Results from the INMUNOSUN-SOGUG trial: a prospective phase II study of sunitinib as a second-line therapy in patients with metastatic renal cell carcinoma after immune checkpoint-based combination therapy.

BACKGROUND: The INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies. PATIENTS AND METHODS: A multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate. RESULTS: Twenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar-plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib. CONCLUSION: Although the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens.

Effect of coating on the environmental applications of zero valent iron nanoparticles: the lindane case.

Commercial stabilized slurry of zero-valent iron nanoparticles (nZVI) as well as laboratory-synthesized polymer-stabilized NZVI nanoparticles were used for lindane (γ-hexachlorocyclohexane) degradation studies in aqueous solution. In the present study, polymer-stabilized iron nanoparticles were stabilized using polyethylene glycol (PEG, Mn ~400 and ~950-1050) and polytetrahydrofuran (PTHF, Mn ~650). To study the effectiveness of the different nanoparticles, a quantitative monitorization of lindane degradation by using solid-phase extraction (SPE) and a qualitative measurement of generated volatile by-products by headspace-solid phase microextraction (HS-SPME) followed by GC/MS were carried out. The obtained data were compared and contrasted with the results obtained in previous work. Results showed that the nanoparticles studied in this work possess superior dechlorination performance compared with previous observations. The freshly prepared Fe(0)-PEG400, Fe(0)-PEG1050 and Fe(0)-PTHF exhibited high reactivity during the dechlorination process of lindane in a very short time. The results obtained with the synthesized nanoparticles were similar to those obtained with commercial nanoparticles. However, in all cases reactivity decreased at reaction's late stage. Degradation of lindane by the studied nanoparticles removed 99.9% of the lindane initial concentration after 72h, except for Fe(0)-PTHF nanoparticles, for which the reaction stopped after 5min. In all cases, the reaction followed a second order kinetics. Finally, comparing the results from this study with our previous work, where different nature polymers were considered (Fe(0)-CMC, Fe(0)-PAA and Fe(0)-PAP), more gradual degradation profile of lindane was observed for Fe(0)-PAA and Fe(0)-CMC. It should be noted that in the present case, the reaction of lindane was speeded up with commercial and Fe(0)-PEG nanoparticles. Nevertheless, in the later case, the composition of by-products was affected by the presence of partially degraded intermediates. Taking into account the current technologies, the high removal rates obtained and the acceptable degradation times required, the proposed technology is suitable for its aimed purpose.

Relevance study of bare and coated zero valent iron nanoparticles for lindane degradation from its by-product monitorization.

Zero-valent iron nanoparticles (NZVI) as well as polymer-stabilized nanoparticles were synthesized and used for lindane (γ-hexachlorocyclohexane) degradation in aqueous solution. To study the effectiveness of the different coated nanoparticles, simple and rapid analytical methods have been developed to measure and to detect lindane and its by-products. For the monitorization of lindane degradation solid-phase extraction (SPE) was used, while volatile by-products formation measurement was carried out by headspace-solid phase microextraction (HS-SPME) followed by GC/MS. The SPE-GC/MS method provides low detection limits (0.2 µg L(-1)), high recovery (above 95%) and it is a valuable tool for kinetic studies of the degradation process for each polymer used, while HS-SPME-GC/MS has proved to be an effective tool for the extraction and evaluation of volatile degradation by-products.

Hollow fibre-based liquid-phase microextraction technique combined with gas chromatography-mass spectrometry for the determination of pyrethroid insecticides in water samples.

A simple, easy-to-use, efficient and environmentally friendly method has been developed for the simultaneous analysis of nine pirethroid pesticides in water samples by the combination of hollow fibre-based liquid-phase microextraction (HF-LPME) and gas chromatography-mass spectrometry (GC/MS). For the developed method, nine pirethroid pesticides (esbiothrin, prallethrin, bifenthrin, tetramethrin, phenothrin, permethrin, cyfluthrin, cypermethrin and deltamethrin) were concentrated and well separated under optimal conditions. Several factors that influence the efficiency of HF-LPME were investigated and optimized by means of experimental design. The proposed method has good linearity in the concentration range of 10-400 µg L(-1) with correlation coefficients between 0.995 and 0.999. Overall enrichment factors for the optimized method ranged from 139 to 255 times except for cypermethrin and deltamethrin which ranged from 35 to 128. Detection and quantitation limits of the chromatographic method were in the range of 0.002-0.012 µg L(-1) and 0.003-0.026 µg L(-1) respectively, with RSD values between 4.2% and 18.4%. The recoveries varied in the range of 69.4%-122.7% except for cypermethrin and deltamethrin (17.5%-64.1%) with relative standard deviations between 1.0% and 24.0% for intra and inter-day experiments at different concentrations (0.1 µg L(-1), 0.5 µg L(-1), 1 µg L(-1)). The HF-LPME method optimized was applied to the analysis of three spiked real water samples with good results.

Gas chromatographic-mass spectrometric analysis of the loop diuretic torasemide in human urine.

A fast and reliable gas chromatographic-mass spectrometric (GC-MS) method for the identification and determination of the loop diuretic torasemide in human urine is described. The usefulness of different derivatization procedures and reagents was studied. Flash methylation using trimethylanilinium hydroxide was the most convenient and appropriate procedure. The optimal urine isolation method comprised alkaline liquid-liquid extraction with ethyl acetate. After evaporation of the organic layer to dryness, the solid residue was reconstituted in the derivatizing reagent and was directly injected into the GC-MS system. Samples were analysed in the multiple ion detection mode using electron impact ionization. No interferences from other urinary compounds were found. Torasemide gave rise to a derivative that was identified by GC with Fourier transform infrared detection. There was a 70 +/- 5% recovery of torasemide. The coefficient of variation was 5% at a concentration of 0.05 microgram/ml. The method was used for the determination of torasemide in urine samples obtained from a healthy volunteer that had received a single, 10 mg dose of torasemide.

Effects of acute intravenous ethanol on basal exocrine pancreatic secretion in rat: cholinergic involvement.

The effect of intravenous infusion of ethanol on the basal exocrine pancreatic secretion of anesthetized rats was studied. The cholinergic involvement on the actions of ethanol was also studied using previously atropinized animals. During the stimulation period, pancreatic flow rate was significantly increased by intravenous ethanol in both un-atropinized (199% compared with basal) and atropinized rats (195% compared with basal). Pancreatic protein output was also increased during ethanol administration in both groups of animals (171% and 165% compared with basal in, respectively, un-atropinized and atropinized rats). After the administration of ethanol, in the poststimulation period, pancreatic flow rate was further increased only in the atropinized group of rats (290% compared with basal), whose values were significantly higher than those of ethanol-treated un-atropinized animals (195% compared with basal). A similar profile of response was observed in pancreatic protein output. Since intravenous ethanol did not stimulate either secretin or VIP release to portal plasma, the present results point to a direct effect of this substance on the exocrine pancreas. Furthermore, atropine revealed the existence of an inhibitory cholinergic effect of ethanol on the exocrine pancreas. In summary, results show that the effect of intravenous ethanol on the basal exocrine pancreatic secretion is dual and antagonistic.

Comparison between the effects of VIP and the novel peptide PACAP on the exocrine pancreatic secretion of the rat.

The effect of intravenous infusion of pituitary adenylate cyclase-activating peptide (PACAP) 27, a novel regulatory peptide that shows a close structural and chemical similarity to vasoactive intestinal peptide (VIP), on the rat exocrine pancreatic secretion was studied. PACAP and VIP stimulated the flow rate of exocrine pancreatic secretion (p < 0.05). However, protein output and amylase secretion were mainly stimulated by PACAP. Intravenous infusion of VIP increased the plasma levels of secretin (p < 0.05). On the other hand, PACAP released neither secretin nor VIP. Our results show: (a) both PACAP and VIP stimulate exocrine pancreatic secretion, (b) PACAP stimulation of pancreatic amylase and protein secretion is greater than that induced by VIP, and (c) PACAP probably exerts a direct effect on exocrine pancreas whereas some of the actions of VIP might be mediated by secretin.

Mechanisms involved in the control of exocrine pancreatic secretion in the interdigestive state in the rabbit.

The effect of rapid wash-out of the duodenum with phosphate buffered saline on exocrine pancreatic secretion and plasma levels of secretin, VIP, gastrin and CCK was studied. Furthermore, the possible nervous role in this effect was checked after atropine and hexamethonium treatment. Rapid wash-out significantly increased protein output (35.0 micrograms/min, in the control group without duodenal perfusion and 72.15 micrograms/min, in the perfused group) and the plasma levels of CCK (from 5.2 to 13.17 fmol/ml). Intravenous infusion of atropine significantly reduced the protein output (from 78.19 to 32.45 micrograms/min) and the plasma levels of CCK (from 10.1 to 5.55 fmol/ml), with no change in the remaining parameters in the intraduodenally perfused group. Intravenous administration of hexamethonium significantly stimulated hydroelectrolyte secretion (from 6.99 to 15.15 microliters/min) and the plasma levels of VIP (from 4.8 to 7.3 fmol/ml) and reduced the protein output (from 61.47 to 30.75 micrograms/min) and the plasma levels of CCK (from 14.56 to 6.25 fmol/ml) in the intraduodenally perfused group. Our results suggest that, in the interdigestive state, the exocrine pancreatic secretion of the rabbit is tonically inhibited. This inhibition can be divided into two different mechanisms: on the one hand there is a decrease in enzyme secretion produced by a duodenal factor and mediated by CCK and muscarinic mechanisms and on the other, there is an inhibition of hydroelectrolyte secretion with no duodenal participation which is probably controlled by nervous non-muscarinic mechanisms and VIP involvement.