Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331☆.

BACKGROUND: Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC. PATIENTS AND METHODS: CheckMate 331 is a randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS). RESULTS: Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy [median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11]. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus <1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%. CONCLUSION: Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.

Non invasive quantification of manganese deposits in the rat brain by local measurement of NMR proton T1 relaxation times.

Up to now, there is no reliable non invasive biomarker for the concentration of manganese (Mn) in the brain after intoxication to this metal. The aim of the present experimental study was to determine the predictive value of the localized measurement of the proton NMR relaxation time T1 as a quantitative estimation of the concentration of Mn in brain. The relationship of the proton relaxation rates (1/T1) was established in rat brain homogenates as a function of the Mn, iron, and copper concentration. Subsequently, an experimental model of Mn neurotoxicity was used: rats were stereotactically injected with increasing amounts of Mn2+ (as MnCl2) in the ventricles. After 3 weeks, local measurements of T1 were carried out in live rats. They were then sacrificed in order to sample the striatum, the cortex, and the cerebellum from the brain and to perform a quantitative determination of the concentration of Mn in these tissues by atomic absorption spectrometry (AAS). The results indicate excellent correlation coefficients between relaxation rates and tissue Mn concentrations (r= 0.84, 0.77 and 0.92 for the striatum, the cortex and the cerebellum, respectively). This methodology offers a unique toolfor monitoring the degree of Mn concentration in different areas of the brain in animal models of Mn intoxication. It will be useful for evaluating the efficacy of treatments aimed at decreasing the metal in the brain. The method could be potentially useful for being transposed in the clinical situation for monitoring Mn-exposed workers.

Changes in tumor oxygenation/perfusion induced by the no donor, isosorbide dinitrate, in comparison with carbogen: monitoring by EPR and MRI.

PURPOSE: In an effort to improve radiotherapy treatments, methods aimed at increasing the quantity of oxygen delivered to tumors were investigated. The aim of this study was to evaluate the effect of one nitric oxide (NO) donor (isosorbide dinitrate) on pO(2) and blood flow in a murine tumor model. The effect was compared to carbogen, used as a reference treatment. METHODS AND MATERIALS: Thirty-six liver tumors implanted in mouse thighs were imaged using magnetic resonance imaging (MRI) at 4.7 Tesla with dynamic Gd-DTPA and blood oxygen level-dependent (BOLD) contrast-enhanced imaging after administration of isosorbide dinitrate or carbogen. The effect on the pO(2) was also tested by EPR oximetry (1.1 GHz) on 52 mice. RESULTS: A significant increase in MRI intensity was observed for both treatments in comparison with the control group. EPR oximetry showed a dose-dependant increase in tumor pO(2) for isosorbide dinitrate (by 5.9 mmHg at 0.2 mg/kg) and a substantially greater change for carbogen breathing (by 23 mmHg). CONCLUSION: Both tumor blood flow and pO(2) were increased by isosorbide dinitrate and carbogen. Carbogen is more efficient than isosorbide dinitrate in increasing the BOLD image intensity, as well as the tumor pO(2), but as efficient as isosorbide dinitrate in the Gd-DTPA contrast-enhanced imaging. We conclude that the effects of carbogen on improving tumor pO(2) involve both improved blood flow and improved hemoglobin oxygenation, whereas the effects of isosorbide dinitrate are predominantly mediated by improved blood flow alone.

Free radicals in licorice-flavored sweets can Be detected noninvasively using low frequency electron paramagnetic resonance after oral administration to mice.

The observation of the fate of free radicals coming from food after oral administration could be important in evaluating their reactivity in vivo. The aim of this study was to demonstrate that it is feasible to detect directly in vivo free radicals coming from food with the use of low frequency electron paramagnetic resonance (EPR) spectroscopy. Because polyphenols are easily oxidized into stable radicals, we assumed that these radicals could be detected in food. We chose licorice, which contains several types of polyphenols. The presence of free radicals was demonstrated in licorice-flavored sweets. Using low frequency EPR spectroscopy, we detected these free radicals directly and noninvasively after oral administration to mice. These radicals were rather stable in the guts of the mice. This study is the first report demonstrating noninvasively the presence of free radicals in vivo coming from food.

Pharmacological modifications of the partial pressure of oxygen in murine tumors: evaluation using in vivo EPR oximetry.

EPR oximetry using an implantable paramagnetic probe was used to quantify the partial pressure of oxygen (pO(2)) in tissues in a transplantable mouse tumor model (TLT) after administration of 34 different vasodilators belonging to one of the following classes: angiotensin-converting enzyme inhibitors, calcium antagonists, alpha antagonists, potassium channel openers, beta-blockers, NO donors, and peripheral vasoactive agents. Twenty-four compounds were efficient in significantly increasing the local pO(2) in a majority of tumors. The increase of local pO(2) using pharmacological treatments was lower than that achieved by using oxygen or carbogen breathing. This technique offers an unprecedented tool for rapidly and accurately measuring treatment-induced modifications of pO(2) in tumors. Magn Reson Med 42:627-630, 1999.

Evidence for a neuroprotective effect of pyrid-3-yl-sulphonyl-urea in photochemically induced focal ischaemia in rats: magnetic resonance imaging evaluation.

A neuroprotective effect can be obtained with N-[(4-cycloheptylaminopyrid-3-yl)sulphonyl]N'-cycloheptyl urea (BM27), a pyrid-3-yl-sulphonylurea structurally related to torasemide, a loop diuretic. We have investigated the neuroprotective effect of BM27 by magnetic resonance imaging and use of the photothrombotic model of cerebral infarction in the rat. This method enables non-invasive quantification of the extent of the cerebral oedema from T2-weighted spin-echo images. This article reports the evolution of the extent of oedema with time (0.5, 1, 2, 4, 6, 24 and 48 h, 7 and 15 days and 1 month after induction of the lesion) in rats pretreated with 5 mg kg(-1) BM27 or an appropriate control. At all times, the rats treated with BM27 had, on average, smaller lesions than control rats (30% decrease between 2 h and 6 h). These results strongly suggest a significant (P < 0.01) but modest neuroprotective effect of BM27 in ischaemic cerebral stroke. Further investigations should be performed to determine if BM27 or its analogues are of clinical interest.

Microencapsulation of paramagnetic particles by pyrroxylin to preserve their responsiveness to oxygen when used as sensors for in vivo EPR oximetry.

Using the broadening of the electron paramagentic resonance (EPR) linewidth of paramagnetic particles by oxygen, it is possible to make measurements of the partial pressure of oxygen in vivo. While the results obtained so far with EPR oximetry are very encouraging, several paramagnetic materials may lose their responsiveness to oxygen in tissues. This aim of this study was to provide evidence that an appropriate coating can preserve the oxygen sensitivity of paramagnetic materials in vivo. Two charcoals that have the oxygen-sensing properties required for EPR oximetry (combined with a tendency to lose responsiveness to oxygen when placed in tissues) were coated using pyroxylin. Sensitivity to variations in pO2 was checked by inducing hypoxia in the muscles of mice injected with charcoal. While the uncoated material lost responsiveness to oxygen within few days, the particles coated with 20-30% of pyroxylin did not lose their responsiveness for more than 2 months.

Regional distribution of manganese found in the brain after injection of a single dose of manganese-based contrast agents.

Manganese (Mn) complexes are unstable and dissociate in vivo. Because of the release of this metal, there exists some concern about the potential long-term neurotoxicity associated with the use of Mn-based contrast agents. This latter problem arises because manganese is known to accumulate in specific regions of the brain of people intoxicated by this metal. It was previously demonstrated that Mn can accumulate in the mice brain after administration of 5 micromol/kg of MnCl2, Mn-diethylenetriaminepentaacetate (Mn-DTPA), or Mn-dipyridoxal diphosphate (Mn-DPDP). In order to better characterize the behavior of Mn complexes after administration, this study assesses the regional distribution of Mn in the brain after i.v. injection of a single dose of MnCl2 or Mn-DTPA. Male Wistar rats received an i.v. injection of 5 micromol/kg of 54Mn as MnCl2 or Mn-DTPA. The rats were killed at one and two weeks post exposure. The distribution of the radioactivity in the slices was monitored by autoradiography. For both MnCl2 or Mn-DTPA, we observed that the radioactivity was dispersed in the entire brain, but the radioactivity was higher in several regions. No difference was observed between MnCl2 or Mn-DTPA in the regional distribution of Mn, and no difference was observed between the two times of exposure (1 week or 2 weeks). The uptake of Mn was minimal in corpus callosum. Maximal Mn concentration was observed in the hippocampal region, thalamus, colliculi, amygdala, olfactory nuclei, and cerebellum.

Carbon-centered radicals as oxygen sensors for in vivo electron paramagnetic resonance: screening for an optimal probe among commercially available charcoals.

It is known that some charcoals possess paramagnetic centers with an electron paramagnetic resonance (EPR) linewidth which can be broadened by oxygen. In order to identify potential candidates as sensors for in vivo EPR oximetry, we carried out a systematic study among commercially available charcoals. A total of 34 charcoals were tested. The steps used for the screening were: (1) to check the presence of paramagnetic centers in the material; (2) to measure the EPR linewidth in nitrogen and in air on the dry material and on a aqueous suspension of particles; (3) to calibrate the oxygen sensitive materials (EPR linewidth vs. pO2); (4) to test the sensitivity and stability of the response to changes of pO2 in a simple model of hypoxia induced in mice. Seventeen charcoals contained paramagnetic centers detectable by low-frequency EPR (1.1 GHz). The EPR spectrum consist of one single line which is typical of carbon-centered radicals (g-factor approximately 2). Eight charcoals presented sufficient interesting EPR properties (linewidth in nitrogen < 0.1 mT, linewidth in air for an aqueous suspension of particles > 0.15 mT) to be further characterized in vivo. Only three charcoals presented a stable, reproducible, and sensitive response to pO2 for more than 2 months. These three coals should be considered as good candidates to be used as oxygen sensor using in vivo EPR spectroscopy.

Accumulation of manganese in the brain of mice after intravenous injection of manganese-based contrast agents.

Because the manganese-based contrast agents used in magnetic, resonance imaging are unstable in vivo, some concern exists about the potential toxicity coming from the Mn2+ released by the complexes. This potential problem arises because the manganese is known to accumulate in the brain of people intoxicated by this metal (manganism): this central accumulation leads to neurological disorders (i.e., parkinsonism-like syndrome). The aim of this study was to assess the amount of Mn found in the brain after administration of MnCl2 or different chelates of Mn in normal mice as well as in mice with impaired biliary elimination. Male NMRI mice received an intravenous injection in a caudal vein of 5 mumol/kg of 54Mn compounds as MnCl2, manganese-diethylenetriaminepentaacetate (Mn-DTPA), or manganese-dipyridoxal diphosphate (Mn-DPDP). The radiolabeled complexes (1:1) were prepared by direct chelation (Mn-DTPA) or transchelation of preformed complex (Mn-DPDP), and the radiochemical purity was assessed by paper chromatography. The mice were killed at various times post-exposure (0-3 months), and the radioactivity present in the organs was determined by gamma counting. For each compound analyzed in the present study, we observed an accumulation of Mn (0.25-0.3% of the amount injected/g of tissue) in the mouse brain, reaching a plateau after 24 h, while the Mn content in the liver was decreasing with time. The amount of Mn accumulated in the brain remained unchanged 1 month later, but decreased to 40% of the maximum amount 3 months after the exposure. In mice whose bile ducts had been ligated 24 h before the administration of the manganese compound, we observed, 1 week after the injection, an amount of manganese accumulated in the brain 2 times higher than in normal mice.

The uptake of Mn-DPDP by hepatocytes is not mediated by the facilitated transport of pyridoxine.

Manganese-dipyridoxal diphosphate (Mn-DPDP) is a liver-selective contrast agent selectively taken up by the hepatocytes. Because of the analogy of structure with pyridoxine (vitamin B6), it was previously suggested that this compound can be selectively taken up by the facilitated transport of vitamers B6. To understand the uptake mechanism, an in vivo binding study was performed based on a competition between 54Mn-DPDP and pyridoxine on the one hand, and Mn-DPDP and [3H]pyridoxine on the other. We found that the [3H]pyridoxine levels in the liver were not significantly different 5 min after intravenous administration of several doses of Mn-DPDP (5 nmol/kg to 50 mumol/kg): 5.0 +/- 0.3% of the injected dose/g tissue. The content of 54Mn (administered as 54Mn-DPDP) in the liver was not affected by a saturation dose of pyridoxine (1 mmol/kg) and was found to be constant (+/- 10% of the injected dose/g tissue) for 60 min. These experiments showed that the uptake of Mn-DPDP is not mediated by the transporter of pyridoxine.