Capecitabine in combination with docetaxel and mitomycin C in patients with pre-treated tumours: results of an extended phase-I trial

Preclinical data suggest that the anti-tumour activity of capecitabine is enhanced by taxanes and mitomycin C through up-regulation of thymidine phosphorylase (TP). Here, we studied safety and efficacy of the combination of capecitabine with docetaxel and mitomycin C. Two dose levels (DL) were investigated: capecitabine 1000 mg m−2 b.i.d. on days 1–14, docetaxel 40 mg m−2 i.v. day 1, mitomycin C 4 or 6 mg m−2 i.v. day 1 (DL I or II). Cycles were repeated every 3 weeks. The primary aim was to determine the dose-limiting toxicities (DLT) during the first two treatment cycles and the maximum tolerated dose (MTD). A total of 46 patients (pts) refractory to standard therapies were enrolled, of whom the majority had gastrointestinal tumours (n=40). 14 pts had received ⩾3 lines of prior chemotherapy. At DL I, one out of six pts experienced DLT. At DL II, two out of six pts had DLT (mucositis grade 3). Thus, DL I was determined as MTD. Among a total of 37 pts treated on DL I the following toxicities were observed during cycles 1 and 2 (number of patients with grade 1/2/3/4 toxicity; NCI-CTC v. 3.0): anaemia 10/8/3/0, leucocytopenia 4/11/1/2, thrombocytopenia 0/1/2/0, diarrhoea 8/1/2/0, stomatitis/mucositis 3/3/1/0, nausea/vomiting 10/2/0/0, and hand-foot skin reaction 5/1/1/0. Of 30 pts who received at least two treatment cycles nine achieved complete or partial remissions, six pts achieved minor remissions, and seven pts had stable disease (tumour control rate 73%). Of note, four out of 10 patients with pancreatic cancer had partial remissions. In conclusion, capecitabine can safely be combined with docetaxel (40 mg m−2) and mitomycin C (4 mg m−2). The established regimen was well tolerated and the preliminary efficacy data in this heavily pre-treated patients population appears to be promising

Scaling up the production of magnetic nanoparticles for biomedical applications: Cost-effective fabrication from basalts

We report here the first results on magnetic nanoparticles fabricated from basalt fragments of the eruption that took place in Lanzarote (Canary Islands) between 1730 and 1736, to be used in technologies of biomedicine. This approach was inspired by the strong and extremely stable remanent magnetization of slowly cooled rocks from basaltic lavas containing finely members of the hematite-ilmenite (Fe2O3-FeTiO3) series. Besides, the presence of titanium may promote good biocompatibility and an adequate corrosion resistance, as it does in prosthesis. The green, simple, fast, and cost-effective synthesis of magnetic nanoparticles was attempted using solar vapor-phase condensation. This technique allows the preparation of large volumes of nanoparticles presenting a narrow particle size distribution without purification steps. Alternatively, high-energy ball-milling of rock powder in the presence of organic surfactants was also studied as a potential method to produce, in a one-step approach, large quantities of nanostructured particles for biomedical applications. As a proof of concept, we explore these materials as candidates to be used in hyperthermia therapy, which promotes selective necrosis of cancer cells by raising the temperature of the tissue slightly above 43 oC. Results are correlated to their chemical and structural properties and compared to initial igneous rock characteristics. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Gemcitabine plus oxaliplatin combination (GEMOX regimen) in pretreated patients with advanced non-small cell lung cancer (NSCLC): A multicenter phase II study

Purpose: To evaluate the activity and tolerance of gemcitabine in combination with oxaliplatin (GEMOX regimen) in pretreated patients with advanced non-small cell lung cancer (NSCLC). Patients and methods: Thirty-two patients with advanced NSCLC who had disease progression after a cisplatin- and taxane-based front-line regimen were treated with gemcitabine (1500 mg/m2 on days 1 and 8) and oxaliplatin (130 mg/m2 on day 8) every 3 weeks. The patients' median age was 62 years and the performance status (WHO) was 0 for 11, 1 for 17 and 2 for 4 patients. The treatment was second line for 22 (69%) and ≥third line for 10 (31%) patients. Results: Partial response was achieved in 5 (16%) patients, stable disease in 8 (25%) and progressive disease in 19 (59%). Two patients with stable disease and one patient with progressive disease while on previous chemotherapy experienced a partial response with GEMOX regimen. The median duration of response was 2.5 months (range, 1-11.5), the median time to tumor progression 3 months (range, 1-18) and the median survival 5.6 months (range, 1-31). Grade III neutropenia occurred in five (16%) patients, grade III thrombocytopenia in two (6%) and grade III anemia in three (9%); moreover, grades II-III asthenia was reported in eight (25%) patients and grades II-III neurotoxicity in three (9%). Conclusion: The GEMOX combination is a relatively active and well tolerated second-line regimen in NSCLC patients pretreated with a taxane- and/or platinum-based chemotherapy. © 2006 Elsevier Ireland Ltd. All rights reserved

Methylation status of the APC and RASSF1A promoter in cell-free circulating DNA and its prognostic role in patients with colorectal cancer

DNA methylation is the most frequent epigenetic alteration. Using methylation-specific polymerase chain reaction (MSP), the methylation status of the adenomatous polyposis coli (APC) and Ras association domain family 1 isoform A (RASSF1A) genes was examined in cell-free circulating DNA from 155 plasma samples obtained from patients with early and advanced colorectal cancer (CRC). APC and RASSF1A hypermethylation was frequently observed in both early and advanced disease, and was significantly associated with a poorer disease outcome. The methylation status of the APC and RASSF1A promoters was investigated in cell-free DNA of patients with CRC. Using MSP, the promoter methylation status of APC and RASSF1A was examined in 155 blood samples obtained from patients with CRC, 88 of whom had operable CRC (oCRC) and 67 had metastatic CRC (mCRC). The frequency of APC methylation in patients with oCRC was 33%. Methylated APC promoter was significantly associated with older age (P=0.012), higher stage (P=0.014) and methylated RASSF1A status (P=0.050). The frequency of APC methylation in patients with mCRC was 53.7%. In these patients, APC methylation was significantly associated with methylated RASSF1A status (P=0.016). The frequency of RASSF1A methylation in patients with oCRC was 25%. Methylated RASSF1A in oCRC was significantly associated with higher stage (P=0.021). The frequency of RASSF1A methylation in mCRC was 44.8%. Methylated RASSF1A in mCRC was associated with moderate differentiation (P=0.012), high levels of carcinoembryonic antigen (P=0.023) and methylated APC status (P=0.016). Patients with an unmethylated APC gene had better survival in both early (81±5 vs. 27±4 months, P<0.001) and advanced disease (37±7 vs. 15±3 months, P<0.001), compared with patients with methylated APC. Patients with an unmethylated RASSF1A gene had better survival in both early (71±6 vs. 46±8 months, P<0.001) and advanced disease (28±4 vs. 16±3 months, P<0.001) than patients with methylated RASSF1A. The observed significant correlations between APC and RASSF1A promoter methylation status and survival may be indicative of a prognostic role for these genes in CRC, which requires additional testing in larger studies. © 2016, Spandidos Publications. All rights reserved

Gefitinib in combination with gemcitabine and vinorelbine in patients with metastatic breast cancer pre-treated with taxane and anthracycline chemotherapy: A phase I/II trial

info:eu-repo/semantics/publishe

Junior doctors’ wellbeing at peak and post-peak pandemic: a repeated cross-sectional study

Introduction: The impact of the COVID-19 pandemic on healthcare professionals has been significant. The aim of this study was to explore the mental state and wellbeing of UK junior doctors at different phases of the initial outbreak. Methods: This is a cross-sectional study of UK-based junior doctors’ perceptions of threat and support during and after the first wave of the COVID-19 pandemic. Levels of anxiety, depression, post-traumatic stress disorder symptoms and use of coping mechanisms were explored through a Google questionnaire. Results 196 participants were included in this study (93 in period A and 103 in period B). Junior doctors reported feeling increased risk (p=0.001) and increased fear of contracting the virus (p15) along with increased cases level of depression (Patient Health Questionnaire-9 score >10) were reported for both periods. Junior doctors described suffering more frequently with flashbacks (p=0.006) and nightmares (p=0.024) in comparison with senior colleagues during period A. During period A, 21.4% of participants felt isolated at work (p<0.001), whereas 13% reported being easily annoyed on a daily basis, 11.7% reported very low morale (p<0.001) and 66% were not aware of any psychological support being available. The use of exercise, peer support and mindfulness apps increased during period B (p=0.023). Conclusions Healthcare systems need to urgently establish robust psychological support mechanisms and infrastructure to protect junior doctors and provide institutional resilience against the adverse consequences of the long physical and mental battle with COVID-19.</p

Prognostic Role of RASSF1A, SOX17 and Wif-1 Promoter Methylation Status in Cell-Free DNA of Advanced Gastric Cancer Patients

Epigenetic modification of several genes is a key component in the development of gastric cancer. The methylation status of RASSF1A, SOX17 and Wif-1 genes was evaluated in the cell free circulating DNA of 70 patients with advanced gastric cancer, using methylation-specific PCR. Patients with higher cell-free DNA concentration seem to have lower PFS, than patients with lower cell-free DNA concentration (p = 0.001). RASSF1A was the tumor suppressor gene, most frequently methylated in metastatic gastric cancer patients, followed by SOX17 and Wif-1 (74.3%, 60.0% and 47.1%, respectively). Patients having the SOX17 promoter methylated, had lower progression free survival and overall survival, than unmethylated ones (p &lt; 0.001). Patients having the Wif-1 promoter methylated, had lower progression free survival and overall survival, than unmethylated ones (p = 0.001). Patients having the RASSF1A promoter methylated, had lower progression free survival and overall survival, than unmethylated ones (p = 0.004). Promoter methylation of the examined genes was significantly associated with a decrease in progression free survival and overall survival, comparing to that of patients without methylation. Simultaneous methylation of the above genes was associated with even worse progression free survival and overall survival. The methylation of RASSF1A, SOX-17 and Wif-1 and genes, is a frequent epigenetic event in patients with advanced gastric cancer

Prognostic role of APC and RASSF1A promoter methylation status in cell free circulating DNA of operable gastric cancer patients

Gastric carcinogenesis is a multistep process including not only genetic mutations but also epigenetic alterations. The best known and more frequent epigenetic alteration is DNA methylation affecting tumor suppressor genes that may be involved in various carcinogenetic pathways. The aim of the present study was to investigate the methylation status of APC promoter 1A and RASSF1A promoter in cell free DNA of operable gastric cancer patients.Using methylation specific PCR, we examined the methylation status of APC promoter 1A and RASSF1A promoter in 73 blood samples obtained from patients with gastric cancer.APC and RASSF1A promoters were found to be methylated in 61 (83.6%) and 50 (68.5%) of the 73 gastric cancer samples examined, but in none of the healthy control samples ( p&lt;. 0.001). A significant association between methylated RASSF1A promoter status and lymph node positivity was observed ( p= 0.005). Additionally, a significant correlation between a methylated APC promoter and elevated CEA ( p= 0.033) as well as CA-19.9 ( p= 0.032) levels, was noticed. The Kaplan-Meier estimates of survival, significantly favored patients with a non-methylated APC promoter status ( p= 0.008). No other significant correlations between APC and RASSF1A methylation status and different tumor variables examined was observed.Serum RASSF1A and APC promoter hypermethylation is a frequent epigenetic event in patients with early operable gastric cancer. The observed correlations between APC promoter methylation status and survival as well as between a hypermethylated RASSF1A promoter and nodal positivity may be indicative of a prognostic role for those genes in early operable gastric cancer. Additional studies, in a larger cohort of patients are required to further explore whether these findings could serve as potential molecular biomarkers of survival and/or response to specific treatments. © 2015 Elsevier B.V