Trifluridine/tipiracil versus placebo for third or later lines of treatment in metastatic gastric cancer: an exploratory subgroup analysis from the TAGS study.

BACKGROUND: Metastatic gastric cancer and cancer of the esophagogastric junction (GC/EGJ) is an aggressive disease with poor prognosis. In the TAGS study, trifluridine/tipiracil (FTD/TPI) improved overall survival (OS) compared with placebo in heavily pre-treated patients. This unplanned, exploratory subgroup analysis of the TAGS study aimed to clarify outcomes when FTD/TPI was used as third-line (3L) treatment and fourth- or later-line (4L+) treatment. PATIENTS AND METHODS: Patients were divided into a 3L group (126 and 64 in FTD/TPI and placebo arms, respectively) and 4L+ group (211 and 106 in FTD/TPI and placebo arms, respectively). Endpoints included OS, progression-free survival (PFS), time to Eastern Cooperative Oncology Group performance status (ECOG PS) deterioration to ≥2, and safety. RESULTS: Baseline characteristics were generally well balanced between FTD/TPI and placebo for 3L and 4L+ treatment. Median OS (mOS) for FTD/TPI versus placebo was: 6.8 versus 3.2 months {hazard ratio (HR) [95% confidence interval (CI)] = 0.68 (0.47-0.97), P = 0.0318} in the 3L group; and 5.2 versus 3.7 months [0.73 (0.55-0.95), P = 0.0192] in the 4L+ group. Median PFS for FTD/TPI versus placebo was 3.1 versus 1.9 months [0.54 (0.38-0.77), P = 0.0004] in the 3L group; and 1.9 versus 1.8 months [0.57 (0.44-0.74), P < 0.0001] in the 4L+ group. Time to deterioration of ECOG PS to ≥2 for FTD/TPI versus placebo was 4.8 versus 2.0 months [HR (95% CI) = 0.60 (0.42-0.86), P = 0.0049] in the 3L group; and 4.0 versus 2.5 months [0.75 (0.57-0.98), P = 0.0329] in the 4L+ group. The safety of FTD/TPI was consistent in all subgroups. CONCLUSIONS: This analysis confirms the efficacy and safety of FTD/TPI in patients with GC/EGJ in third and later lines with a survival benefit that seems slightly superior in 3L treatment. When FTD/TPI is taken in 3L as recommended in the international guidelines, physicians can expect to provide patients with an mOS of 6.8 months.

Effects of Passiflora edulis flavicarpa on the radiolabeling of blood constituents, morphology of red blood cells and on the biodistribution of sodium pertechnetate in rats.

The aim of this study was to evaluate possible effects of Passiflora edulis flavicarpa (P. flavicarpa) extract on the labeling of blood constituents with (99m)Tc, on the morphology of red blood cells, and on the biodistribution of sodium pertechnetate (sodium (99m)Tc). Male Wistar rats were treated with either P. flavicarpa extract or 0.9% NaCl. After that, radiolabeling of blood constituents, morphological analysis of red blood cells and biodistribution of sodium (99m)Tc was evaluated. Radiolabeling of blood constituents and shape of red blood cells were not modified, but a significant (p<0.05) alteration of the biodistribution of sodium (99m)Tc was observed after treatment with P. flavicarpa extract. Although our results were obtained with animals, they could contribute to reduce the risk of misdiagnosis and/or repetition of the examinations in nuclear medicine.

Effect of a commercial extract of Paullinia cupana (guarana) on the binding of 99mTc-DMSA on blood constituents: An in vivo study.

We studied the influence of a commercial extract of Paullinia cupana (guarana) on the binding of technetium-99m-dimercaptosuccinic acid ((99m)Tc-DMSA) on blood constituents. Plasma (P) and blood cells (BC) from Wistar rats (control and treated) were separated. P and BC were precipitated with trichloroacetic acid (TCA) or ammonium sulphate (AS) and soluble (SF) and insoluble fractions (IF) isolated. The percentage of incorporated radioactivity (%ATI) in each fraction was determined. The treatment influenced the %ATI in IF-P and in IF-BC isolated by TCA precipitation.

Effect of oral ingestion of an extract of the herb Uncaria tomentosa on the biodistribution of sodium pertechnetate in rats.

The aim of the present study was to determine the effect of the oral ingestion of an extract of the herb Uncaria tomentosa (cat's claw) on the biodistribution of the radiobiocomplex sodium pertechnetate (Na99mTcO4) in rats. The animals (male Wistar rats, 2 months old, 180-220 g), were treated (1 mL) with an U. tomentosa extract (32 mg/mL, N = 5) or 0.9% NaCl solution (control, N = 5) for 7 days. After this period, Na99mTcO4 (3.7 MBq, 0.3 mL) was injected through the ocular plexus and after 10 min the rats were killed, the organs isolated and counted in a well-gamma counter. A significant (P < 0.05) alteration in Na99mTcO4 uptake i) from 0.57 +/- 0.008 to 0.39 +/- 0.06 %ATI/organ (P < 0.05) and from 0.57 +/- 0.17 to 0.39 +/- 0.14 %ATI/g (P < 0.05) was observed in the heart, ii) from 0.07 +/- 0.02 to 0.19 +/- 0.07 %ATI/g in the pancreas, and iii) from 0.07 +/- 0.01 to 0.18 +/- 0.07 %ATI/g (P < 0.05) in muscle after treatment with this extract. Although these results were obtained with animals, caution is advisable in the interpretation of the nuclear medicine examination when the patient is using this herb. This finding is probably an example of drug interaction with a radiopharmaceutical, a fact that could lead to misdiagnosis of the examination in clinical practice with unexpected consequences for the patient.

Effect of oral ingestion of an extract of the herb Uncaria tomentosa on the biodistribution of sodium pertechnetate in rats

The aim of the present study was to determine the effect of the oral ingestion of an extract of the herb Uncaria tomentosa (cat's claw) on the biodistribution of the radiobiocomplex sodium pertechnetate (Na99mTcO4) in rats. The animals (male Wistar rats, 2 months old, 180-220 g), were treated (1 mL) with an U. tomentosa extract (32 mg/mL, N = 5) or 0.9 percent NaCl solution (control, N = 5) for 7 days. After this period, Na99mTcO4 (3.7 MBq, 0.3 mL) was injected through the ocular plexus and after 10 min the rats were killed, the organs isolated and counted in a well-gamma counter. A significant (P < 0.05) alteration in Na99mTcO4 uptake i) from 0.57 ± 0.008 to 0.39 ± 0.06 percentATI/organ (P < 0.05) and from 0.57 ± 0.17 to 0.39 ± 0.14 percentATI/g (P < 0.05) was observed in the heart, ii) from 0.07 ± 0.02 to 0.19 ± 0.07 percentATI/g in the pancreas, and iii) from 0.07 ± 0.01 to 0.18 ± 0.07 percentATI/g (P < 0.05) in muscle after treatment with this extract. Although these results were obtained with animals, caution is advisable in the interpretation of the nuclear medicine examination when the patient is using this herb. This finding is probably an example of drug interaction with a radiopharmaceutical, a fact that could lead to misdiagnosis of the examination in clinical practice with unexpected consequences for the patient.

Experimental model to assess possible medicinal herb interaction with a radiobiocomplex: qualitative and quantitative analysis of kidney, liver and duodenum isolated from treated rats.

Ginkgo biloba extract (EGb) has been used as a medicinal herb. Several biological properties have been associated with this extract, especially, in the increase of the blood flow, in the action as platelet activating factor antagonism and in the prevention of the membrane against the damage caused by free radicals. Radiobiocomplexes have been utilized in various nuclear medicine procedures helping in the diagnosis and/or treatment of human diseases. Many substances have been reported to affect the bioavailability of different radiobiocomplexes. The aim of this work was to evaluate the possible influence of an EGb on the bioavailability of the sodium pertechnetate (99mTcO4Na) and on the morphometry of some organs isolated from rats. These animals were treated with EGb and 99mTcO4Na was injected. The animals were sacrificed, the organs isolated, counted in a well counter and the percentage of radioactivity per gram of each organ was calculated. The results showed that EGb decreased the uptake of the 99mTcO4Na in the duodenum (P<0.05). Moreover, morphometric analysis has revealed significant modifications (P<0.05) on kidney, liver and duodenum due to the cited treatment. It is speculated that the substances present in the EGb could act directly or generate metabolites capable to promote changes in organs (kidney, liver and duodenum), however, only significant alteration in the uptake of the 99mTcO4Na in the duodenum.

Protection of plasmid DNA by a Ginkgo biloba extract from the effects of stannous chloride and the action on the labeling of blood elements with technetium-99m.

Ginkgo biloba extract (EGb) is a phytotherapeutic agent used for the treatment of ischemic and neurological disorders. Because the action of this important extract is not fully known, assays using different biological systems need to be performed. Red blood cells (RBC) are labeled with technetium-99m (Tc-99m) and used in nuclear medicine. The labeling depends on a reducing agent, usually stannous chloride (SnCl2). We assessed the effect of different concentrations of EGb on the labeling of blood constituents with Tc-99m, as sodium pertechnetate (3.7 MBq), and on the mobility of a plasmid DNA treated with SnCl2 (1.2 microg/ml) at room temperature. Blood was incubated with EGb before the addition of SnCl2 and Tc-99m. Plasma (P) and RBC were separated and precipitated with trichloroacetic acid, and soluble (SF-P and SF-RBC) and insoluble (IF-P and IF-RBC) fractions were isolated. The plasmid was incubated with Egb, SnCl2 or EGb plus SnCl2 and agarose gel electrophoresis was performed. The gel was stained with ethidium bromide and the DNA bands were visualized by fluorescence in an ultraviolet transilluminator system. EGb decreased the labeling of RBC, IF-P and IF-RBC. The supercoiled form of the plasmid was modified by treatment with SnCl2 and protected by 40 mg/ml EGb. The effect of EGb on the tested systems may be due to its chelating action with the stannous ions and/or pertechnetate or to the capability to generate reactive oxygen species that could oxidize the stannous ion.

Protection of plasmid DNA by a Ginkgo biloba extract from the effects of stannous chloride and the action on the labeling of blood elements with technetium-99m

Ginkgo biloba extract (EGb) is a phytotherapeutic agent used for the treatment of ischemic and neurological disorders. Because the action of this important extract is not fully known, assays using different biological systems need to be performed. Red blood cells (RBC) are labeled with technetium-99m (Tc-99m) and used in nuclear medicine. The labeling depends on a reducing agent, usually stannous chloride (SnCl2). We assessed the effect of different concentrations of EGb on the labeling of blood constituents with Tc-99m, as sodium pertechnetate (3.7 MBq), and on the mobility of a plasmid DNA treated with SnCl2 (1.2 æg/ml) at room temperature. Blood was incubated with EGb before the addition of SnCl2 and Tc-99m. Plasma (P) and RBC were separated and precipitated with trichloroacetic acid, and soluble (SF-P and SF-RBC) and insoluble (IF-P and IF-RBC) fractions were isolated. The plasmid was incubated with Egb, SnCl2 or EGb plus SnCl2 and agarose gel electrophoresis was performed. The gel was stained with ethidium bromide and the DNA bands were visualized by fluorescence in an ultraviolet transilluminator system. EGb decreased the labeling of RBC, IF-P and IF-RBC. The supercoiled form of the plasmid was modified by treatment with SnCl2 and protected by 40 mg/ml EGb. The effect of EGb on the tested systems may be due to its chelating action with the stannous ions and/or pertechnetate or to the capability to generate reactive oxygen species that could oxidize the stannous ion.

Evaluation of the phytic acid effect on the labeling of blood elements with technetium-99m and on the survival of a strain of Escherichia coli treated with stannous fluoride.

The labeling of red blood cells with technetium-99m (99mTc) depends on a reducing agent and stannous ions, as chloride or fluoride, are widely utilized. This labeling may also be altered by drugs. Moreover, some authors have reported that the survival of Escherichia coli (E. coli) cultures decreases in presence of stannous ions. Phytic acid is present in the daily diet and we evaluated its influence on: (i) the labeling of blood elements with 99mTc and (ii) on the survival of an E. coli strain treated with stannous fluoride. Heparinized whole blood was withdrawn from Wistar rats and it was incubated with stannous chloride and with 99mTc, as sodium pertechnetate, centrifuged and plasma (P) and blood cells (BC) were isolated. Samples of P and BC were also precipitated with trichloroacetic acid, centrifuged and soluble (SF) and insoluble fractions (IF) isolated. E. coli culture was treated with stannous fluoride in presence of phytic acid. As phytic acid altered the fixation of 99mTc on BC, on IF-P and on IF-BC and, moreover, it abolished the lethal effect of stannous fluoride on the E. coli culture, we can suggest that, probably, phytic acid would have chelating properties to the stannous ions.