morbi mortality The neoadjuvant therapy NT with radiotherapy and chemotherapy plays a leading role in the management of this neoplasm according to oncological results and the preservation of anal function Magnetic resonance imaging MRI is one of the main tools for the evaluation of NTresults in rectal cancer in order to manage the patient rsquo s therapy Objectives To compare the results of the MRI performed right after NTwith histopathologic findings of surgical specimens in patients with RC whom underwent radical surgery Methods This retrospective study of patients with extraperitoneal RC Whom underwent radical surgery with a total mesorectal excision TME and with the preservation of sphincter after performing an NT The selected patients underwent an pelvis MRI with an emphasis on the rectum before and after performing an NT The initial stage of the disease was detected on the first MRI and the second MRI post NT was responsible for determining the tumor rsquo s regression grade TRG and downstaging disease This TRG was compared with the estimated regression obtained by histopathology of the specimen based on Dworak TRG classification and TNM classification and trying to analyze the degree of agreement of the two methods and the occurrence of downstaging Results Most patients presented a downstaging of of thedisease after NT when compared to the initial stage Six patients achieved a complete pathological response An MRI had a sensitivity of and specificity of with Positive Predictive Value PPV Negative Predictive Value NPV and an accuracy of in estimating the TRG compared to histopathology There was no correlation between patient characteristics and pathological findings and the results of TRG Conclusion An MRI of the pelvis with an emphasis on the rectum has a high accuracy rate when evaluating patients with RC submitted to NTwith radiotherapy and quimioterapy compared with histopathology and should be used routinely in clinical practice

Serum relaxin-2 as a novel biomarker for prostate cancer

Prostate cancer is a common neoplasia in men and its incidence continues to rise in many countries. Some patients never experience symptoms or disease progression, whereas others will have a rapid ...

Abstract 1476: Cell-free miR-141 as a molecular marker for prostate cancer metastasis

Abstract Prostate cancer is the second most commonly diagnosed neoplasia in men. Currently, there is no available non-invasive tool to assist in the identification of the aggressive form of this disease. Cell-free nucleic acid has been tested as a potential new molecular tool that can be useful in the diagnosis and prognosis of prostate cancer. MicroRNAs are a class of non-coding RNAs, that are shown to impact the development and progression of prostate cancer and their detection in plasma have been indicated as a promising non-invasive tool for disease screening and prognosis assessment. Among the several deregulated miRNAs that are observed in prostate cancer, the miRNA-141-3p was observed with upregulated expression levels in prostate cancer, particularly in the metastatic lesions. Therefore, the main aim of this study was to verify the diagnostic potential of miR-141 as a circulating tumor marker for prostate cancer and determine its functional role in modulating tumorigenesis in prostate cancer metastatic cell lines. MiR-141 expression analysis was performed in plasma samples of 102 prostate cancer patients without treatment and of 50 health controls by RT-qPCR. The experimental assays were performed by transfecting the PC3 cell line using miRNA-141 mimic/ inhibitor systems and directly accessing their effect in classical tumor phenotypes. Expression of the miR-141 were found significantly upregulated in the metastatic patients’ plasma specimens (FC=9.11, p=0.04; AUC=0.66) when compared to the patients without metastasis, showing its screening potential for prostate cancer metastasis. The in vitro ectopic expression of miR-141 in PC3 cell line showed a significant increased in cell proliferation, associated with changes in cell cycle (decreased number of cells in the G1 phase). Conversely, the inhibition of miR-141 showed an increase in the migratory ability, cell adhesion and in the Docetaxel cytotoxicity of the PC3 cells. Western-blot analysis showed that the inhibition of the miR-141 levels reduced the expression of the EMT inducers markers E-CADHERIN and CLAUDIN, and up-regulated the levels of ZEB-1, pAKT and VIMENTIN, consistent with their repression roles in the EMT process. These findings showed that miR-141 presents a direct function in controlling some of the in vitro metastatic phenotypes in prostate cancer, through the regulation of the epithelial-mesenchymal transition expression proteins. In conclusion, miR-141 presents a potential use as a minimally invasive molecular marker for prostate cancer diagnosis and can be used as a druggable target for therapy, particularly in the metastatic clinical setting. Citation Format: Marilesia Ferreira de Souza, Ilce Mara de Syllos Cólus, Aline Simoneti Fonseca, Hellen Kuasne, Paulo Emilio Fuganti, Deepak Kumar, Silvia Regina Rogatto, Luciane Regina Cavalli. Cell-free miR-141 as a molecular marker for prostate cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1476. doi:10.1158/1538-7445.AM2017-1476

Breast cancer in men: about 40 cases and literature review

Le cancer du sein chez l'homme est une affection rare représentant environ 1% de tous les cancers du sein et moins de 1% de l'ensemble des néoplasies masculines. L'objectif de notre étude est de décrire les différents aspects cliniques, histologique, pronostic et thérapeutiques de cette tumeur rare afin de contribuer à l'amélioration de la prise en charge de cette affection. Il s'agit d'une étude rétrospective portant sur 40 patients colligés au Centre Mohamed VI pour le traitement des cancers de Casablanca de Janvier 2000 à Décembre 2012. L'âge médian a été de 62 ans, le délai moyen de consultation a été de 12 mois, l'autopalpation d'un nodule péri aréolaire a été le principal motif de consultation dans 90% des cas. Le carcinome canalaire infiltrant a été le type histologique prédominant dans 90% des cas. La prise en charge thérapeutique multimodale a consisté en une mastectomie suivie d'un traitement adjuvant à type de chimiothérapie, radiothérapie et/ou hormonothérapie en fonction du stade de la tumeur et des caractéristiques histologiques. Le suivi moyen a été de 38 mois, l'évolution a été caractérisée par une rémission complète chez 16 patients (soit 40%), rechute locale chez 3 patients (soit 7.5%) et par une rechute métastatique chez 5 patients (soit 12.5%). Le site métastatique le plus fréquent a été l'os (62%), suivi par le poumon et le foie. Le décès était survenu chez 10 patients (25%). Le cancer du sein chez l'homme présente des similitudes avec le cancer mammaire chez la femme. Mais il présente aussi beaucoup de particularités, d'où l'intérêt de mener des études prospectives randomisés à plus large échelle afin d'améliorer la prise en charge et le pronostic de cette affection dont l'impact psychosociale est considérable.

Metastatic Testicular Choriocarcinoma Leading to Upper GI Bleed

Introduction: Testicular cancer is the most common neoplasia in men between the ages of 15 to 35 years. Choriocarcinoma represent less than 1% of testicular tumors. It usually characterized by early hematogenous spread to the lungs and brain (seen in 80% of the cases). Metastasis to the gastrointestinal tract is extremely rare. Most metastatic lesions in the GI tract are seen in the small bowel. Metastasis to the stomach is rarely seen and only reported in few case reports. Clinical Case: We present a 30 year-old African American male with a past medical history significant for non-seminomatous germ cell testicular cancer. Diagnosis was made via inguinal lymph node biopsy followed by right orchiectomy in April 2015. The patient was initially put on chemotherapy; however, he was not compliant with his treatment. In February 2016, he presented to the hospital with shortness of breath and chest pain. A CT angiography of the chest was done which showed multiple masses scattered in all lung fields. Those lesions were believed to be metastatic in nature. Laboraptory testing showed a human chorionic gonadotropin beta of 40,453 IU/L, LDH 258 IUnits/L and alfa-fetoprotein 8.9 ng/mL. His hospital stay was complicated with melena and a fall of his hemoglobin from a baseline of 12 to 7 gm/dL. He was given 2 units of packed red cells and started on pantoprazole drip. An EGD showed three erythematous friable nodules in the gastric body (figure 1). Biopsy results came back showing cytotrophoblast and syncytiotrophoblast which represent hallmark findings for metastatic choriocarcinoma (figure 2). The patient was offered salvage chemotherapy however he refused treatment and was discharged home.Figure 1Figure 2Discussion: Choriocarcinomas are the most aggressive and rapidly arising germ cell tumors. By the time they are diagnosed nearly half of the cases have already metastasized. Patients usually present with symptoms of hemorrhage in metastatic sites due to the high level of vascularization of those lesions. Gastrointestinal metastases from choriocarcinomas are very rare which account for 5% of all metastatic lesions. Of those less than 1% affect the stomach. The presenting symptoms of stomach metastases is melena and/or hematemesis along with anemia. Conclusion: Although extremely rare, gastric metastasis of choriocarcinoma should be kept in mind as part of the differential diagnosis for young patients with upper gastrointestinal bleeding.

Risk of Advanced Neoplasia in First-Degree Relatives with Colorectal Cancer: A Large Multicenter Cross-Sectional Study.

BackgroundFirst-degree relatives (FDR) of patients with colorectal cancer have a higher risk of developing colorectal cancer than the general population. For this reason, screening guidelines recommend colonoscopy every 5 or 10 y, starting at the age of 40, depending on whether colorectal cancer in the index-case is diagnosed at <60 or ≥60 y, respectively. However, studies on the risk of neoplastic lesions are inconclusive. The aim of this study was to determine the risk of advanced neoplasia (three or more non-advanced adenomas, advanced adenoma, or invasive cancer) in FDR of patients with colorectal cancer compared to average-risk individuals (i.e., asymptomatic adults 50 to 69 y of age with no family history of colorectal cancer).Methods and FindingsThis cross-sectional analysis includes data from 8,498 individuals undergoing their first lifetime screening colonoscopy between 2006 and 2012 at six Spanish tertiary hospitals. Of these individuals, 3,015 were defined as asymptomatic FDR of patients with colorectal cancer (“familial-risk group”) and 3,038 as asymptomatic with average-risk for colorectal cancer (“average-risk group”). The familial-risk group was stratified as one FDR, with one family member diagnosed with colorectal cancer at ≥60 y (n = 1,884) or at <60 y (n = 831), and as two FDR, with two family members diagnosed with colorectal cancer at any age (n = 300). Multiple logistic regression analysis was used for between-group comparisons after adjusting for potential confounders (age, gender, and center). Compared with the average-risk group, advanced neoplasia was significantly more prevalent in individuals having two FDR with colorectal cancer (odds ratio [OR] 1.90; 95% confidence interval [CI] 1.36–2.66, p < 0.001), but not in those having one FDR with colorectal cancer diagnosed at ≥60 y (OR 1.03; 95% CI 0.83–1.27, p = 0.77) and <60 y (OR 1.19; 95% CI 0.90–1.58, p = 0.20). After the age of 50 y, men developed advanced neoplasia over two times more frequently than women and advanced neoplasia appeared at least ten y earlier. Fewer colonoscopies by 2-fold were required to detect one advanced neoplasia in men than in women.Major limitations of this study were first that although average-risk individuals were consecutively included in a randomized control trial, this was not the case for all individuals in the familial-risk cohort; and second, the difference in age between the average-risk and familial-risk cohorts.ConclusionsIndividuals having two FDR with colorectal cancer showed an increased risk of advanced neoplasia compared to those with average-risk for colorectal cancer. Men had over 2-fold higher risk of advanced neoplasia than women, independent of family history. These data suggest that screening colonoscopy guidelines should be revised in the familial-risk population.

Selection and characterization of Anticalins targeting human prostate-specific membrane antigen (PSMA).

Although prostate carcinoma (PCa) is by far the most commonly diagnosed neoplasia in men, corresponding diagnostic and therapeutic modalities have limited efficacy at present. Anticalins comprise a novel class of binding proteins based on a non-immunoglobulin scaffold that can be engineered to specifically address molecular targets of interest. Here we report the selection and characterization of Anticalins that recognize human prostate-specific membrane antigen (PSMA), a membrane-tethered metallopeptidase constituting a disease-related target for imaging and therapy of PCa as well as solid malignancies in general. We used a randomized lipocalin library based on the human lipocalin 2 (Lcn2) scaffold together with phage display and ELISA screening to select PSMA-specific variants. Five Anticalin candidates from the original panning were expressed in Escherichia coli as soluble monomeric proteins, revealing affinities toward PSMA down to the low nanomolar range. Binding characteristics of the most promising candidate were further improved via affinity maturation by applying error-prone PCR followed by selection via phage display as well as bacterial surface display under more stringent conditions. In BIAcore measurements, the dissociation constant of the best Anticalin was determined as ∼500 pM, with a substantially improved dissociation rate compared with the first-generation candidate. Finally, immunofluorescence microscopy revealed specific staining of PSMA-positive tumor cell lines while flow cytometric analysis confirmed the ability of the selected Anticalins to detect PSMA on live cells. Taken together, Anticalins resulting from this study offer a viable alternative to antibody-based PSMA binders for biomedical applications, including in vivo imaging of PCa or neovasculature of solid tumors.

Knocking Down TMPRSS2-ERG Fusion Oncogene by siRNA Could be an Alternative Treatment to Flutamide

Our purpose was to develop a new pharmacological approach for the treatment of prostate cancer (PCa), the most common neoplasia in men. Recently, we developed siRNA against the fusion oncogene TMPRSS2-ERG found in 50% of patients and showed an antitumoral activity in animal model. Herein, we want to compare or combine the developed siRNA to flutamide (FLU), one of the gold-standard treatment of PCa. Therefore, concomitant or subsequent association of FLU to siRNA TMPRSS2-ERG was performed in VCaP cells and in SCID mice bearing xenografted VCaP tumors. ERG, androgen receptor, cleaved-caspase-3 as well as phase 1 and 2 drug-metabolizing enzymes were investigated within tumors. We observed similar results in terms of TMPRSS2-ERG knock-down and cell viability impairment for all distinct schedules of administration. The association of siRNA TMPRSS2-ERG-squalene nanoparticles with flutamide displayed similar tumor growth inhibition as mice treated with siRNA TMPRSS2-ERG-squalene nanoparticles alone and was paralleled with modification of expression of ERG, androgen receptor, and cleaved-caspase-3. Phase 1 and 2 enzymes were essentially affected by FLU and reverted when combined with squalenoylated siRNA. In conclusion, these results confirm the therapeutic effectiveness of squalenoyl siRNA nanomedicine for PCa based on siRNA TMPRSS2-ERG.

Inactivating mutation in the prostaglandin transporter gene, SLCO2A1, associated with familial digital clubbing, colon neoplasia, and NSAID resistance.

HPGDand SLCO2A1 genes encode components of the prostaglandin catabolic pathway, with HPGD encoding the degradative enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and SLCO2A1 encoding the prostaglandin transporter PGT that brings substrate to 15-PGDH. HPGD-null mice show increased prostaglandin E2 (PGE2), marked susceptibility to developing colon tumors, and resistance to colon tumor prevention by nonsteroidal anti-inflammatory drugs (NSAID). But in humans, HPGD and SLCO2A1 mutations have only been associated with familial digital clubbing. We, here, characterize a family with digital clubbing and early-onset colon neoplasia. Whole-exome sequencing identified a heterozygous nonsense mutation (G104X) in the SLCO2A1 gene segregating in 3 males with digital clubbing. Two of these males further demonstrated notably early-onset colon neoplasia, 1 with an early-onset colon cancer and another with an early-onset sessile serrated colon adenoma. Two females also carried the mutation, and both these women developed sessile serrated colon adenomas without any digital clubbing. Males with clubbing also showed marked elevations in the levels of urinary prostaglandin E2 metabolite, PGE-M, whereas, female mutation carriers were in the normal range. Furthermore, in the male proband, urinary PGE-M remained markedly elevated during NSAID treatment with either celecoxib or sulindac. Thus, in this human kindred, a null SLCO2A1 allele mimics the phenotype of the related HPGD-null mouse, with increased prostaglandin levels that cannot be normalized by NSAID therapy, plus with increased colon neoplasia. The development of early-onset colon neoplasia in male and female human SLCO2A1 mutation carriers suggests that disordered prostaglandin catabolism can mediate inherited susceptibility to colon neoplasia in man.

Influence of peripheral whole-blood microRNA-7 and microRNA-221 high expression levels on the acquisition of castration-resistant prostate cancer: evidences from in vitro and in vivo studies.

Prostate cancer (PC) is the more frequently diagnosed neoplasia in men in developed countries. The evolution of PC to castration-resistant prostate cancer (CRPC) represents real problems of clinical management, in consequence to the limited therapeutic options. MicroRNAs (miRNAs) are small noncoding RNAs that play an important role in gene expression and function regulation. The increased evidence that miRNAs are involved in cancer development and progression has made them potential biomarkers for cancer diagnosis, prognosis, and aggressiveness. Our purpose was to identify a miRNA expression profile associated with the development of CRPC. We firstly observed a miRNA expression profile differentially expressed between the castration-resistant (CR) PC3 cell line and the hormone-sensitive LnCaP cell line, where miR-7, miR-221, and miR-222 were upregulated in PC3 (11.3-fold increase, P = 0.012; 11.3-fold increase, P = 0.002; 8.6-fold increase, P = 0.002, respectively). We also observed that the trend of miR-1233 expression levels was higher in PC3 (3.7-fold increase, P = 0.057). These miRNAs differentially expressed in vitro were studied in a peripheral whole-blood samples from PC patients. We observed that patients presenting an early CR acquisition (≤ 20 months) had higher expression levels of miR-7 and miR-221 (P = 0.034 and P = 0.036, respectively). Furthermore, we found that patients diagnosed with high-Gleason score tumors and presenting simultaneous higher miR-7 expression levels have a significant reduce time to CR compared with patients who present lower miR-7 expression levels (11 vs. 51 months, log-rank test P = 0.004). We also found that patients diagnosed with high-Gleason score tumors and higher expression levels of miR-221 have an early CRPC compared to patients with lower miR-221 expression levels (10 vs. 46 months, log-rank test P = 0.012). We observed a significantly lower overall survival in patients with higher peripheral whole-blood expression levels of miR-7 (28 vs. 116 months, log-rank test P = 0.001). Our results suggest that miR-7 and miR-221 peripheral whole-blood expression levels can be potential predictive biomarkers of CRPC development.