Double-strand break repair and colorectal cancer: gene variants within 3' UTRs and microRNAs binding as modulators of cancer risk and clinical outcome

Genetic variations in 3' untranslated regions of target genes may affect microRNA binding, resulting in differential protein expression. microRNAs regulate DNA repair, and single-nucleotide polymorphisms in miRNA binding sites (miRSNPs) may account for interindividual differences in the DNA repair capacity. Our hypothesis is that miRSNPs in relevant DNA repair genes may ultimately affect cancer susceptibility and impact prognosis.In the present study, we analysed the association of polymorphisms in predicted microRNA target sites of double-strand breaks (DSBs) repair genes with colorectal cancer (CRC) risk and clinical outcome. Twenty-one miRSNPs in non-homologous end-joining and homologous recombination pathways were assessed in 1111 cases and 1469 controls. The variant CC genotype of rs2155209 in MRE11A was strongly associated with decreased cancer risk when compared with the other genotypes (OR 0.54, 95% CI 0.38-0.76, p = 0.0004). A reduced expression of the reporter gene was observed for the C allele of this polymorphism by in vitro assay, suggesting a more efficient interaction with potentially binding miRNAs. In colon cancer patients, the rs2155209 CC genotype was associated with shorter survival while the TT genotype of RAD52 rs11226 with longer survival when both compared with their respective more frequent genotypes (HR 1.63, 95% CI 1.06-2.51, p = 0.03 HR 0.60, 95% CI 0.41-0.89, p = 0.01, respectively). miRSNPs in DSB repair genes involved in the maintenance of genomic stability may have a role on CRC susceptibility and clinical outcome

Detection of let-7 miRNAs in urine supernatant as potential diagnostic approach in non-metastatic clear-cell renal cell carcinoma

IntroductionUrinary microRNAs (miRNAs) are emerging as a clinically useful tool for early and non-invasive detection of various types of cancer. The aim of this study was to evaluate whether let-7 family miRNAs differ in their urinary concentrations between renal cell carcinoma (RCC) cases and healthy controls. Materials and methodsIn the case-control study, 69 non-metastatic clear-cell RCC patients and 36 gender/age-matched healthy controls were prospectively enrolled. Total RNA was purified from cell-free supernatant of the 105 first morning urine specimens. Let-7 family miRNAs were determined in cell-free supernatant using quantitative miRNA real-time reverse-transcription PCR and absolute quantification approach. ResultsConcentrations of all let-7 miRNAs (let-7a, let-7b, let-7c, let-7d, let-7e and let-7g) were significantly higher in urine samples obtained from RCC patients compared to healthy controls (P < 0.001; P < 0.001; P = 0.005; P = 0.006; P = 0.015 and P = 0.002, respectively). Subsequent ROC analysis has shown that let-7a concentration possesses good ability to differentiate between cases and controls with area under curve being 0.8307 (sensitivity 71%, specificity 81%). ConclusionsWe have shown that let-7 miRNAs are abundant in the urine samples of patients with clear-cell RCC, and out of six let-7 family members, let-7a outperforms the others and presents promising non-invasive biomarker for the detection of RCC

Fusobacterium nucleatum tumor DNA levels are associated with survival in colorectal cancer patients

Made available in DSpace on 2019-10-06T17:16:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-01-01There is increasing evidence indicating a role for Fusobacterium nucleatum (F. nucleatum) in colorectal cancer (CRC) development and prognosis. This study evaluated F. nucleatum as a prognostic biomarker, by assessing its association with post-diagnosis survival from CRC. From September 2008 to April 2012 CRC patients (n = 190) were recruited from three hospitals within the Czech Republic. F. nucleatum DNA copies were measured in adjacent non-malignant and colorectal tumor tissues using quantitative real-time PCR. Cox Proportional Hazards (HR) models were applied to evaluate the association between F. nucleatum DNA and overall survival, adjusting for key confounders. Risk prediction modeling was conducted to evaluate the ability to predict survival based on F. nucleatum status. High, compared with low, levels of F. nucleatum in colorectal tumor tissues were associated with poorer overall survival (adjusted HR 1.68, 95% CI 1.02–2.77), which was slightly attenuated after additional adjustment for microsatellite instability status. However, inclusion of F. nucleatum in risk prediction models did not improve the ability to identify patients who died beyond known prognostic factors such as disease pathology staging. Although the increased presence of F. nucleatum was associated with poorer prognosis in CRC patients, this may have limited clinical relevance as a prognostic biomarker.Centre for Public Health Queen’s University BelfastDepartment of Biology São Paulo State University UNESPInstitute of Biology and Medical Genetics First Faculty of Medicine Charles UniversityDepartment of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of SciencesDepartment of Surgery General University Hospital in PragueDepartment of Surgery First Faculty of Medicine Charles University and Thomayer HospitalBiomedical Centre Faculty of Medicine in Pilsen Charles UniversityDepartment of Oncology First Faculty of Medicine Charles University and Thomayer HospitalCancer Biology and Therapeutics Group School of Biomolecular and Biomedical Science UCD Conway Institute University College DublinDepartment of Biology São Paulo State University UNES

Phase 3 CLEAR study in patients with advanced renal cell carcinoma: outcomes in subgroups for the lenvatinib-plus-pembrolizumab and sunitinib arms

IntroductionThe phase 3 CLEAR study demonstrated that lenvatinib plus pembrolizumab significantly improved efficacy versus sunitinib as first-line treatment for patients with advanced renal cell carcinoma (RCC). Prognostic features including presence and/or site of baseline metastases, prior nephrectomy, and sarcomatoid features have been associated with disease and treatment success. This subsequent analysis explores outcomes in patients with or without specific prognostic features.MethodsIn CLEAR, patients with clear cell RCC were randomly assigned (1:1:1) to receive either lenvatinib (20 mg/day) plus pembrolizumab (200 mg every 3 weeks), lenvatinib (18 mg/day) plus everolimus (5 mg/day), or sunitinib alone (50 mg/day, 4 weeks on, 2 weeks off). In this report, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were all assessed in the lenvatinib-plus-pembrolizumab and the sunitinib arms, based on baseline features: lung metastases, bone metastases, liver metastases, prior nephrectomy, and sarcomatoid histology.ResultsIn all the assessed subgroups, median PFS was longer with lenvatinib-plus-pembrolizumab than with sunitinib treatment, notably among patients with baseline bone metastases (HR 0.33, 95% CI 0.21–0.52) and patients with sarcomatoid features (HR 0.39, 95% CI 0.18–0.84). Median OS favored lenvatinib plus pembrolizumab over sunitinib irrespective of metastatic lesions at baseline, prior nephrectomy, and sarcomatoid features. Of interest, among patients with baseline bone metastases the HR for survival was 0.50 (95% CI 0.30–0.83) and among patients with sarcomatoid features the HR for survival was 0.91 (95% CI 0.32–2.58); though for many groups, median OS was not reached. ORR also favored lenvatinib plus pembrolizumab over sunitinib across all subgroups; similarly, complete responses also followed this pattern.ConclusionEfficacy outcomes improved following treatment with lenvatinib-plus-pembrolizumab versus sunitinib in patients with RCC—irrespective of the presence or absence of baseline lung metastases, baseline bone metastases, baseline liver metastases, prior nephrectomy, or sarcomatoid features. These findings corroborate those of the primary CLEAR study analysis in the overall population and support lenvatinib plus pembrolizumab as a standard of care in 1L treatment for patients with advanced RCC.Clinical trial registrationClinicalTrials.gov, identifier NCT0281186

Diagnosis and treatment of pancreatic duct disruption or disconnection: an international expert survey and case vignette study

Background: Pancreatic duct disruption or disconnection is a potentially severe complication of necrotizing pancreatitis. With no existing treatment guidelines, it is unclear whether there is any consensus among experts in clinical practice. We evaluated current expert opinion regarding the diagnosis and treatment of pancreatic duct disruption and disconnection in an international case vignette study. Methods: An online case vignette survey was sent to 110 international expert pancreatologists. Expert selection was based on publications in the last 5 years and/or participation in development of IAP/APA and ESGE guidelines on acute pancreatitis. Consensus was defined as agreement by at least 75% of the experts. Results: The response rate was 51% (n = 56). Forty-four experts (79%) obtained a MRI/MRCP and 52 experts (93%) measured amylase levels in percutaneous drain fluid to evaluate pancreatic duct integrity. The majority of experts favored endoscopic transluminal drainage for infected (peri)pancreatic necrosis and pancreatic duct disruption (84%, n = 45) or disconnection (88%, n = 43). Consensus was lacking regarding the treatment of patients with persistent percutaneous drain production, and with persistent sterile necrosis. Conclusion: This international survey of experts demonstrates that there are many areas for which no consensus existed, providing clear focus for future investigation

Bunky prezentujici antigen a jejich vyuziti v lecbe hematologickych malignit - optimalizace ziskavani a expanze dendritickych bunek.

Anticancer immunotherapy is a strategy aimed at the induction and maintenance of immune responses against malignant cells. In the last decade, vaccines containing antigen-presenting cells (APC) loaded with tumor-associated antigens have been assessed in clinical experiments. Dendritic cells (DC) are known as the most efficient APC. Development and optimization of DC culture methods for vaccination purposes and the elaboration of a protocol for DC-based immunotherapy of multiple myeloma was the objective of this thesis. Series of experiments were performed in order to compare the yield, immunophenotype and function of DCs generated by different methods. The experimental design permitted us to use appropriate tests for pairs in the analysis of results. The generation of DCs from PBSC in two-step protocol was recommended for clinical use as the most suitable. Culture in plastic wells provides superior yields while culture in bags is preferable according to GMP. DCs alone are apparently insufficient for the production of cytolytic T-lymphocytes and non-specific stimulation with cytokines has been proposed for the future clinical trial.Available from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Spontaneous Regression of Metastatic Renal Cell Carcinoma after SARS-CoV-2 Infection: A Report of Two Cases

Spontaneous regression of metastatic renal cell carcinoma (mRCC) is a rare event, often associated with an activation of innate immunity by various triggers. SARS-CoV-2 infection induces a strong inflammatory response in some patients and a cytokine storm is one of the main causes of severe morbidity and mortality associated with the virus. Here, we describe two cases of patients with histologically and radiologically proven mRCC whose treatment was delayed due to COVID-19 and who experienced spontaneous tumour regression following the infection. Both patients reported here had predominantly pulmonary and mediastinal involvement and underwent nephrectomy. The interval between the diagnosis of COVID-19 and the detection of tumour regression was 3 and 4 months, respectively. Although approved vaccines and other measures are clearly the best way to prevent COVID-19-associated morbidity and mortality in cancer patients, we hypothesize that innate immunity activation by the infection can contribute to tumour regression in special circumstances

Chemotherapy for hormone-resistant prostate cancer: Where are we today?

Significant progress has been achieved in chemotherapy for hormone-resistant prostate cancer (HRPC) in the last five years. Although the disease was long considered to be chemoresistant, docetaxel-based regimens in particular have been shown to both palliate symptoms and prolong survival in HRPC patients. Docetaxel is now considered the best available chemotherapy for prostate cancer progressing on first-line hormonal treatment. Other cytotoxics including mitoxantrone, anthracyclines, vinorelbin and vinblastine can alleviate symptoms and improve progression-free survival in HRPC without affecting overall survival. The survival benefit from chemotherapy seen in randomized studies has been small or nonexistent. Results of a recent trial suggest that the survival benefit may have been underestimated as a result of crossover from the less active to the active arm