Summary Background In previous clinical trials of patients with metastatic renal-cell carcinoma, patients treated with axitinib as second-line therapy had longer median progression-free survival than ...those treated with sorafenib. We therefore undertook a phase 3 trial comparing axitinib with sorafenib in patients with treatment-naive metastatic renal-cell carcinoma. Methods In this randomised, open-label, phase 3 trial, patients with treatment-naive, measurable, clear-cell metastatic renal-cell carcinoma from 13 countries were stratified by Eastern Cooperative Oncology Group performance status, and then randomly assigned (2:1) by a centralised registration system to receive axitinib 5 mg twice daily, or sorafenib 400 mg twice daily. The primary endpoint was progression-free survival, assessed by masked independent review committee in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov , NCT00920816. Findings Between June 14, 2010, and April 21, 2011, we randomly assigned 192 patients to receive axitinib, and 96 patients to receive sorafenib. The cutoff date for this analysis was July 27, 2012, when 171 (59%) of 288 patients died or had disease progression, as assessed by the independent review committee. There was no significant difference in median progression-free survival between patients treated with axitinib or sorafenib (10·1 months 95% CI 7·2–12·1 vs 6·5 months 4·7–8·3, respectively; stratified hazard ratio 0·77, 95% CI 0·56–1·05). Any-grade adverse events that were more common (≥10% difference) with axitinib than with sorafenib were diarrhoea (94 50% of 189 patients vs 38 40% of 96 patients), hypertension (92 49% vs 28 29%), weight decrease (69 37% vs 23 24%), decreased appetite (54 29% vs 18 19%), dysphonia (44 23% vs ten 10%), hypothyroidism (39 21% vs seven 7%), and upper abdominal pain (31 16% vs six 6%); those more common with sorafenib than with axitinib included palmar-plantar erythrodysaesthesia (PPE; 37 39% of 96 patients vs 50 26% of 189), rash (19 20% vs 18 10%), alopecia (18 19% vs eight 4%), and erythema (18 19% vs five 3%). The most common grade 3 or 4 adverse events in patients treated with axitinib included hypertension (26 14% of 189 patients), diarrhoea (17 9%), asthenia (16 8%), weight decrease (16 8%), and PPE (14 7%); common grade 3 or 4 adverse events in patients treated with sorafenib included PPE (15 16% of 96 patients), diarrhoea (five 5%), and asthenia (five 5%). Serious adverse events were reported in 64 (34%) of 189 patients receiving axitinib, and 24 (25%) of 96 patients receiving sorafenib. Interpretation Axitinib did not significantly increase progression-free survival in patients with treatment-naive metastatic renal-cell carcinoma compared with those treated with sorafenib, but did demonstrate clinical activity and an acceptable safety profile. Funding Pfizer Inc.
Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase III trial compared tivozanib with sorafenib as initial ...targeted therapy in patients with metastatic renal cell carcinoma (RCC).
Patients with metastatic RCC, with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted therapy and mammalian target of rapamycin inhibitor were not permitted. The primary end point was progression-free survival (PFS) by independent review.
A total of 517 patients were randomly assigned to tivozanib (n = 260) or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the overall population (median, 11.9 v 9.1 months; hazard ratio HR, 0.797; 95% CI, 0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed on sorafenib crossed over to receive tivozanib. The final overall survival (OS) analysis showed a trend toward longer survival on the sorafenib arm than on the tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P = .105). Adverse events (AEs) more common with tivozanib than with sorafenib were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and diarrhea (33% v 23%).
Tivozanib demonstrated improved PFS, but not OS, and a differentiated safety profile, compared with sorafenib, as initial targeted therapy for metastatic RCC.
Summary
Aim
To assess the phospholipid bilayer of white blood cells (WBCs) and the ability of leukocytes to generate reactive oxygen species (ROS) in rats orally exposed to GdVO
4
:Eu
3+
nanoparticle ...(VNP) solution for 2 weeks by fluorescent probes—ortho-hydroxy derivatives of 2,5-diaryl‑1,3‑oxazole.
Methods
Steady-state fluorescence spectroscopy, i.e., a study by the environment-sensitive fluorescent probes 2‑(2′-OH-phenyl)-5-(4′-phenyl-phenyl)-1,3-oxazole (probe O6O) and 2‑(2′-OH-phenyl)-phenanthro9,10-1,3-oxazole (probe PH7), and flow cytometry, i.e., analysis of 2′,7′-dichlorofluorescein (DCF), a product of a dye 2′,7′-dichlorodihydrofluorescein diacetate (H
2
DCFDA), fluorescence in CD45
+
/7-aminoactinomycin D (7-AAD)
−
cells, were used to evaluate the state of cell membranes and reactive oxygen species (ROS) generation in leukocytes of rats orally exposed to gadolinium orthovanadate nanoparticles(VNPs).
Results
No significant changes were detected in the spectra of the fluorescent probes bound to the WBCs from the rats orally exposed to nanoparticles in comparison with the corresponding spectra of the probes bound to the cells from the control group of animals. This indicates that in the case of the rats orally exposed to nanoparticles, no noticeable changes in physicochemical properties (i.e., in the polarity and the proton-donor ability) are observed in the lipid membranes of WBCs in the region where the probes locate. There was no statistically significant difference in the amount of ROS
high
viable leukocytes in rats treated with VNPs and control samples.
Conclusion
Neither changes in the physical and chemical properties of the leukocyte membranes nor in ROS generation by WBCs are detected in the rats orally exposed to VNP solution for 2 weeks.
Background: Inconsistent results have been found in previous human studies on male reproductive toxicity of persistent organochlorine pollutants. The majority of studies have been conducted among ...selected populations of infertility clients or among occupational cohorts including a limited number of participants. Methods: We conducted a cross-sectional study of semen quality and serum concentration of 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p′-DDE) among 763 men. We included men from all regions in Greenland (n = 194), fishermen from Sweden (n = 185), inhabitants of the city of Kharkiv, Ukraine (n = 195), and inhabitants of the city of Warsaw, Poland (n = 189). Blood samples were analyzed for CB-153 and p,p′-DDE using gas chromatography-mass spectrometry and adjusted for serum lipids. Results: Sperm concentration was not impaired with increasing serum CB-153 or p,p′-DDE levels in any of the separate groups or overall. Similarly, the proportion of morphologically normal sperm was not associated with either CB-153 or p,p′-DDE blood concentration. However, sperm motility was inversely related to CB-153 concentration in Greenland and the Swedish fishermen population. Across all 4 regions, the sperm motility decreased on average by 3.6% (95% confidence interval = 1.7% to 5.6%) per one-unit increase in the log of blood CB-153 (ng/g lipid). The concentration of p,p′-DDE was negatively associated with sperm motility in the Greenlandic population and in the compiled dataset. Conclusion: Adult exposure to persistent organochlorine pollutants within the ranges observed in the present study is not likely to cause reduction in sperm concentration or morphology. However, higher exposure may be associated with impaired sperm motility.
Objective. The purpose of this study was to investigate safety and feasibility of some surgical approaches to the supradiaphragmatic inferior vena cava (IVC) and the right atrium through the ...diaphragm from the abdominal cavity. Materials and Methods. The material of the anatomical study included 35 fresh cadavers. Several options of surgical access to the supradiaphragmatic IVC were successively performed. Feasibility and risk level of each of the approaches were evaluated with the use of a special scale. Results. The isolation of the supradiaphragmatic IVC and cavoatrial junction was most easily performed via T-shaped or circular diaphragmotomy (grade “easy” was registered in 74.3% and 80% of patients, resp., compared to 31.4% for transverse diaphragmotomy and 40% for isolation of the IVC in the pericardial cavity). The risk analysis has demonstrated the highest safety level for T-shaped diaphragmotomy (grade “safe” was registered in 60% of cases). The intervention via transverse diaphragmotomy, circular diaphragmotomy, and IVC isolation in the pericardial cavity was graded as “risky” in 80%, 62.9%, and 82.9% of cases, respectively. Conclusions. In our opinion, T-shaped diaphragmotomy is the most safe and easy-to-perform access for mobilization of the supradiaphragmatic IVC through the abdominal cavity.
The work presents a rare case of spontaneous migration of an 11-week fetus from the uterine cavity into the urinary bladder cavity through the long-standing vesicouterine fistula.
Exposure to persistent organohalogen pollutants was suggested to impair male reproductive function. A gene-environment interaction has been proposed. No genes modifying the effect of persistent ...organohalogen pollutants on reproductive organs have yet been identified. We aimed to investigate whether the CAG and GGN polymorphisms in the androgen receptor gene modify the effect of persistent organohalogen pollutant exposure on human sperm characteristics.
Semen and blood from 680 men mean (SD) age 34 (10) years from Greenland, Sweden, Warsaw (Poland) and Kharkiv (Ukraine) were collected. Persistent organohalogen pollutant exposure was assessed by measuring serum levels of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and dichlorodiphenyl dichloroethene (p,p'-DDE). Semen characteristics (volume, sperm concentration, total count, proportion of progressively motile and morphology) and DNA fragmentation index (DFI) were determined. CAG and GGN repeat lengths were determined by direct sequencing of leukocyte DNA.
A statistically significant interaction was found between the CB-153 group and CAG repeat category in relation to sperm concentration and total sperm count (P=0.03 and 0.01, respectively). For p,p'-DDE, in the European cohorts a significant interaction was found in relation to DFI (P=0.01). For CAG<20, sperm concentration and total sperm count were 35 and 42% lower, respectively, when the group with CB-153 exposure above median was compared with that below the median. DFI was 40% higher in the high p,p'-DDE exposure group for CAG<or=21.
This study indicated that the androgen receptor CAG repeat length might modify the susceptibility of an individual to the adverse effects of persistent organohalogen pollutant exposure on semen quality. Other studies regarding this matter are warranted.
Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may ...benefit patients with this disease.
In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group.
Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval CI, 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02).
As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 ClinicalTrials.gov.).
The modern approach in the treatment of urolithiasis involves the use of non-invasive and minimally invasive techniques based on the stone fragmentation, among which shock wave lithotripsy (SWL) is ...considered as the first-line treatment for kidney stones < 2 cm and proximal ureter stones.
To study the microstructure and mineral composition of kidney stones and to evaluate their influence on the stones' susceptibility to fragmentation by shock waves.
The microstructure and mineral composition of kidney stone samples obtained from shock wave lithotripsy in 87 patients were studied using crystal optical analysis and infrared spectroscopy. The volume fraction of amorphous and crystalline phases of the stone composition, the quantitative and qualitative composition of mineral components were assessed. The fragmentation features of stones with different microstructure were retrospectively analyzed based on the total number of shock waves required for complete stone fragmentation.
Three kidney stone structure types were identified: amorphous-crystalline structure stones predominantly including the amorphous phase (type A); amorphous-crystalline structure stones predominantly including the crystalline phase (type B); fully crystalline structure stones (type C). Significant positive correlation between the total number of shock waves required for complete stone fragmentation and the volume fraction of crystalline phase was found.
The structure type of kidney stones is determined by the volume ratio between the amorphous and crystalline phases of their composition. The amorphous-crystalline structure stones with the predominant content of the amorphous phase are more sensitive to shock-wave exposure. The increase in the volume fraction of crystalline phase in the stone structure reduces the stone's susceptibility to fragmentation by shock waves.
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