[Clinical tolerability and pharmacokinetics of troxacitabine].

Objective: To investigate the safety and efficacy of troxatabine in advanced or relapsed malignant tumors resistant to standard therapy in China. Methods: This is a phase Ⅰ prospective study. During dose escalation, patients in Cancer Hospital, Chinese Academy of Medical Sciences received a single-dose intravenous infusion of troxacitabine. The planned dosing groups were 1.8, 3.6, 4.8, 6.4 and 8.0 mg/m(2) on days 1 and 8 every 3 weeks. The data of all patients were collected for safety analyses. Safety and tolerability were evaluated by monitoring adverse events. Results: Nineteen patients were enrolled from April 2018 to May 2019. The major adverse events were fatigue (89.5%, 17/19), leukopenia (84.2%, 16/19) and neutropenia (78.9%, 15/19). The dose limiting toxicity was neutropenia. The maximum tolerated dose was 6.4 mg/m(2). The best effect was stable disease (43.8%). The half-life of elimination phase from 15.91 hours to 76.63 hours in each dose group. Conclusions: The toxicity of troxacitabine is well tolerant. We recommend that the dose for Phase Ⅱ clinical trial should be 6.4 mg/m(2).

Breast ductal carcinoma in situ with micro-invasion versus ductal carcinoma in situ: a comparative analysis of clinicopathological and mammographic findings.

AIM: To determine the differences in clinicopathological and mammographic findings between ductal carcinoma in situ (DCIS) and ductal carcinoma in situ with micro-invasion (DCIS-MI) and explore clinicopathological and mammographic factors associated with DCIS-MI. MATERIALS AND METHODS: All DCIS patients with or without micro-invasion who underwent preoperative mammography at The Affiliated Hospital of Qingdao University from January 2016 through June 2020 were identified retrospectively. The correlations of clinicopathological findings with DCIS-MI were evaluated using univariate and multivariate binary logistic regression analyses. Imaging findings were compared between the groups by using the Pearson chi-square test. RESULTS: A total of 445 DCIS lesions and 151 DCIS-MI lesions were included in the final analysis. Large extent (≥2.7 cm), high nuclear grade, comedo-type, negative progesterone receptor (PR), negative oestrogen receptor (ER), high Ki-67 and axillary lymph node metastasis were more frequently found in DCIS-MI than in DCIS (all p<0.05), and the first four of these were found to be independent predictors of DCIS-MI in the multivariate analysis (all p<0.05). Regarding imaging findings, compared to DCIS, DCIS-MI showed fewer occult lesions and more lesions with calcifications in mass, asymmetry, and architectural distortion (p=0.004). Grouped calcifications were usually associated with DCIS, while regional calcifications were commonly found in DCIS-MI (p<0.05). CONCLUSION: Large extent, high nuclear grade, comedo-type and negative PR were found to be independent predictors of DCIS-MI. Lesions with calcifications and regional calcifications were more likely associated with DCIS-MI on mammography.

[Long term follow-up results of anlotinib in the treatment of advanced renal cell carcinoma].

Objective: Anlotinib is an oral multi-target tyrosine kinase inhibitor (TKI) with dual effects of anti-proliferation and anti-angiogenesis. Phase Ⅰ clinical trials showed anlotinib was well tolerated and had therapeutic effects on a variety of tumors. The aim of this study is to explore the safety and efficacy of anlotinib in the treatment of metastatic renal cell carcinoma. Methods: Between January 2014 and November 2015, a single-center data was obtained from a phase Ⅱ clinical study of anlotinib versus sunitinib on advanced renal cell carcinoma and a phase Ⅱ clinical study of anlotinib on advanced renal cell carcinoma which failed to respond to TKI treatment. Kaplan-Meier method was used for survival analysis, while Log-rank test was used to compare the survival rates. Results: A total of 36 patients with advanced renal cell carcinoma were enrolled in this study, including 19 patients without any target drug treatment, 12 patients with sunitinib treatment and 5 patients with sorafenib treatment. The median number of treatment cycle was 16. Partial response (PR) was obtained in 11 patients (30.6%) and stable disease (SD) was obtained in 24 patients (66.7%). The disease control rate (DCR) was 97.2%. The median progression free survival (PFS) was 12.6 months, the 1-year survival rate was 80.6%, and the median survival time was 22.2 months. Up to the follow-up deadline, 3 patients still received treatment, the PFSs were 52.6 months, 65.0 months, and 66.7 months. The most common treatment-related adverse events of grade 3 or 4 included hypertension (19.4%), hand-foot skin reaction (11.1%), proteinuria (5.6%) and anemia (5.6%). Conclusions: Anlotinib shows good anti-tumor activity and is generally well-tolerated in the treatment of advanced renal cell carcinoma. The adverse reactions of anlotinib are milder than sunitinib or pazopanib.

[Analysis of metastatic colorectal cancer patients treated with regorafenib in real-world practice].

Objective: To evaluate the dose, efficacy and tolerability of regorafenib in a real-world clinical setting of metastatic colorectal cancer patients. Methods: The clinical data of patients with metastatic colorectal cancer who had received at least two previous treatment lines treated with regorafenib from May 2018 to December 2019 at National Cancer Center/Cancer Hospital was retrospectively analyzed. Patients'demographics, treatment, dosimetry, safety and survival data were collected. The primary endpoint was overall survival (OS). Results: A total of 114 patients were enrolled in this study, including male 83 and female 31, with a median age of 61.Of all patients, 83 were treated with regorafenib and 31 were given combination therapy with regorafenib. Starting dose was 80 mg in 57 (50.0%) patients, 120 mg in 24 (21.1%) patients, and 160 mg in 28 (24.6%) patients. Dose increases were observed in 30.9% (25/81) of patients receiving 80 mg and 120 mg as the initial dose. Forty-five (39.5%) and 36 (31.6%) patients took the last daily dose of 80 mg and 120 mg, respectively. Median follow-up time was 8.5 months.Objective response rate (ORR) and disease control rate(DCR) were 1.0% and 52.1%, respectively. The median progression free survivalrate (PFS) was 2.4 moths (95%CI: 0.80-10.57), median OS was 11.0 moths(95%CI: 9.03-not available). The difference of the PFS and OS in the different dose groups was not statistically significant. But patients who received 120 mg regorafenib showed much longer survival with a median OS of 16.7 month. The difference of survival between the regorafenib group and combination group was not statistically significant either. Twenty patients continued with regorafenib as treatment even after progression. These patients had longer survival compared with those (n=52) who stopped regorafenib with median OS of 16.7 month vs 9.1 month (χ(2)=2.305, P=0.116), respectively.There were 7.9%(9/114) of the patients who discontinued regorafenib therapy because of the adverse event, such as hand-foot skin reaction (HFSR), gastrointestinal bleeding, proteinuria and liver function injury. Conclusions: Patients with advanced colorectal cancer who failed to respond to standard therapy have a good survival benefit. The initial dose of 120 mg of regorafenib has a better risk/benefit ratio and is more suitable for patients with advanced colorectal cancer.

[Carcinogenicity study of CD133(+)CD44(+) laryngeal cancer stem cells and identification of related microRNAs].

Objective: To compare the carcinogenic abilities of CD133(+)CD44(+) laryngeal cancer stem cells and general laryngeal cancer stem cells and to identify the mechanism underlying the action of miRNAs. Methods: Solid tumor-derived laryngeal carcinoma stem cells and Hep-2-derived laryngeal carcinoma stem cells were cultured, and CD133(+)CD44(+) laryngeal cancer stem cells were sorted by flow cytometry. Boden chamber invasion assay, cell migration assay and tumor formation assay were then performed to compare the invasion, migration and tumorigenic abilities of CD133(+)CD44(+) laryngeal cancer stem cells and general laryngeal cancer stem cells. And then, miRNAs isolated from two laryngeal cancer stem cells were detected and analysed with miRNA chip. Results: (1)In Boyden chamber invasion assay, the cell invasion rate of CD133(+)CD44(+) laryngeal cancer stem cells was obviously higher (80.2%±2.3% vs. 63.9%±3.2%, t=5.011, P=0.027); (2)CD133(+)CD44(+) laryngeal cancer stem cells also had higher mobility in cell migration assay (82.9%±1.1% vs. 70.9%±0.6%, t=4.514, P=0.031); (3)In tumor formation assay, the tumor formation rate of CD133(+)CD44(+) laryngeal cancer stem cells was also higher (80% vs. 50%). What's more, we identified 15 miRNAs that were significantly upregulated in CD133(+)CD44(+) laryngeal cancer stem cells and 3 miRNAs that were significantly downregulated in CD133(+)CD44(+) laryngeal cancer stem cells, compared with normal laryngeal cancer stem cells. Conclusions: CD133(+)CD44(+) laryngeal cancer stem cells have stronger invasion, migration and tumorigenic abilities compared with normal laryngeal cancer stem cells, and the difference of miRNAs' expression is one of the possible causes.

[Biweekly paclitaxel and platinum chemotherapy followed by surgery for esophageal squamous cell carcinoma].

Objective: To evaluate the feasibility and efficacy of biweekly paclitaxel and platinum chemotherapy followed by surgery for esophageal squamous cell carcinoma. Methods: We retrospectively analyzed the clinicopathological data of 20 patients with esophageal squamous cell carcinoma treated in our hospital between January 2012 and March 2016. All patients received biweekly paclitaxel and platinum chemotherapy followed by surgery. Results: 20 cases received preoperative chemotherapy for 3-8 cycles with an average of 4 cycles. The main chemotherapy-related adverse events were bone marrow suppression (18/20, 90.0%), followed by vomiting and nausea (10/20, 50.0%). Five patients (25.0%) had grade 4 neutropenia and all toxicities were torlerable and manageable. After chemotherapy, all patients received surgery. The histological responses in the primary tumors were grade 1 in 13 (65.0%) patients, grade 2 in 7 (35.0%) patients, and grade 3 in 0 (0%) patient. None had disease progression. Downstaging of T-stage was observed in 5 cases (25.0%) after chemotherapy. Among them, 4 cases were with moderate histologicl responses and one case with mild histological response. The incidence of postoperative complications was 25.0%(5/20), and the complications were improved following symptomatic treatments. There was no treatment-related death. Conclusions: Biweekly paclitaxel and platinum chemotherapy followed by surgery for esophageal squamous cell carcinoma is safe and effective. Further randomized clinical trial should be conducted to assess the value of this therapeutic regimen in the preoperative chemotherapy for esophageal cancer.

[Association between hand-foot skin reaction and effectiveness of vascular endothelial growth factor receptor tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma].

Objective: To investigate the association between hand-foot skin reaction (HFSR) in the treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) and the effectiveness of VEGFR-TKIs. Methods: Clinical data of 155 patients with metastatic renal cell carcinoma (mRCC) treated with VEGFR-TKIs at the Cancer Hospital of Chinese Academy of Medical Sciences between January 2006 and January 2014 were retrospectively analyzed. All the patients received first-line VEGFR-TKI therapy. The treatment effectiveness and outcome between patients developing HFSR and those without HFSR were compared. Comparison of treatment response rate (RR) was performed with χ2 test, survival analysis was performed using Kaplan-Meier method, with a significance level of 0.05. Results: The median survival of all the 155 patients was 36.2 months. Among the 117 (75.5%) patients who developed HFSR, 19 patients (12.3%) had grade Ⅰ HFSR, 73 (47.1%) had grade Ⅱ, and 25 (16.1%) had grade Ⅲ; there were no grade Ⅳ events. The RR and median progression-free survival (mPFS) in patients who did not develop HFSR were 15.8% and 6.7 months, respectively; while the RR and mPFS in patients who developed HFSR were 52.1% and 13.8 months, respectively (P<0.001, P=0.002). The RR and mPFS in patients with grade Ⅰ HFSR were 42.1% and 9.5 months, respectively; those in patients with grade Ⅱ HFSR were 56.2% and 12.2 months, respectively, in patients with grade Ⅲ were 48.0% and 22.2 months, respectively, with statistically significant differences among the three grades of HFSR (P=0.001, 0.009). Conclusions: HFSR might be an effective predictor for effectiveness of VEGFR-TKIs in mRCC patients. Large-sample studies are warranted to further prove these results.

[Relationship between treatment-related hypertension and therapeutic efficacy of vascular endothelial growth factor receptor tyrosine kinase inhibitors in metastatic renal cell carcinoma].

OBJECTIVE: Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) are widely used for the treatment of metastatic renal cell carcinoma (mRCC). The aim of this study was to investigate the association between treatment-related hypertension and the therapeutic efficacy of VEGFR-TKIs. METHODS: Clinical data of 155 mRCC patients treated with VEGFR-TKIs at the Cancer Hospital of Chinese Academy of Medical Sciences from 2006 to 2014 were retrospectively analyzed. All patients received first-line TKI therapy. Among them, 69 patients were treated with sunitinib, 14 cases with pazopanib, and 51 cases with fazotinib. Kaplan-Meier curves were used to evaluate the survival of the patients. RESULTS: The median survival for the whole group (n=155) was 36.2 months. Among the 98 (63.2%) patients who developed hypertension, 9 patients (5.8%) were evaluated as grade Ⅰ, 54 (34.8%) as grade Ⅱ and 35 (22.6%) as grade Ⅲ, and there was no patient with grade Ⅳ hypertension. The occurrence of TKI-related hypertension was correlated with age and MSKCC score (P<0.05), while not significantly correlated with gender, nephrectomy, T stage, number of metastases, lung metastasis or sunitinib treatment (P>0.05 for all). For the whole group (n=155), the therapeutic efficacy rate was 43.2% (67/155), the median progression-free survival (PFS) was 12.0 months, and the median overall survival (OS) was 36.2 months. The response rate (RR) was 26.3% (15/57) in patients with normal blood pressure and 53.1% (52/98) in patients with hypertension (P=0.001). The median PFS was 7.1 months in the cases with normal blood pressure and 13.8 months in patients with hypertension (P=0.032). The response rates were 33.3% (3/9), 51.9% (28/54) and 60.0% (21/35) in patients with grade Ⅰ, Ⅱ and Ⅲ hypertension (P=0.006). The median PFS was 7.1, 9.7, and 12.0 and 19.5 months in patients with normal blood pressure, and patients with grade Ⅰ, Ⅱ and Ⅲ hypertension, respectively (P=0.039). Both univariant and multivariant analyses indicated that treatment-related hypertension is an important predictive factor for the efficacy of VEGFR-TKIs therapy. CONCLUSIONS: Hypertension might be an effective predictive factor for efficacy of VEGFR-TKIs therapy in mRCC patients. Large-sample studies are warranted to further prove these results.

Microstructure and antibacterial property of in situ TiO(2) nanotube layers/titanium biocomposites.

The TiO(2) nanotube layer was in situ synthesized on the surface of pure titanium by the electrochemical anodic oxidation. The diameter of nano- TiO(2) nanotubes was about 70~100 nm. The surface morphology and phase compositions of TiO(2) nanotube layers were observed and analyzed using the scanning electron microscope (SEM). The important processing parameters, including anodizing voltage, reaction time, concentration of electrolyte, were optimized in more detail. The photocatalytic activity of the nano- TiO(2) nanotube layers prepared with optimal conditions was evaluated via the photodegradation of methylthionine in aqueous solution. The antibacterial property of TiO(2) nanotube layers prepared with optimal conditions was evaluated by inoculating Streptococcus mutans on the TiO(2) nanotube layers in vitro. The results showed that TiO(2) nanotube layers/Ti biocomposites had very good antibacterial activity to resist Streptococcus mutans. As a dental implant biomaterial, in situ TiO(2) nanotube layer/Ti biocomposite has better and wider application prospects.

Quantum-dot growth simulation on periodic stress of substrate.

InAs quantum dots (QDs) are grown on the cleaved edge of an In(x)Ga(1-x)AsGaAs supperlattice experimentally and a good linear alignment of these QDs on the surface of an In(x)Ga(1-x)As layer has been realized. The modulation effects of periodic strain on the substrate are investigated theoretically using a kinetic Monte Carlo method. Our results show that a good alignment of QDs can be achieved when the strain energy reaches 2% of the atomic binding energy. The simulation results are in excellent qualitative agreement with our experiments.