Combination of T-DM1 and platinum-based chemotherapy in patient-derived xenograft models of muscle-invasive bladder cancer.

Objectives: To assess the efficacy and safety of T-DM1, as an anti-HER2 antibody-drug conjugate (ADC), alone and in combination with two platinum-based chemotherapy regimens in patient-derived xenografts (PDXs) of muscle-invasive bladder cancer (MIBC) established in immunodeficient mice. Materials and Methods: After treatment initiation, tumor size was measured twice a week. Percent of tumor growth inhibition (TGI) and tumor response rates were calculated as efficacy endpoints. To evaluate treatment toxicity, relative body weight (RBW) was calculated for each group. For comparison of TGIs between treatment groups, the Kruskal-Wallis test was used. Also, the significance of the overall response (OR) rate between placebo groups with treatment groups was analyzed using Fisher's exact test. Immunohistochemistry and fluorescence in situ hybridization techniques were used to evaluate the level of HER2 expression. Results: Our data showed that T-DM1 alone induced a moderate antitumor activity. While chemotherapy regimens induced a slight TGI when administered alone, interestingly, they showed strong antitumor activity when administered combined with T-DM1. The OR rates were higher when T-DM1 was combined with chemotherapy regimens than T-DM1 alone. When compared with the placebo group, the OR rates of combination groups were statistically significant. Our data also showed that the administered dose of each drug was well tolerated in mice. Conclusion: The combination of T-DM1 and platinum-based chemotherapy may represent a new treatment option for bladder tumors with even low HER2 expression, and could also provide substantial novel insight into tackling the challenges of MIBC management.

Development and immunohistochemical characterization of patient-derived xenograft models for muscle invasive bladder cancer.

Objectives: Patient-derived xenograft (PDX) models have become a valuable tool to evaluate chemotherapeutics and investigate personalized cancer treatment options. The role of PDXs in the study of bladder cancer, especially for improvement of novel targeted therapies, continues to expand. In this study, we aimed to establish autochthonous PDX models of muscle-invasive bladder cancer (MIBC) to provide a useful tool to conduct research on personalized therapy. Materials and Methods: Tumors from MIBC patients undergoing radical cystectomy were subcutaneously transplanted into immunodeficient mice. The tumor size was measured by a caliper twice a week for up to five months. After the first growth in mice, they were serially passaged. Hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) of 11 markers (Ki67, P63, GATA3, KRT5/6, KRT20, E-cadherin, 34ßE12, PD-L1, EGFR, Nectin4, and HER2) were used to evaluate phenotype maintenance of original tumors. Results: From 10 MIBC patients, two PDX models (P8X20 and P8X26) were successfully established (20% success rate). These models mostly retained primary tumor characteristics including histology, morphology, and molecular nature of the original cancer tissues. IHC analysis showed that the expression level of 7 markers for the model P8X20, and 8 markers for the model P8X26 was exactly similar between the patient tumor and the next generations. Conclusion: We developed the first autochthonous PDX models of MIBC in Iran. Our data suggested that the established MIBC PDX models reserved mostly histopathological characteristics of primary cancer and could provide a new tool to evaluate novel biomarkers, therapeutic targets, and drug combinations.

Lifetime attributable risk of cancer incidence and mortality in routine digital radiology procedures.

PURPOSE: Digital radiography has the potential to improve the practice of radiography but it also has the potential to significantly increase patient doses. Considering rapidly growing digital radiography in many centers, concerns rise about increasing the collective dose of the human population and following health effects. This study aimed to estimate organ and effective doses and calculate the lifetime attributable risk (LAR) of cancer incidence and mortality in digital radiography procedures in Iran. METHODS: Organ and effective doses of 12 routine digital radiography examinations including the skull, cervical spine, chest, thoracic spine, lumbar spine, pelvic and abdomen were estimated using PCXMC software based on Monte Carlo simulation method. Then, LARs of cancer incidence and mortality were estimated using the BEIR VII method. RESULTS: Organ doses ranged from 0.01 to a maximum of 2.5 mGy while effective doses ranged from 0.01 to 0.7 mSv. Radiation risk showed dependence on the X-ray examination type and the patient's sex and age. In skull and cervical X-rays, the thyroid; in the chest and thoracic spine X-rays, the lung, and breast; and in the lumbar spine, pelvic and abdominal X-rays, the colon and bladder had the highest LAR of cancer incidence and mortality. Furthermore, younger patients and also females were at higher radiation risk. CONCLUSION: The lifetime attributable risk of cancer incidence and mortality due to radiation exposure is not trivial. Therefore efforts should be made to reduce patient doses while maintaining image quality.

Predicting chemotherapy-induced thrombocytopenia in cancer patients with solid tumors or lymphoma.

PURPOSE: Chemotherapy-induced thrombocytopenia is a serious complication in chemotherapy-treated patients. Identification of patients at risk for chemotherapy-induced thrombocytopenia could have clinical value in personalized management of patients and optimized administration of prophylactic thrombopoietic agents. The aim of this study was to develop a predictive model for chemotherapy-induced thrombocytopenia (platelet count < 100,000/µl) in cancer patients undergoing chemotherapy. METHODS: A total of 14 covariates were prospectively assessed as explanatory variables in a cohort of consecutive patients with solid tumors or lymphoma. A multivariable logistic regression model was developed after univariable analysis. A bootstrapping technique was applied for internal validation. RESULTS: Data from 305 patients during 1732 chemotherapy cycles were considered for analysis. Forty-eight patients (15.73%) developed chemotherapy-induced thrombocytopenia during their treatment course. The multivariable model exhibited three final predictors for chemotherapy-induced thrombocytopenia, including high ferritin (odds ratio, 4.41; bootstrap P = 0.001), estimated glomerular filtration rate <60 ml/min/1.73 m2 (odds ratio, 3.08; bootstrap P = 0.005), and body mass index <23 kg/m2 (odds ratio, 2.23; bootstrap P = 0.044). The main characteristics of the model include sensitivity 75%, specificity 65.4%, positive likelihood ratio 2.16, and negative likelihood ratio 0.382. Moreover, the model was well calibrated (Hosmer-Lemeshow P = 0.713) and the area under the receiver operating characteristic curve was 0.735 (95% confidence interval, 0.654-0.816; P < 0.001). CONCLUSIONS: We developed a predictive model for chemotherapy-induced thrombocytopenia based on readily available and easily assessable clinical and laboratory factors. This study may provide a valuable insight to guide optimized treatment of cancer patients. Further studies with larger sample size are warranted.

Enhanced cytotoxic and genotoxic effects of gadolinium-doped ZnO nanoparticles on irradiated lung cancer cells at megavoltage radiation energies.

The purpose of this study was to investigate the radiation dose enhancement effects of gadolinium-doped zinc oxide nanoparticles (Gd-doped ZnO NPs) under the megavoltage (MV) X-ray irradiation. ZnO NPs have preferred photocatalytic properties under UV light for cancer killing. UV light has limited applications in cancer treatment and it is necessary to use X-ray photons with MV energies. In order to increase the absorption of radiation and also to enhance the imaging visualization capabilities of ZnO NPs, gadolinium (Gd) as a high atomic number element was selected for doping into the structure of ZnO NPs. Gd-doped ZnO NPs were synthesized by a chemical precipitation method and characterized by transmission electron microscopy, powder X-ray diffraction, ultraviolet-visible spectroscopy, and energy-dispersive X-ray techniques. Cellular uptake was assessed by TEM and inductively coupled plasma mass spectrometry. NPs cytotoxicity was analyzed by MTT assay and radiation dose enhancement was measured by clonogenic survival assay. Apoptosis induction, cell cycle progression, micronucleus formation and expression of DNA double-strand break repair genes of XRCC2 and XRCC4 were determined by flow cytometry, micronucleus assay, and quantitative real-time polymerase chain reaction. CT and MR imaging were used to analyze the image visualization capabilities of NPs. NPs characterization showed that highly pure crystalline Gd-doped ZnO NPs with a narrow size distribution and grain size of 9 nm were synthesized. Gd-doped ZnO NPs were distributed in the cells and showed dose-dependent toxicity. Combination of Gd-doped ZnO NPs with 6 MV X-rays induced dose-dependent radiosensitivity with sensitizer enhancement ratios (SER) of 1.47 and 1.61 for 10 and 20 µg/mL NPs concentrations. Cancer cells blocked in G1, apoptosis rates, and micronuclei formation was enhanced and inversely, the DNA repair efficiency was impaired by down regulation of the mRNA levels of XRCC2 and XRCC4 genes. Gd-doped ZnO NPs enhanced the contrasts of CT and MR images of cancer cells. Overall, the results of this study provide detailed biological insights on the dose enhancement of Gd-doped ZnO NPs at MV radiations, which would contribute to the further development of this potent theranostic platform for clinical applications.