Topoisomerase I but not thymidylate synthase is associated with improved outcome in patients with resected colorectal cancer treated with irinotecan containing adjuvant chemotherapy

<p>Abstract</p> <p>Background</p> <p>Thymidylate synthase (TS) and Topoisomerase I (Topo I) are significant biomarkers in colorectal cancer (CRC). We aimed to study the expression of TS and Topo I in patients with resected CRC who received adjuvant chemotherapy and correlated it with clinical outcome.</p> <p>Methods</p> <p>All patients diagnosed with CRC between 1989 and 2007 and treated with adjuvant chemotherapy within Hellenic Cooperative Oncology Group's (HeCOG) protocols, were identified. Archival paraffin-embedded tumor tissues were used for immunohistochemical detection of TS and Topo I. Immunohistochemistry was performed on tissue microarray slides using monoclonal antibodies against TS and Topo I. The results were correlated with survival (OS) and disease free survival (DFS).</p> <p>Results</p> <p>A cohort of 498 patients with a median age of 61 years and Dukes' stage B (49%) and C (51%) fulfilled the criteria of the study. All patients received adjuvant 5-FU-based chemotherapy, 38% irinotecan-containing. Positive TS and Topo I expression was found in 43% and 48% of cases, respectively. Five-year OS was 74% and DFS was 68%. In univariate analysis no association of TS and Topo I expression with OS and DFS was identified. In multivariate analysis however, Topo I expression was associated with a reduced risk of death (HR = 0.61, 95% CI 0.42-0.88, p = 0.009). In the irinotecan-treated subgroup, those patients who expressed Topo I had a better OS (HR = 0.47, 95% CI 0.23-0.94, p = 0.033).</p> <p>Conclusion</p> <p>Patients with resected CRC expressing Topo I seem to benefit from irinotecan-containing adjuvant chemotherapy. However randomised prospective trials are needed to confirm these results.</p

A Multispecies Fungal Biofilm Approach to Enhance the Celluloyltic Efficiency of Membrane Reactors for Consolidated Bioprocessing of Plant Biomass

The constraints and advantages in cellulolytic enzymes production by fungal biofilms for a consolidated bioconversion process were investigated during this study. The biofilm cultivations were carried out in reactors designed for consolidated bioprocessing Multispecies Biofilm Membrane reactors, (MBM) where an aerobic fungal biofilm produces the lignocellulolytic enzymes while a fermenting microorganism forms the fermentation product at anaerobic conditions. It was shown that although mycelial growth was limited in the MBM reactors compared to submerged cultivations, the secretion of cellulolytic enzymes per cell dry weight was higher. When Trichoderma reesei was used as the sole enzyme producer, cellobiose accumulated in the liquid medium as the result of the deficiency of β-glucosidase in the fungal secretome. To enhance β-glucosidase activity, T. reesei was co-cultivated with A. phoenicis which is a β-glucosidase overproducer. The two fungi formed a multispecies biofilm which produced a balanced cellulolytic cocktail for the saccharification of plant biomass. The mixed biofilm reached a 2.5 fold increase in β-glucosidase production, compared to the single T. reesei biofilm. The enzymatic systems of single and mixed biofilms were evaluated regarding their efficiency on cellulosic substrates degradation. Washed solids from steam pretreated beechwood, as well as microcrystalline cellulose were used as the substrates. The enzymatic system of the multispecies biofilm released four times more glucose than the enzymatic system of T. reesei alone from both substrates and hydrolyzed 78 and 60% of the cellulose content of washed solids from beechwood and microcrystalline cellulose, respectively

Combination chemotherapy with gemcitabine and ifosfamide as second-line treatment in metastatic urothelial cancer. A phase II trial conducted by the Hellenic Cooperative Oncology Group

Purpose: The aim of the study was to evaluate the efficacy and safety of the combination of gemcitabine and ifosfamide as a second-line treatment for advanced urothelial cancer. Patients and methods: Thirty-four patients with metastatic urothelial cancer previously treated with cisplatin (CDDP)/carboplatin (CBDCA) and/or taxanes-based chemotherapy were studied. Gemcitabine was administered at a dose of 800 mg/m(2) on days 1 and 8 and ifosfamide at a dose of 2 g/m(2) on days 1 and 8 with adequate amount of Mesna, every three weeks. Hematopoietic growth factors were given between days 3 to 5 and 12 to 16 to maintain the treatment schedule. Results: On an intent to treat basis, there was one complete response (CR) (3%) (95% confidence interval (95% CI): 0% to 10%) and six partial responses (PR) (18%) (95% CI: 7% to 34%), inducing an objective response rate (RR) of 21% (95% CI: 9% to 38%); 12 (35%) patients achieved a stable disease (SD) and 15 (44%) a progressive disease (PD). The median time to tumor progression (TTP) was four months (range, 0.52 to 21.6 months) and the median survival nine months (range 0.52 to 28 months). This regimen also provided the opportunity for symptomatic improvement of pain, dysuria, haematuria and leg oedema. Grade 3-4 neutropenia was experienced by 9 (27%) patients, grade 3-4 anemia by 6 (18%) and grade 3-4 thrombocytopenia by 4 (12%). Six patients were hospitalized due to febrile neutropenia. Despite the prophylactic use of hematopoietic growth factors, 8 (23.5%) patients required dose reduction due to myelosuppression. Grade 3 alopecia occurred in 14 (41%) patients, grade 3-4 nausea in 1 (3%), grade 2 fever in 3 (9%), grade 2-3 diarrhea in 2 ( 6%) and grade 2 allergic reaction in 1 (3%). Conclusion: We conclude that the combination of gemcitabine and ifosfamide is an active salvage regimen for the treatment of urothelial cancer and that the treatment also has a tolerable toxicity profile; it warrants further investigation in combination with CDDP in chemotherapy-naive patients

Combination chemotherapy with gemcitabine and ifosfamide as second-line treatment in metastatic urothelial cancer. A phase II trial conducted by the Hellenic Cooperative Oncology Group

Purpose: The aim of the study was to evaluate the efficacy and safety of the combination of gemcitabine and ifosfamide as a second-line treatment for advanced urothelial cancer. Patients and methods: Thirty-four patients with metastatic urothelial cancer previously treated with cisplatin (CDDP)/carboplatin (CBDCA) and/or taxanes-based chemotherapy were studied. Gemcitabine was administered at a dose of 800 mg/m(2) on days 1 and 8 and ifosfamide at a dose of 2 g/m(2) on days 1 and 8 with adequate amount of Mesna, every three weeks. Hematopoietic growth factors were given between days 3 to 5 and 12 to 16 to maintain the treatment schedule. Results: On an intent to treat basis, there was one complete response (CR) (3%) (95% confidence interval (95% CI): 0% to 10%) and six partial responses (PR) (18%) (95% CI: 7% to 34%), inducing an objective response rate (RR) of 21% (95% CI: 9% to 38%); 12 (35%) patients achieved a stable disease (SD) and 15 (44%) a progressive disease (PD). The median time to tumor progression (TTP) was four months (range, 0.52 to 21.6 months) and the median survival nine months (range 0.52 to 28 months). This regimen also provided the opportunity for symptomatic improvement of pain, dysuria, haematuria and leg oedema. Grade 3-4 neutropenia was experienced by 9 (27%) patients, grade 3-4 anemia by 6 (18%) and grade 3-4 thrombocytopenia by 4 (12%). Six patients were hospitalized due to febrile neutropenia. Despite the prophylactic use of hematopoietic growth factors, 8 (23.5%) patients required dose reduction due to myelosuppression. Grade 3 alopecia occurred in 14 (41%) patients, grade 3-4 nausea in 1 (3%), grade 2 fever in 3 (9%), grade 2-3 diarrhea in 2 ( 6%) and grade 2 allergic reaction in 1 (3%). Conclusion: We conclude that the combination of gemcitabine and ifosfamide is an active salvage regimen for the treatment of urothelial cancer and that the treatment also has a tolerable toxicity profile; it warrants further investigation in combination with CDDP in chemotherapy-naive patients