Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study.

BACKGROUND: Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. PATIENTS AND METHODS: Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. CONCLUSION: In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.

[Survival analysis of malignant tumors in cancer registration areas of Hubei province in China, 2013 to 2015].

Objective: To analyze the survival of newly diagnosed malignant tumors in cancer registration areas of Hubei Province from 2013 to 2015. Methods: From January 1, 2013 to December 31, 2015, all newly diagnosed malignant tumors were collected from cancer registration areas in Hubei Province, and patients were followed up using a combination of active and passive methods. Cancer survival was analyzed using the strs package in Stata software. Observed and expected survival were calculated using the life table and Ederer Ⅱ methods, and the difference in survival rate of patients with different sex, age, urban and rural areas and different cancer species was compared. Results: From 2013 to 2015, 83 987 new malignant tumors were diagnosed in cancer registration areas in Hubei Province, including 45 742 males (54.46%) and 38245 females (45.54%). The overall 5-year relative survival rate was 41.46%, 34.43% for men and 49.63% for women. With the increase of age, the observed survival rate and relative survival rate of patients of different genders showed a decreasing trend. The 5-year relative survival rate of patients with malignant tumors was 47.58% in urban areas and 26.58% in rural areas. The observed survival rate and relative survival rate in rural areas were significantly lower than those in urban areas. The overall 5-year relative survival rates for common malignancies were 20.61% for lung cancer, 15.36% for liver cancer, 22.89% for esophageal cancer, 34.92% for gastric cancer, and 54.87% for colorectal cancer. In addition, the 5-year relative survival rates of common malignant tumors in women were 78.65% for breast cancer and 52.55% for cervical cancer. Conclusions: In Hubei Province, the survival rate of malignant tumors is different among different genders, regions, age groups and cancer species. Prevention and treatment and health education should be strengthened for malignant tumor patients in rural areas and those with high incidence and low survival rate such as liver cancer and lung cancer, and relevant strategies should be formulated according to the gender and age distribution characteristics of different cancer species.

Cytotoxicity study of benzo[a]pyrene on blood cells of Wistar rat in vitro.

The effect of benzo[a]pyrene (BaP) on Wistar rat lymphocyte activity, lymphocyle membrane integrity and erythrocytes hemolysis were examined using the MTT assay, the release of the lactate dehydrogenase (LD) and the hemoglobin release respectively in vitro. The results showed that lymphocyte activity had no remarkable response to BaP after a low dose of exposure. But the membrane change was found after higher dose of BaP exposure, and the significant release of LD was observed. The release of LD increased with exposure time prolonging and exposure dose increasing. The results also showed that BaP didn't change the release of hemoglobin from erythrocytes. But the release of hemoglobin was affected significantly by synergistic effects of BaP and pentachlorophenol (PCP) and the release of hemoglobin increased with the dose of the mixture of BaP and PCP. Therefore, there is an obvious cytotoxicity of BaP in lower dose to blood cells of Wistar rat. The damage of lymphocyte membrane is more sensitive than lymphocyte activity and erythrocytes hemolysis to lower dose of BaP. It is suggested that the release of LD as a biomarker could be used to monitor and evaluate the contamination of BaP. The blood of Wistar rats were taken and checked after a fixed time interval (6 hours) of acute BaP exposure. The level of whole genomic DNA methylation was found to decrease significantly in the blood of rats.

Two New Species of the Genus Criotettix Bolivar (Orthoptera: Tetrigidae), with a Key to the Species of the Genus from China.

Two new species of the tetrigid genus Criotettix Bolivar from China, namely Criotettix interruptaoides Deng & Zheng n. sp. and Criotettix shiwanshanensis Deng & Zheng n. sp. are described. An updated key to all known species of the genus from China is given.

Genetic profile of tuberculosis among the migrant population in Fujian Province, China.

SETTING: The Fujian District in China has a high migrant worker population. Although tuberculosis (TB) among migrants is a serious threat to public health in Fujian, little is known about the molecular characteristics of TB isolates in this population. OBJECTIVE: To investigate the genetic profile of TB among the migrant population in Fujian. RESULTS: Our study enrolled 243 pulmonary TB patients registered in Fujian. Our data demonstrated that the Beijing genotype was the most common genotype in Fujian, and that the proportion of migrants with the Beijing genotype was significantly higher than that of permanent residents. Furthermore, the population structure of Mycobacterium tuberculosis strains in Fujian was diverse, with no difference in the distribution of mycobacterial interspersed repetitive units-variable number of tandem repeat (MIRU-VNTR) subgroups between the migrant and permanent populations. In addition, the discriminatory power of MIRU-VNTR in this study was higher than that found in other regions of China, possibly due to the high percentage of migrants in Fujian. CONCLUSION: The Beijing genotype was the predominant genotype in Fujian. TB strains isolated from this migrant population revealed a genetic profile similar to that of the permanent population. Improvement in public medical and insurance programmes for migrants might be crucial in the effective control of TB in Fujian.

[Analysis of fatty acids in rat liver peroxisomes].

Peroxisomes of rat liver from normal and di (2-ethylhexyl) phthalate (DEHP)-treated animals were isolated by density gradient centrifuge method. The fatty acids in the liver peroxisomes were extracted with chloroform and methanol, and were esterified with boron trifluoride and methanol. The fatty acids methyl esters were separated on SPB-1 (similar to SE-30, OV-101) capillary column, and were determined using heptadecanoic acid (C17:0) as an internal standard for the eleven fatty acids (C10:0-C22:6) in these peroxisomes by gas chromatography. The ratio of unsaturated fatty acids to total fatty acids in the control was significantly less than that in DEHP-treated animals (P < 0.05), but there was no difference between the control and DEHP-treated animals for the content of total fatty acids and the ratio of long chain fatty acids to total fatty acids. The results show that DEHP-treatment can alter the fatty acid composition of peroxisome. The membrane structure of the treated peroxisome was different to that of the control.

Nitric oxide modulation of pulmonary blood flow distribution in lobar hypoxia.

BACKGROUND: Nitric oxide, endogenously produced or inhaled, has been shown to play an important role in the regulation of pulmonary blood flow. The inhalation of nitric oxide reduces pulmonary arterial pressure in humans, and the blockade of endogenous nitric oxide production increases the pulmonary vascular response to hypoxia. This study was performed to investigate the hypothesis that intravenous administration of an nitric oxide synthase inhibitor and regional inhalation of nitric oxide can markedly alter the distribution of pulmonary blood flow during regional hypoxia. METHODS: Hypoxia (5% O2) was induced in the left lower lobe of the pig, and the blood flow to this lobe was measured with transit-time ultrasound. Nitric oxide was administered in the gas ventilating the hypoxic lobe and the hyperoxic lung regions with and without blockade of endogenous nitric oxide production by means of N omega-nitro-L-arginine methyl ester (L-NAME). RESULTS: Hypoxia in the left lower lobe reduced blood flow to that lobe to 27 +/- 3.9% (mean +/- SEM) of baseline values (P < 0.01). L-NAME caused a further reduction in lobar blood flow in all six animals to 12 +/- 3.5% and increased arterial oxygen tension (PaO2) (P < 0.01). Without L-NAME, the inhalation of nitric oxide (40 ppm) to the hypoxic lobe increased lobar blood flow to 66 +/- 5.6% of baseline (P < 0.01) and, with L-NAME, nitric oxide delivered to the hypoxic lobe resulted in a lobar blood flow that was 88 +/- 9.3% of baseline (difference not significant). When nitric oxide was administered to the hyperoxic lung regions, after L-NAME infusion, the blood flow to the hypoxic lobe decreased to 2.5 +/- 1.6% of baseline and PaO2 was further increased (P < 0.01). CONCLUSIONS: By various combinations of nitric oxide inhalation and intravenous administration of an nitric oxide synthase inhibitor, lobar blood flow and arterial oxygenation could be markedly altered during lobar hypoxia. In particular, the combination of intravenous L-NAME and nitric oxide inhalation to the hyperoxic regions almost abolished perfusion of the hypoxic lobe and resulted in a PaO2 that equalled the prehypoxic values. This possibility of adjusting regional blood flow and thereby of improving PaO2 may be of value in the treatment of patients undergoing one-lung ventilation and of patients with acute respiratory failure.

Effects of inhaled nitric oxide on methacholine-induced bronchoconstriction: a concentration response study in rabbits.

Inhaled nitric oxide (NO), at a concentration of 80 ppm, counters the increase in respiratory resistance (Rrs) induced by methacholine, but fails to prevent a reduction in lung compliance (Crs) in a rabbit model. This study reports the effects of 3, 30 and 300 ppm of inhaled NO. New Zealand White rabbits were intubated and mechanically ventilated with 30% oxygen during neurolept anaesthesia. Methacholine (3 mg.ml-1) was nebulized, with or without NO inhalation. Inhalation of 3 and 30 ppm NO had no effect on the induced bronchoconstriction, whereas 300 ppm fully blocked the increase in Rrs. The decrease in Crs due to methacholine was not countered by 3, 30 or 300 ppm NO. On the contrary, inhalation of 300 ppm NO in itself decreased Crs from 5.0 +/- 0.1 to 4.3 +/- 0.1 ml.cmH2O-1. Also, mean arterial pressure (60 +/- 7 to 54 +/- 5 mmHg), alveolar-arterial oxygen tension gradient (0.8 +/- 0.8 to 2.3 +/- 1.8 kPa) and methaemoglobin (0.5 +/- 0.2 to 1.5 +/- 0.5%) changed significantly on inhalation of NO 300 ppm prior to methacholine challenge. We conclude that 3 and 30 ppm NO inhalation does not alter methacholine-induced bronchoconstriction. Inhalation of 300 ppm NO blocks an increase in resistance but fails to counter the reduction in compliance due to methacholine. This suggests that the bronchodilating effects of NO in rabbits in vitro are confined to the large airways.

Neurogenic vasodilation in rabbit hindlimb mediated by tachykinins and nitric oxide.

We investigated the role of nitric oxide (NO) in the mediation of nerve stimulation-induced vasodilation in skeletal muscle. Hindlimb blood flow and vascular resistance were measured in pentobarbital-anesthetized, paralyzed, and guanethidine-treated rabbits. Centrifugal electrical stimulation of the sciatic nerve bundle induced reproducible, frequency-, voltage-, and pulse duration-dependent decrements in vascular resistance. The tachykinin antagonist CP-96,345 (1 mg/kg intravenously, i.v.) attenuated the vasodilation induced by intraarterially (i.a.) administered substance P but not by adenosine. Furthermore, CP-96,345 attenuated the decrease in vascular resistance in response to nerve stimulation, from 22.9 +/- 3.2 to 4.5 +/- 4.1% of control resting resistance (p < 0.005), without affecting basal vascular resistance. An inhibitor of NO formation, N omega-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg i.v.), increased vascular resistance from 6.1 +/- 0.5 to 9.1 +/- 1.2 resistance units (p < 0.05) and significantly attenuated the vascular response to i.a. administered substance P but not adenosine. Finally, nerve stimulation-induced reduction in vascular resistance was attenuated by L-NAME, from 22.6 +/- 2.7 to 7.0 +/- 1.0% of control (p < 0.001). These findings suggest that tachykinins and NO are involved in mediation of vasodilation in response to the present type of nerve stimulation. The data are consistent with the hypothesis that NO is produced subsequent to neural release of tachykinin-type transmitter(s).

Leukemic cell creatine kinase and its isoenzymes.

Using malachite green single agent coloration and acetate membrane electrophoresis, we studied the cellular creatine kinase (CK) activity and its isoenzymes in 7 normal controls and 26 leukemia patients. The leukemic cellular CK activity was 12.62 +/- 4.86 u/mg protein, 2.2 times higher than the normal value (5.73 +/- 2.66 u/mg protein, p less than 0.05). Only 2 of 5 normal leukocyte samples showed '+' CK isoenzyme MM. 22 leukemia patients had CK isoenzyme. CK-BB appeared mainly in acute granulocytic leukemic, and CK-MM mainly in other types. CK-MB was also found in 6 patients. The recurrence of CK-BB may indicate atavism, and the enhanced anaerobic glycolysis and the accelerated energetic turnover may be on of the metabolic characteristics of leukemic cell.