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.

[Analysis of influencing factors of ureteral anastomotic stenosis following urinary diversion after laparoscopic radical cystectomy].

Objective: To investigate the influencing factors of ureteroenteric strictures (UES) in patients undergoing laparoscopic radical cystectomy plus urinary diversion (UD). Method: A total of 412 patients who underwent UD after radical prostatectomy from January 2008 to December 2016 were retrospectively included in this study. Age, gender, body mass index (BMI), diversion type, time to diagnosis of UES, duration of ureteral stent, postoperative complications, including urinary tract infections, ureteroenteric leakage and UES were collected. Kaplan-Meier curves were used to describe time to developing UES. Prognostic factors of UES were analyzed using COX proportional hazard regression model. Result: Median follow-up time was 37 (IQR 17-120) months. A total of 59 patients (70 sides) developed UES, including 34 cases on the left side, 14 cases on the right side and 11 cases on both sides, following UD after radical cystectomy. The median time to diagnosis of UES was 7 (IQR 4-11) months. The total incidence of UES was 14.3%. The incidence of UES was 10.9%, 13.3% and 14.1% at 1, 3 and 5 years after UD, respectively. Cox proportional hazard regression model analysis demonstrated that BMI≥25kg·m(-2) (P=0.008), ureteroenteric leakage (P=0.001) and urinary tract infections (P=0.037) were the independent risk factors associated with UES following UD after radical cystectomy. Conclusion: The incidence rate of UES following UD after radical cystectomy was relatively high, which occurs more common on the left side. Obese patients, combined with ureteroenteric leakage, urinary tract infection after UD, are more likely to develop into UES.

[Impact of diverse shapes of prostatic apex on positive apical margin rate and biochemical recurrence following laparoscopic radical prostatectomy].

Objective: To explore the effects of various forms of prostatic apex on positive apical margin rate (PAM) and biochemical recurrence (BCR) after laparoscopic radical prostatectomy. Methods: A retrospective analysis of 309 patients (aging (65±6) years) who were experienced laparoscopic radical prostatectomy from January 2010 to December 2016 at the Department of Urology, First Affiliated Hospital of Fujian Medical University. According to the relationship between prostate apex and membrane urethra at the mid-sagittal plane of preoperative MRI, all patients were classified into 4 categories. There were 31 patients for type 1, apex covering both anterior and posterior aspects of membranous urethra, 139 patients for type 2, apex covering anterior side of membranous urethra, 63 patients for type 3, apex covering posterior aspect of membranous urethra, 76 patients for type 4, apex not covering membranous urethra. PAM and BCR after operation were compared between this four groups respectively. The χ(2) test was used to compare PAM among the 4 types. Logistic regression analysis were undertaken to analyze the factors affecting PAM. Cox's proportional hazards regression model was undertaken to identify the variables influencing BCR. Results: There was no significant difference in the 4 groups concerning age, body mass index, prostate volume, preoperative prostate-specific antigen (PSA) value, postoperative Gleason score and pathological stage (P>0.05).The median follow-up time was 32 months (ranged from 12 to 60 months).The data showed that the apical type 3 patients has the highest PAM. There was statistical difference among the 4 groups in PAM (χ(2)=15.592, P=0.001). Preoperative level of PSA (OR=20.356, 95% CI: 2.440 to 169.810, P=0.005), postoperative Gleason score (OR=4.113, 95% CI: 1.911 to 8.849, P=0.001), pathological stage (OR=3.422, 95% CI: 1.600 to 7.319, P=0.002) and apical type 3 (OR=6.134, 95% CI: 2.196 to 17.132, P=0.001) were independent relactive factors of PAM. Preoperative level of PSA (HR=1.362, 95% CI: 1.006 to 1.843, P=0.045), postoperative Gleason score (HR=1.920, 95% CI: 1.384 to 2.665, P=0.001), pathological stage (HR=1.476, 95% CI: 1.098 to 1.983, P=0.010), PAM (HR=3.497, 95% CI: 2.407 to 5.081, P=0.001)and apical type 3 (HR=1.828, 95% CI: 1.266 to 2.639, P=0.001) were independent prognosis factors of BCR. Conclusion: Prostate apical type 3 could be a significant independent predictor of PAM, and an independent prognosis factor for BCR.

[Effects of urethral fibrosis on urinary control after laparoscopic radical prostatectomy].

Objective: To determine the influence of urethral fibrosis on the recovery of urinary continence after laparoscopic radical prostatectomy. Method: A retrospective study of 203 patients from January 2010 to January 2014 who were underwent laparoscopic radical prostatectomy for prostate cancer in the First Affiliated Hospital of Fujian Medical University. The patients were divided into 2 groups according to preoperative T2-weighted magnetic resonance imaging of fibrosis status of the urethral wall and periurethral tissue. One hundred and forty-four(≤2 grade) and 59 (≥3 grade) were classified into the no/mild and severe urethral fibrosis groups respectively. Urinary continence at 1, 3, 6, 12 months after operation were compared between this two groups respectively. Result: There was no significant difference in the two groups with respect to age, body mass index (BMI), Charlson comorbidity index (CCI), international prostate symptom score (IPSS), prostate volume, preoperative prostate-specific antigen value, nerve-sparing procedure, postoperative Gleason score and pathological stage. The operation was completed successfully in all cases. With a median follow-up time of 15 months (ranged from 12 to 24 months), there was no statistical difference between the two groups in urinary continence at 1 month after operation (P>0.05). The incidences of continence in patients with no/mild fibrosis were significantly higher at 3, 6, 12 months after operation than those with severe fibrosis. (In the no/mild fibrosis group and severe fibrosis group, the continue rate at 3 mouths was 50.0% vs 28.8% P=0.005; at 6 mouths was 91.0% vs 59.3% P<0.001; at 12 mouths was 98.6% vs 88.1% P=0.003). Conclusion: Preoperative urethral fibrosis could be a significant predictor of recovery of the long-term urinary continence status after laparoscopic radical prostatectomy. Compared with no/mild fibrosis, severe fibrosis had worse long-term continence status.

Mechanism of pingyangmycin-induced apoptosis of cultured human umbilical vein endothelial cells.

In this study, we investigated the effects of pingyangmycin (PYM) on the growth inhibition and apoptosis of human umbilical vein endothelial cells (HUVEC). In this study, we aimed to explore the optimal concentration of PYM to induce the apoptosis of HUVEC and to determine its mechanism of action. After treatment of HUVEC with different concentrations of PYM for 24 h, cell counting kit-8 (CCK-8) was used to detect growth inhibiting effects. Annexin V-FITC/propidium iodide stain was used to detect apoptosis, and western blot was used to detect the expression of glucose-related protein 78 (GPR78) and C/EBP homologous protein (CHOP) endoplasmic reticulum stress proteins. With increasing PYM concentration, the growth inhibition of HUVEC increased (P < 0.05), the apoptotic numbers of HUVEC increased (P < 0.05), with higher PYM concentrations inducing necrosis, and the protein expression of GRP78 and CHOP increased (P < 0.05). PYM could obviously inhibit the proliferation and promote the apoptosis of HUVEC. Necrotic cells were more prevalent than apoptotic cells at high PYM concentrations. This study helped to determine the proper concentration of PYM to induce more apoptosis than necrosis, which is critical to minimize inflammation, enhance the healing of the skin, and maintain safety for the patient. PYM might induce HUVEC apoptosis through the endoplasmic reticulum stress pathway.

Clinicopathological features and prognosis of triple-negative breast cancer: a comparison between younger (<60) and elderly (≥60) patients.

Triple-negative breast cancer (TNBC) has attracted more attention both clinically and experimentally because of its high-risk biological characteristics and lacking of effective treatment method. The tumour characteristics, patterns of recurrence and metastasis, therapy methods and prognosis in younger TNBC patients have been widely formulated, but the relevant data of the elderly people are lacking. We conducted this retrospective study to compare and analyse the above-related characteristics between the younger and elderly patients with TNBC to estimate the relevance for the elderly TNBC patients. A total of 1489 female patients with primary breast cancer were diagnosed and treated at the department of General Surgery, the Chinese PLA General Hospital, China, from January 2004 to December 2008. In the 1489 patients, 302 patients (20.28%) with TNBC histopathologically confirmed were retrospectively analysed. The 302 TNBC patients were divided into two groups: the younger (<60 years) group and the elderly (≥60 years) group. The relevant characteristics of the two groups were compared. There were no statistically significant differences between the two groups in common clinical data of the patients, clinicopathological features of tumour and the features of local recurrences and metastases of tumour, and the 5-year disease-free survival and overall survival were all significantly higher in the elderly group than those in the younger group, although the elderly group patients accepted significantly less radiotherapy and chemotherapy than the younger group patients. The elderly and younger TNBC patients may belong to different subtypes of TNBC and we probably could take a more conservative and cautious attitude in choosing the post-operative adjuvant treatment for the elderly patients with TNBC.

Application of biochar from sewage sludge to plant cultivation: Influence of pyrolysis temperature and biochar-to-soil ratio on yield and heavy metal accumulation.

Applying biochar products from sewage sludge (SS) pyrolysis as soil amendment for plant cultivation was investigated in this study with special attention paid to heavy metal accumulation in the plants when pyrolysis temperature and biochar-to-soil mass ratio (C:S) were changed. Biochar obtained at four different temperatures were adopted as soil amendment for Allium sativum L. garlic plant cultivation. Experimental results revealed that biochars were rich in nutrient contents and they improved garlic yields. Although contents of heavy metals including As, Zn, Pb, Ni, Cd, Cr and Cu, etc. were elevated in the biochars compared to local soil, they fell within the acceptable limits for land application and SS is a suitable biochar resource, especially biochar produced at 450°C had rich micropores, relatively stable functional groups in structure and rugged surface to contact well with soil, conducive to its usage as a biochar. The garlic grew faster when planted in the biochar-amended soil and had higher final dry matter yields than those planted in the reference soil, especially biochar produced at 450°C corresponding to the highest final yields. The C:S ratio related to the highest garlic yields changed when the pyrolysis temperature was changed and this ratio was 1:4 for the biochar produced at 450°C. General heavy metal accumulation in the garlic occurred only for the most enriched Zn and Cu, and mainly in the roots & bulbs; in addition this bioaccumulation was increasing as leaching from biochar increased but not increasing with C:S ratio. The garlic planted in soil amended with biochar of 450°C contained the lowest level of heavy metals compared to other biochars. Those results indicated that heavy metal accumulation in plants can be inhibited through proper pyrolysis temperature choice and prevention of heavy metal leaching from the SS biochar.

In vivo study on biocompatibility and bonding strength of hydroxyapatite-20vol%Ti composite with bone tissues in the rabbit.

Biocompatibility and bonding strength of hydroxyapatite-20vol%Ti composite fabricated by hot-pressing technique with bone tissues in the rabbit were investigated by in vivo studies in comparison with those of Ti metal and dense HA ceramic. Although fibrous tissues formed at the interface between the composite and bone tissues at 3 weeks in vivo, bonding strength of the composite increases faster than that of dense HA after 4 weeks. At 3 months in vivo, bonding strength of the composite is higher than that of dense HA and exceeds 6.5 MPa. Moreover, as compared with the visible bonding interfaces between dense HA and new bones, the bonding interfaces for the composite cannot already be distinguished and the composite was osseointegrated fully with bone tissues into one bony body. The shear fracture of bonding strength test for the composite occurred in new bone zones near the interface, which indicates that bonding strength of the composite could even exceed the shear strength of new bones after 3 months in vivo. In conclusion, HA-Ti composite has better osteoconduction and osseointegration abilities than Ti metal and dense HA ceramic after 3 months in vivo and is a promising biomaterial for hard tissue replacement.

Predicting gas chromatographic retention times of 209 polybrominated diphenyls (PBBs) for different temperature programs.

A method has been developed to predict the retention times of 209 individual polybrominated diphenyl congeners for different temperature programs. The retention equations lnk'=A+B/T of five PBBs in gas chromatography (GC) were used to evaluate the properties of the regression coefficients A and B, which are widely accepted as being highly reliable chromatographic retentions. The quantitative relationships between the A and B values of PCBs and those of PBBs were found. The regression equations derived have coefficients of determination greater than 0.999. The A, B values of any PBB can be predicted by using the A, B values of the PCB according to these relationships. Using these predicted A and B values, the retention times of all PBBs can be predicted. This is an important advance in the identification of PBBs because at present there are only a few PBB standards available.

Quantitative relationships between molecular structures, environmental temperatures and octanol-air partition coefficients of polychlorinated biphenyls.

A quantitative model that incorporates information on both environmental temperatures (T) and molecular structures, for logarithm of octanol-air partition coefficient to base 10 (logK(OA)) of polychlorinated biphenyls (PCBs) was developed. Partial least squares (PLS) analysis together with 16 theoretical molecular structural descriptors was used to develop the Quantitative relationships between structures, environmental temperatures and properties (QRSETP) model. The cross-validated Q(cum)(2) value for the optimal QRSETP model is 0.976, indicating a good predictive ability for logK(OA) of PCBs at different environmental temperatures. T, E(LUMO) (the energy of the lowest unoccupied molecular orbital), molecular size or average molecular polarizability (alpha), and the net atomic charges on chlorine, hydrogen and carbon atoms of PCB molecules, are major factors governing logK(OA). The lower the E(LUMO), the greater the intermolecular interactions between octanol and PCB molecules, and thus the greater the logK(OA) values. Because of intermolecular dispersive forces, the more chlorine atoms in PCB molecules, the greater the molecular size or alpha, the greater the logK(OA). The largest negative net atomic charge on a carbon atom (q(C)(-)) and molecular size or average molecular polarizability (alpha) are major factors governing temperature dependence of logK(OA). PCB molecules with low q(C)(-) values and more chlorines (big size or alpha) tend to have strong temperature dependence, due to intermolecular electrostatic interactions and dispersive forces, respectively.

Computer-assisted automatic peak recognition and result evaluation for analysis of chlorinated hydrocarbons in environmental samples.

A data manipulation method has been developed for automatic peak recognition and result evaluation in the analysis of organic chlorinated hydrocarbons with dual-column gas chromatography. Based on the retention times of two internal standards, pentachlorotoluene and decachlorobiphenyl, the retention times of chlorinated hydrocarbons can be calibrated automatically and accurately. It is very convenient to identify the peaks by comparing the retention times of samples with the calibrated retention times calculated from the relative retention indices of standards. Meanwhile, with a suggested two-step evaluation method the evaluation coefficients and the suitable quantitative results of each component can be automatically achieved for practical samples in an analytical system using two columns with different polarities and two internal standards.

Quantitative relationships between molecular structures, environmental temperatures and octanol-air partition coefficients of PCDD/Fs.

A concise quantitative model that incorporates information on both environmental temperature (T) and molecular structures, for logarithm of octanol-air partition coefficient (K(OA)) to base 10 (logK(OA)) of PCDDs, was developed. Partial least squares (PLS) analysis together with 14 quantum chemical descriptors were used to develop the quantitative relationships between structures, environmental temperatures and properties (QRSETP) model. It has been validated that the obtained QRSETP model can be used to predict logK(OA) of other PCDDs. Molecular size, environmental temperature (T), q+ (the most positive net atomic charge on hydrogen or chlorine atoms in PCDD molecules) and E(LUMO) (the energy of the lowest unoccupied molecular orbital) are main factors governing logK(OA) of PCDD/Fs under study. The intermolecular dispersive interactions and thus the size of the molecules play a leading role in governing logK(OA). The more chlorines in PCDD molecules, the greater the logK(OA) values. Increasing E(LUMO) values of the molecules leads to decreasing logK(OA) values, implying possible intermolecular interactions between the molecules under study and octanol molecules. Greater q+ values results in greater intermolecular electrostatic repulsive interactions between PCDD and octanol molecules and smaller logK(OA) values.

[Recognition and quantitative contrast characteristic components for root of Chinese angelica].

A method of multi-component quantitative analysis in root of Chinese Angelica has been developed. The analytical mode was reversed-phase HPLC with photodiode array detector. Based on comparison of UV spectra, a software of UV spectra database to assist recognition has been established. The solvent system, a gradient program of mobile phase with 2-propanol/acetonitrile/water can separate a lot of liposoluble components in root of Chinese Angelica. UV detection wavelength was set at 202 nm and the flow rate was 1 mL/min on a Hypersil ODS column. Twenty-three components in two roots of Chinese Angelica were recognized using characteristic parameters of chromatography and UV spectroscopy. It is the base of quantitative contrast to recognize many characteristic components without standard components in root of Chinese Angelica. For two samples of root of Chinese Angelica both have 23 characteristic components and the concentrations of some components were similar and those of others were different. The method is convenient and reproducible. It can be used for the quality control of the root of Chinese Angelica without the use of standards.

[Application of the quantitation with curve-fitting method on chiral separation by high performance liquid chromatography].

We propose for the first time that curve-fitting method should be applied to the quantitation of overlapping peaks in chiral separation by high performance liquid chromatography (HPLC). We have examined the separation of eight isomers of cyfluthrin on a chiral stationary phase (CSP), and found that in comparing with the perpendicular-drop method, the accuracy of quantitation of overlapping peaks with curve-fitting was much higher. Generally, errors in peak area measurement using the perpendicular-drop method become larger as the degree of peak overlap increases. Meanwhile, by using curve-fitting method errors have no apparent difference for different degrees of peak overlap. Generally, for the same chiral compounds, although the resolutions are different with different mobile phase strength, the results of peak areas are the same by using curve-fitting method.

A novel strategy for inhibiting growth of human pancreatic cancer cells by blocking cyclin-dependent kinase activity.

Pancreatic cancers frequently carry mutations in the K-ras, p53, and p16 genes, which regulate cell proliferation. Transition from G1 to S phase of the cell cycle requires activation of cyclin-dependent kinase 2 (Cdk2) which is inhibited by olomoucine and roscovitine. The purpose of this study was to determine whether olomoucine and roscovitine can block Cdk2 kinase activity and inhibit proliferation of four human pancreatic cancer cell lines with various genetic alterations. Human pancreatic carcinoma cell lines BxPC-3, PANC-1 Capan-2, and CAV were treated with olomoucine or roscovitine. Cdk2 kinase activity was determined using histone H1 as the substrate. Cell cycle distribution was analyzed by DNA flow cytometry. Cell numbers were quantitated by Coulter counter. Olomoucine and roscovitine blocked Cdk2 activity in all four pancreatic cancer cell lines. Both compounds also inhibited cell proliferation in a dose-dependent fashion. Roscovitine was at least threefold more potent than olomoucine for both Cdk2 activity and cell proliferation. We have shown that Cdk inhibitors, olomoucine and roscovitine, block proliferation of human pancreatic cancer cells regardless of their mutations in K-ras p53, or p16 genes. These compounds represent a novel therapeutic strategy with potential therapeutic benefits for pancreatic cancers.

Cyclin-dependent kinase inhibitors block proliferation of human gastric cancer cells.

BACKGROUND: Olomoucine and roscovitine are novel compounds that are designed to inhibit cyclin-dependent kinases (e.g., Cdk2 and cdc2). Cdks regulate progression through key checkpoints of the cell cycle. The purpose of this study was to determine (1) whether olomoucine and roscovitine inhibit Cdk2 and cdc2 kinase activities of the human gastric cancer cell line SIIA and (2) whether olomoucine and roscovitine block cell proliferation and cell cycle progression. METHODS: SIIA cells were treated with olomoucine or roscovitine and examined for Cdk2 and cdc2 activities by using histone H1 as the substrate. Cell numbers were counted with a Coulter counter. Cell cycle distribution was analyzed by DNA flow cytometry. RESULTS: Olomoucine and roscovitine completely blocked Cdk2 and cdc2 activities in SIIA cells. Both compounds were also able to inhibit proliferation of SIIA cells, as well as three other human gastric cancer cell lines (AGS, MKN45-630, and SNU-1). Cell cycle analysis showed that treatment with olomoucine or roscovitine for 24 hours led to a decrease in the S phase population and an increase in the G2/M population. CONCLUSIONS: We have shown that Cdk inhibitors, olomoucine and roscovitine, are a new class of antineoplastic molecules with potential therapeutic benefits for gastric cancers.