levoleucovorin and pyrimidine

The MSI phenotype in colon cancer is a good prognostic factor, with an impact probably more pronounced for stage II than stage III tumor. This survival advantage may be related to the tumor-infiltrating lymphocytes observed in MSI tumors, thus explaining the existence of a probably more effective anti-tumor immune response. In addition, the MSI status would also be a biomarker able to predict the lack of efficacy of adjuvant 5-fluorouracil (5FU) chemotherapy. In contrast, as observed in MSS colon cancer, the MSI tumors would have a survival benefit with the addition of oxaliplatin to adjuvant 5FU chemotherapy. Based on these data, the "French National Thesaurus of Digestive Oncology" suggests for patients with MSI colon cancer, an adjuvant chemotherapy combining fluoropyrimidine and oxaliplatin for stage III, and surgery alone without adjuvant chemotherapy for stage II (excepted for pT4b tumors in which the combination of fluoropyrimidine and oxaliplatin may be a therapeutic option). Beyond these recommendations, the discussion of adjuvant treatment in MSI tumors should also include other factors such as the patient's age and comorbidities. The duration of the adjuvant treatment (3 or 6 months) and the regimen used (FOLFOX or XELOX) should be based on the recommendations of the international IDEA consortium pending the results of the translational studies of this trial. Finally, the promising results of immunotherapy in metastatic MSI colorectal led to the development of clinical trials evaluating "immune checkpoint blockers" in combination with FOLFOX in the treatment of stage III MSI colon cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Immunotherapy; Leucovorin; Lymphocytes, Tumor-Infiltrating; Microsatellite Instability; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Phenotype; Prognosis; Pyrimidines

The use of bevacizumab in combination with fluoropyrimidine-containing chemotherapy is a well-established first-line and second-line treatment for patients with metastatic colorectal cancer (mCRC). However, there remains a need for reproducible, validated, inexpensive and accessible prognostic markers to aid treatment selection. The optimal treatment duration and the role of bevacizumab in certain patient subgroups, considered at particular risk of bevacizumab-mediated toxicity, also require further investigation. The aim of the ASCENT study [an Australian translational Study to evaluate the prognostic role of inflammatory markers in patients with metastatic ColorEctal caNcer Treated with bevacizumab (Avastin™)] is to evaluate the relationship between the host inflammatory response as measured by neutrophil/lymphocyte ratio (NLR) and treatment outcomes in patients with previously untreated mCRC receiving bevacizumab-based first- and second-line treatment.. This open-label, prospective, single arm, phase IV, Australian multi-centre study evaluates the relationship between the host inflammatory response as measured by NLR and treatment outcomes in patients with previously untreated mCRC receiving bevacizumab-based first- and second-line treatment. 150 patients will be recruited from 16 centres around Australia. Patients will receive trial treatments in two phases: Phase A: XELOX or mFOLFOX6 plus bevacizumab administered from study start until first disease progression; and Phase B: FOLFIRI plus bevacizumab administered from first disease progression until second disease progression. The primary analysis will test the association between NLR and progression free survival using a proportional Hazards Model. Secondary analyses will investigate whether the relationship can be improved upon with other prognostic biomarkers, and further characterise the safety of bevacizumab following treatment initiation, and when continued after progression in combination with standard chemotherapy regimens (presented through summary statistics and Kaplan Meier curves).. Quantifying the relationship between NLR and PFS will inform decision making on the extent to which this simple metric may be applied clinically.. ClinicalTrials.gov: NCT01588990.

Topics: Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease Progression; Female; Fluorouracil; Humans; Inflammation; Leucovorin; Lymphocytes; Male; Neutrophils; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Prognosis; Proportional Hazards Models; Prospective Studies; Pyrimidines; Reproducibility of Results

Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3-4 toxicity.. Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms.. Reported grade ≤ 2 and 3-4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70-10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19-1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity.. Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Case-Control Studies; Confidence Intervals; Dihydrouracil Dehydrogenase (NADP); DNA-Binding Proteins; Endonucleases; Female; Fluorouracil; Gene Frequency; Genes, p53; Genotype; Glutathione S-Transferase pi; Glycine Hydroxymethyltransferase; Humans; Leucovorin; Logistic Models; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Multienzyme Complexes; Nomograms; Odds Ratio; Organoplatinum Compounds; Orotate Phosphoribosyltransferase; Orotidine-5'-Phosphate Decarboxylase; Platinum Compounds; Polymorphism, Single Nucleotide; Pyrimidines; Quality of Life; Retrospective Studies; Stomach Neoplasms; Xeroderma Pigmentosum Group D Protein

The ML18174 study, which showed benefits of bevacizumab (BEV) continuation beyond progression (BBP) for metastatic colorectal cancer (mCRC), excluded patients with first-line progression-free survival (PFS) shorter than 3 months. The present study was conducted to evaluate the efficacy of second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab.. The subjects of this study were mCRC patients who experienced disease progression < 100 days from commencement of first-line chemotherapy containing BEV initiated between Apr 2007 and Dec 2016. Second-line chemotherapy regimens were classified into two groups with and without BEV/other anti-angiogenic agents (BBP and non-BBP) and efficacy and safety were compared using univariate and multivariate analysis.. Sixty-one patients were identified as subjects of this study. Baseline characteristics were numerically different between BBP (n = 37) and non-BBP (n = 25) groups, such as performance status (0-1/> 2/unknown: 89/8/3 and 56/40/4%), RAS status (wild/mutant/unknown: 32/54/16 and 76/16/8%). Response rate was 8.6% in BBP group and 9.1% in non-BBP group (p = 1.00). Median PFS was 3.9 months in BBP group and 2.8 months in non-BBP group (HR [95%CI]: 0.79 [0.46-1.34], p = 0.373, adjusted HR: 0.87 [0.41-1.82], p = 0.707). Median overall survival was 8.5 months in BBP group and 5.4 months in non-BBP group (HR 0.66 [0.38-1.12], p = 0.125, adjusted HR 0.53 [0.27-1.07], p = 0.078).. In mCRC patients who experienced early progression in first-line chemotherapy, second-line chemotherapy showed poor clinical outcomes regardless use of anti-angiogenic agents.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Japan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Progression-Free Survival; Pyrimidines; Retrospective Studies; Time Factors

Diabetes can be caused by an insufficiency in β-cell mass. Here, we performed a genetic screen in a zebrafish model of β-cell loss to identify pathways promoting β-cell regeneration. We found that both folate receptor 1 (folr1) overexpression and treatment with folinic acid, stimulated β-cell differentiation in zebrafish. Treatment with folinic acid also stimulated β-cell differentiation in cultures of neonatal pig islets, showing that the effect could be translated to a mammalian system. In both zebrafish and neonatal pig islets, the increased β-cell differentiation originated from ductal cells. Mechanistically, comparative metabolomic analysis of zebrafish with/without β-cell ablation and with/without folinic acid treatment indicated β-cell regeneration could be attributed to changes in the pyrimidine, carnitine, and serine pathways. Overall, our results suggest evolutionarily conserved and previously unknown roles for folic acid and one-carbon metabolism in the generation of β-cells.

Topics: Animals; Animals, Genetically Modified; Animals, Newborn; Carbon; Carnitine; Cell Differentiation; Cells, Cultured; Folate Receptor 1; Gene Expression Regulation; Humans; Insulin-Secreting Cells; Larva; Leucovorin; Metabolic Networks and Pathways; Mice; Pyrimidines; Swine; Zebrafish