Internal cross-linked polymeric nanoparticles with dual sensitivity for combination therapy of muscle-invasive bladder cancer.

BACKGROUND: Chemotherapy is a standard cancer treatment which uses anti-cancer drugs to destroy or slow the growth of cancer cells. However, chemotherapy has limited therapeutic effects in bladder cancer. One of the reasons of this resistance to chemotherapy is that higher levels of glutathione in invasive bladder cancer cells. We have fabricated nanoparticles that respond to high concentrations of glutathione and near-infrared laser irradiation in order to increase the drug accumulation at the tumor sites and combine chemotherapy with photothermal therapy to overcome the challenges of bladder cancer treatment. METHODS: The DOX&IR780@PEG-PCL-SS NPs were prepared by co-precipitation method. We investigated the tumor targeting capability of NPs in vitro and in vivo. The orthotopic bladder cancer model in C57BL/6 mice was established for in vivo study and the photothermal effects and therapeutic efficacy of NPs were evaluated. RESULTS: The DOX&IR780@PEG-PCL-SS NPs were synthesized using internal cross-linking strategy to increase the stability of nanoparticles. Nanoparticles can be ingested by tumor cells in a short time. The DOX&IR780@PEG-PCL-SS NPs have dual sensitivity to high levels of glutathione in bladder cancer cells and near-infrared laser irradiation. Glutathione triggers chemical structural changes of nanoparticles and preliminarily releases drugs, Near-infrared laser irradiation can promote the complete release of the drugs from the nanoparticles and induce a photothermal effect, leading to destroying the tumor cells. Given the excellent tumor-targeting ability and negligible toxicity to normal tissue, DOX&IR780@PEG-PCL-SS NPs can greatly increase the concentration of the anti-cancer drugs in tumor cells. The mice treated with DOX&IR780@PEG-PCL-SS NPs have a significant reduction in tumor volume. The DOX&IR780@PEG-PCL-SS NPs can be tracked by in vivo imaging system and have good tumor targeting ability, to facilitate our assessment during the experiment. CONCLUSION: A nanoparticle delivery system with dual sensitivity to glutathione and near-infrared laser irradiation was developed for delivering IR780 and DOX. Chemo-photothermal synergistic therapy of both primary bladder cancer and their metastases was achieved using this advanced delivery system.

The Impact of Radiotherapy Facility Volume on the Survival and Guideline Concordance of Patients With Muscle-invasive Bladder Cancer Receiving Bladder-preservation Therapy.

OBJECTIVES: Higher facility surgical volume predicts for improved outcomes in patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy. We investigated the association between facility radiotherapy (RT) case volume and overall survival (OS) for patients with MIBC who received bladder-preserving RT, and the relationship with adherence to National Comprehensive Cancer Network (NCCN) guidelines for bladder preservation. METHODS: The National Cancer Database was used to identify patients diagnosed with nonmetastatic MIBC from 2004 to 2015 and received RT at the reporting center. Facility case volume was defined as the total MIBC patients treated with RT during the period. Facilities were stratified into high-volume facility (HVF) or low-volume facility at the 80th percentile of RT case volume. OS was assessed using Kaplan-Meier analysis. Rates of compliance with NCCN guidelines regarding the use of transurethral resection of the bladder tumor before RT, planned use of concurrent chemotherapy, and total RT dose were compared. Cox proportional hazard model was used to evaluate predictors of OS. RESULTS: There were 7562 patients included. No differences in age, Charlson-Deyo score, T stage, or node-positive rates were observed between groups. HVFs exhibited greater compliance with NCCN guidelines for bladder preservation (P<0.0001). Treatment at an HVF was associated with the improved OS for all patients (P=0.001) and for the subset of patients receiving NCCN-recommended RT doses (P=0.0081). Volume was an independent predictor of OS (P=0.002). CONCLUSIONS: Treatment at an HVF is associated with improved OS and greater guideline-concordant management among patients with MIBC.

Is hyperthermia combined with radiotherapy adequate in elderly patients with muscle-invasive bladder cancers? Thermo-radiobiological implications from an audit of initial results.

PURPOSE: The aim of this study was to evaluate the outcomes of loco-regional hyperthermia (HT) with radiotherapy (RT) and/or chemotherapy (CT) in elderly patients with muscle-invasive bladder cancers (MIBC). MATERIAL AND METHODS: Twenty consecutive MIBC patients were treated with HTRT (n = 8) or HTCTRT (n = 12) following transurethral resection of their bladder tumours. Weekly HT was administered prior to RT to a mean temperature of 40.6-42.7 °C for 60 min. A mean RT dose of 54.6 Gy (SD ± 4.2) was delivered. Single-agent cisplatin (n = 2) or carboplatin (n = 10) was used in HTCTRT patients. RESULTS: The median age was 81 years. HTRT patients received a mean RT dose of 51.0 Gy compared to 57.1 Gy with HTCTRT (p < 0.001) in a shorter overall treatment time (OTT) (30.8 ± 6.9 versus 43.9 ± 4.0 days, p < 0.001). All HTRT patients had long-term local disease control, while 41.6% of HTCTRT recurred during follow-up. None of the HTRT patients experienced grade III/IV acute and late toxicities, while these were evident in two and one HTCTRT patients respectively. Taken together, the 3-year bladder preservation, local disease-free survival, cause-specific survival and overall survival were 86.6%, 60.7%, 55% and 39.5% respectively. Even though the mean biological effective dose (BED) for both groups was similar (57.8 Gy15), the thermo-radiobiological BED estimated from HT-induced reduction of α/ß was significantly higher for HTRT patients (91 ± 4.4 versus 85.8 ± 4.3 Gy3, p = 0.018). CONCLUSIONS: Thermal radiosensitisation with consequent reduction in α/ß results in a higher thermo-radiobiological BED with a relatively higher RT dose/fraction and shorter OTT. This translates into a favourable outcome in elderly MIBC patients. Any benefit of CT in these patients needs further investigation.

Treatment options for muscle-invasive urothelial cancer for patients who were not eligible for cystectomy or neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin: report of Southwest Oncology Group Trial 8733.

BACKGROUND: Many patients with invasive urothelial cell cancer are poor candidates for cisplatin-based chemotherapy, and many are high risk for cystectomy. Southwest Oncology Group Trial 8733 was designed to address treatment for such patients. METHODS: Eligible patients had primary or recurrent muscle-invasive disease with transitional cell or squamous cell histology, a performance status from 0 to 2, no extrapelvic disease, a life expectancy >3 months, and adequate hematologic function. The treating clinician assigned patients to operable or inoperable groups. All patients received 2 cycles of 5-fluorouracil (5-FU) at a dose of 1000 mg/m(2) per day x 4 starting concurrently with radiation at a dose of 200 centigrays per day x 10 each cycle. After 2 cycles, operable patients with positive biopsies underwent cystectomy, and patients with negative biopsies received a third cycle of chemoradiotherapy. Patients in the inoperable group received 3 cycles without interim biopsy. RESULTS: Eighteen of 24 eligible patients in the operable group were evaluable for response. Five patients had a complete response (CR), 9 patients had stable disease, 1 patient had progressive disease, and 3 patients were not assessable. The median progression-free survival was 10 months (95% confidence interval [95% CI], 4-14 months), and the median overall survival was 18 months (95% CI, 7-28 months). In the inoperable group, 35 of 37 eligible patients were evaluable for response with 17 CRs (49%; 95% CI, 31%-66%). The median progression-free survival was 13 months (95% CI, 10-17 months), and the median overall survival was 20 months (95% CI, 11-53 months). There were no episodes of grade 4 toxicity. CONCLUSIONS: In the current study, the combination of 5-FU and radiation was found to be tolerated well by patients with numerous comorbidities who could not tolerate cisplatin-based therapy or cystectomy.

Pulsed 1064-nm Nd:YAG laser therapy for noninvasive treatment of a massive hemangioma: case report.

OBJECTIVE: The author determined whether cutaneous Nd:YAG laser therapy is a viable treatment option for a massive hemangioma located in the musculus soleus muscle of a patient's left leg. SUMMARY BACKGROUND DATA: Giant hemangiomas generally require aggressive medical or surgical therapy to address complications. Because of the size of the lesions, there are risks inherent with conventional treatment options. In selected patients, Nd:YAG laser therapy is a noninvasive approach to treating large, subcutaneous hemangiomas. METHODS: A 59-year-old female patient, who was diagnosed with a large, venous-type hemangioma in the musculus soleus muscle of the left leg, was treated during two treatment sessions with Nd:YAG laser therapy. A Plexiglas ring was placed on the leg, over the hemangioma, to force the hemangioma closer to the surface and laser irradiation was applied to the skin. RESULTS: At 6-month follow-up after the second treatment, magnetic resonance imaging (MRI) demonstrated 75%-80% reduction in lesion size. There were no permanent adverse effects encountered with the treatment method. CONCLUSIONS: The author concludes that in carefully selected cases Nd:YAG laser therapy can be used to treat large hemangiomas whose size poses risks with surgical and other treatments.

Enhancement of radiation effect by Ginkgo biloba extract in C3H mouse fibrosarcoma.

BACKGROUND AND PURPOSE: Ginkgo biloba leaf extract (GBE) is known to increase peripheral blood circulation. The hypothesis that GBE may be able to enhance radiosensitivity of tumor by improving tumor blood flow and thus decreasing hypoxic fraction was tested. MATERIALS AND METHODS: Fibrosarcoma (FSaII) growing in C3H mouse leg muscle was used as a tumor model. GBE was given i.p. 1 h before irradiation with or without priming dose given 1 day earlier. Effect on tumor and normal tissue radiation reaction was investigated. RESULTS: Tumor growth delay by radiation was more elongated after two doses (1-day interval) of GBE than after a single dose. Radiation dose for 3-day tumor growth delay was decreased from 12.45 (10.97-13.93) Gy to 6.06 (3.89-8.22) Gy by two doses of GBE [enhancement ratio = 2.06 (1.32-2.79)]. Hypoxic cell fraction was 10.6% (6.3-18.2%) for control, 7.2% (3.8-14.0%) after a single dose (P = 0.18) and 2.7% (1.5-5.0%) after two doses (P < 0.001). Radiation effect on normal tissue, estimated by acute skin reaction and jejunal crypt assay, was not affected by GBE. CONCLUSION: Ginkgo biloba extract enhances radiation effect on tumor without increasing acute normal tissue radiation damage in this model system probably by increasing tumor blood flow and further investigation for this possible radiosensitizer is needed.