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Background: In the randomized phase II REGOMA trial, regorafenib showed promising activity in patients with recurrent glioblastoma. We conducted a large, multicenter, prospective, observational study to confirm the REGOMA data in a real-world setting., Patients and Methods: The major inclusion criteria were histologically confirmed diagnosis of glioblastoma according to the World Health Organization (WHO) 2016 classification and relapse after radiotherapy with concurrent/adjuvant temozolomide treatment, good performance status [Eastern Cooperative Oncology Group performance status (ECOG PS 0-1)] and good liver function. Regorafenib was administered at the standard dose of 160 mg/day for 3 weeks on/1 week off. Brain magnetic resonance imaging was carried out within 14 days before starting regorafenib and every 8-12 weeks. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate, disease control rate (DCR), safety and health-related quality of life. The Response Assessment in Neuro-Oncology (RANO) criteria were used for response evaluation and Common Terminology Criteria for Adverse Events (CTCAE) version 5 for assessment of adverse events (AEs)., Results: From September 2020 to October 2022, 190 patients with recurrent glioblastoma were enrolled from 30 cancer centers in Italy: their median age was 58.5 years [interquartile range (IQR) 53-67 years], 68% were male and 85 (44.7%) were in optimal clinical condition (ECOG PS 0). The number of patients taking steroids at baseline was 113 (60%); the second surgery was carried out in 39 (20.5%). O 6 -methylguanine-DNA methyltransferase (MGMT) was methylated in 80 patients (50.3%) and 147 (92.4%) of the patients analyzed had isocitrate dehydrogenase (IDH) wild type. The median follow-up period was 20 months (IQR 15.6-25.5 months). The median OS was 7.9 months ([95% confidence interval (CI) 6.5-9.2 months] and the median PFS was 2.6 months (95% CI 2.3-2.9 months). Radiological response was partial response and stable disease in 13 (7.3%) and 26 (14.6%) patients, respectively, with a DCR of 21.9%. The median number of regorafenib cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 drug-related adverse events were reported in 22.6% of patients. A dose reduction due to AEs was required in 36% of patients. No deaths were considered as treatment-related AEs., Conclusions: This large, real-world observational study showed similar OS with better tolerability of regorafenib in patients with relapsed glioblastoma compared with the REGOMA study., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The relationship between 5-fluorouracil (5-FU) pharmacokinetics and toxicity following i.v. bolus administration has not been extensively studied., Patients and Methods: One hundred and eighty-one patients on adjuvant therapy with 5-FU plus leucovorin for colorectal cancer were the study population. 5-FU pharmacokinetics was determined on day 2 of the first, third, and fifth cycles; type and the grade of adverse reactions were recorded on the next cycle., Results: The 5-FU area under the curve (AUC) measured at the first cycle ranged between 146 and 1236 mg x min/l and was significantly correlated with drug dose, patients' body weight (BW) and gender, females having higher AUCs. These covariates explained only 23% of AUC variability. AUC and age were the only covariates which discriminated between toxic (grade > or =2) and nontoxic cycles (grade <2), with an optimal AUC cut-off value of 596 mg x min/l. Such a correlation was lost during the next cycles following dose reduction because of toxicity in 80 patients., Conclusions: A method for calculating the initial 5-FU dose is proposed which takes into account patient BW, gender and a target AUC of 596 mg x min/l. Nevertheless, it appears that a substantial part of 5-FU toxicity is not linked to pharmacokinetic factors and dose adjustments must still be on the basis of careful clinical surveillance.

Background: Gemcitabine is a nucleoside analogue with proven activity in advanced and metastatic breast cancer. Its action is associated with a favourable toxicity profile which is mainly hematological. Its unique mechanism of action along with not overlapping toxicity is particularly useful both in combination treatment with other active drugs and a sequential therapy in the palliative setting., Design: Phase II studies of gemcitabine performed over the last decade were reviewed., Results and Conclusions: Despite some conflicting results in some trials, gemcitabine confirmed to be a useful drug to treat this condition.

Locus control region (LCR) sequences are involved in the establishment of open chromosomal domains. To evaluate the possibility of exploiting the human CD2 LCR to regulate gene expression by Moloney murine leukemia virus (Mo-MLV)-based retroviral vectors in T cells, it was included in vectors carrying the enhanced green fluorescence protein (EGFP) reporter gene; then transduction in vitro of lymphoid and nonlymphoid cell lines was performed. Deletion of the viral enhancer in the Mo-MLV long terminal repeat was necessary to detect LCR activity in the context of these retroviral vectors. It was found that a full-length (2.1 kb), but not a truncated (1.0 kb), CD2 LCR retained the ability to modulate reporter gene expression by Mo-MLV-derived retroviral vectors, leading to a homogeneous, unimodal pattern of EGFP expression that remained unmodified in culture over time, specifically in T-cell lines; on the other hand, viral titer was strongly reduced compared with vectors not carrying the LCR. Lentiviral vectors containing the CD2 LCR could be generated at higher titers and were used to analyze its effects on gene expression in primary T cells. Subcutaneous implantation of genetically modified cells in immunodeficient mice showed that retroviral vectors carrying the CD2 LCR conferred an advantage in terms of transgene expression in vivo, compared with the parental vector, by preventing the down-modulation of EGFP expression. These findings suggest a potential application of this LCR to increase gene expression by retroviral and lentiviral vectors in T lymphocytes.