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.

Modified Glasgow prognostic score can predict survival of muscle invasive bladder cancer patients after radiotherapy.

In patients with various cancers, modified Glasgow prognostic score (mGPS) before treatment has predicted prognoses after antitumor therapy. This study aimed to assess whether pretreatment mGPS also has predictive value in patients with muscle-invasive bladder cancer (MIBC) after radiotherapy. A retrospective review accumulated 98 consecutive MIBC patients treated with definitive 3D-conformal radiotherapy from January 2011 to December 2016 in a single center. It included cT2-4bN0-3M0 patients with a median age of 79 years (range: 49 to 95 years). Radiotherapy was delivered at 60-66 Gy for bladder cancer. Patients were categorized in terms of their pretreatment serum albumin and C-reactive protein (CRP) values as mGPS_0, mGPS_1, and mGPS_2. Among them, cumulative overall survival (OS) rates were compared by Kaplan-Meier plots with log-rank tests. The number of patients with mGPS_0, mGPS_1, and mGPS_2 were 40, 40, and 18, respectively. The median follow-up time for all patients was 19 months (range: 2-73 months). The 2-year OS rate for all patients was 75.7%. The 2-year OS rates for mGPS_0, mGPS_1, and mGPS_2 were 85.1%, 71.3%, and 60.9%, respectively. Kaplan-Meier curves revealed a significantly higher cumulative OS rate for mGPS_0 compared with mGPS_1 and mGPS_2 (P = 0.003). Using multivariate Cox regression analysis, mGPS_0 and good performance status were associated with favorable OS rates, of which mGPS_0 was more significant (Hazard ratio 2.74, 95% CI 1.30-5.57, P = 0.008). Modified Glasgow prognostic score may be a novel biomarker that can predict survival in patients with MIBC after radiotherapy.

BioXmark® liquid fiducial markers for image-guided radiotherapy in muscle invasive bladder cancer: a safety and performance trial.

OBJECTIVE: This study evaluated the performance of the novel liquid fiducial marker (BioXmark®) in IGRT for bladder cancer. METHODS: 20 patients with muscle invasive bladder cancer were entered in this prospective, single center, Phase I-II study. The novel BioXmark® liquid markers were injected around the tumor using a flexible cystoscopy. Visibility and stability of the markers were evaluated on planning-CT and CBCT. Prospectively defined threshold for success was set at a visibility of 75%. RESULTS: In total, 76 markers were implanted in 20 patients. Of those, 60 (79% 95% CI ± 9%) were visible on CT scan. Due to the learning curve of the technique, the visibility improved in the last 75% of patients (86% visibility) compared to the first 25% of patients with 58% visibility. Concerning stability of the BioXmark® marker, all visible markers after CT acquisition were still detectable at the last CBCT without displacement. In 15/20 (75%) of the patients, three or more markers were visible on CT. No BioXmark® related adverse events were reported. CONCLUSION: The success rate of this novel fiducial marker was 79%, which is above the prospectively defined threshold rate. A distinct learning curve of the injection of the liquid marker was seen over the study period. The marker showed sustained visibility and positional stability during treatment phases and also appears to be safe and easy to inject. ADVANCES IN KNOWLEDGE: This novel liquid BioXmark® marker seems to be a very promising tool in daily-adaptive IGRT for bladder preserving chemoradiotherapy in muscle invasive bladder cancer.

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.

Survival after radiotherapy versus radical cystectomy for primary muscle-invasive bladder cancer: A Swedish nationwide population-based cohort study.

BACKGROUND: Studies of survival comparing radical cystectomy (RC) and radiotherapy for muscle-invasive bladder cancer have provided inconsistent results and have methodological limitations. The aim of the study was to investigate risk of death after radiotherapy as compared to RC. METHODS: We selected patients with muscle-invasive urothelial carcinoma without distant metastases, treated with radiotherapy or RC from 1997 to 2014 in the Bladder Cancer Data Base Sweden (BladderBaSe) and estimated absolute and relative risk of bladder cancer death and all-cause death. In a group of patients, theoretically eligible for a trial comparing radiotherapy and RC, we calculated risk difference in an instrumental variable analysis. We have not investigated chemoradiotherapy as this treatment was not used in the study time period. RESULTS: The study included 3 309 patients, of those 17% were treated with radiotherapy and 83% with RC. Patients treated with radiotherapy were older, had more advanced comorbidity, and had a higher risk of death as compared to patients treated with RC (relative risks of 1.5-1.6). In the "trial population," all-cause death risk difference was 6 per 100 patients lower after radiotherapy at 5 years of follow-up, 95% confidence interval -41 to 29. CONCLUSION(S): Patient selection between the treatments make it difficult to evaluate results from conventionally adjusted and propensity-score matched survival analysis. When taking into account unmeasured confounding by instrumental variable analysis, no differences in survival was found between the treatments for a selected group of patients. Further clinical studies are needed to characterize this group of patients, which can serve as a basis for future comparison studies for treatment recommendations.

Risk factors for loco-regional recurrence after radical cystectomy of muscle-invasive bladder cancer: A systematic-review and framework for adjuvant radiotherapy.

BACKGROUND: Radical cystectomy (RC) associated with pelvic lymph node dissection (PLND) is the most common local therapy in the management of non-metastatic muscle invasive bladder cancer (MIBC). Loco-regional recurrence (LRR), however, remains a common and important therapeutic challenge associated with poor oncologic outcomes. We aimed to systematically review evidence regarding factors associated with LRR and to propose a framework for adjuvant radiotherapy (RT) in patients with MIBC. METHODS: We performed this systematic review in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. We searched the PubMed database for articles related to MIBC and associated treatments, published between January 1980 and June 2015. Articles identified by searching references from candidate articles were also included. We retrieved 1383 publications from PubMed and 34 from other sources. After an initial screening, a review of titles and abstracts, and a final comprehensive full text analysis of papers assessed for eligibility, a final consensus on 32 studies was obtained. RESULTS: LRR is associated with specific patient-, tumor-, center- or treatment-related variables. LRR varies widely, occurring in as many as 43% of the cases and is strongly related to survival outcomes. While perioperative treatment does not impact on LRR, pathological factors such as pT, pN, positive margins status, extent of PLND, number of lymph nodes removed and/or invaded are correlated with LRR. Patients with pT3-T4a and/or positive lymph-nodes and/or limited pelvic lymph-node dissection and/or positive surgical margins have been distributed in LRR risk groups with accuracy. CONCLUSIONS: LRR patterns are well-known and for selected patients, adjuvant treatments could target this event. Intrinsic tumor subtype may guide future criteria to define a personalized treatment strategy. Prospective trials evaluating safety and efficacy of adjuvant RT are ongoing in several countries.

Vulvar Melanoma with Isolated Metastasis to the Extraocular Muscles: Case Report and Brief Literature Review.

BACKGROUND/AIM: Orbital metastasis of systemic cancer is exceedingly rare. This is a case report of a patient treated for locally recurrent vulvar melanoma who later presented with unilateral proptosis and was found to have an isolated biopsy-proven extraocular muscle metastasis. PATIENTS AND METHODS: A 94-year-old female with locally recurrent vulvar melanoma presented with eye discomfort and blurry vision. Patient underwent histopathological, genetic, and imaging studies. RESULTS: All prior work-up, including brain MRI and PET/CT, was negative for disease elsewhere from local recurrence. Orbital MRI demonstrated a mass involving the extraocular muscle, and immunohistochemistry staining of biopsy was consistent with metastasis. The patient underwent radiation therapy and tolerated treatment well. CONCLUSION: This is the first reported case of vulvar melanoma with extraocular muscle metastasis. The absence of findings on imaging as part of the staging work-up underscores the importance of considering extraocular muscle (EOM) metastasis as a differential for patients with vulvar melanoma who present with proptosis.

Kilovoltage radiotherapy for companion animals: dosimetric comparison of 300 kV, 450 kV, and 6 MV X-ray beams.

Radiotherapy for the treatment of cancer in companion animals is currently administered by using megavoltage X-ray machines. Because these machines are expensive, most animal hospitals do not perform radiotherapy. This study evaluated the ability of relatively inexpensive kilovoltage X-ray machines to treat companion animals. A simulation study based on a commercial treatment-planning system was performed for tumors of the brain (non-infectious meningoencephalitis), nasal cavity (malignant nasal tumors), forefoot (malignant muscular tumors), and abdomen (malignant intestinal tumors). The results of kilovoltage (300 kV and 450 kV) and megavoltage (6 MV) X-ray beams were compared. Whereas the 300 kV and 6 MV X-ray beams provided optimal radiation dose homogeneity and conformity, respectively, for brain tumors, the 6 MV X-rays provided optimal homogeneity and radiation conformity for nasal cavity, forefoot, and abdominal tumors. Although megavoltage X-ray beams provided better radiation dose distribution in most treated animals, the differences between megavoltage and kilovoltage X-ray beams were relatively small. The similar therapeutic effects of the kilovoltage and 6 MV X-ray beams suggest that kilovoltage X-ray beams may be effective alternatives to megavoltage X-ray beams in treating cancers in companion animals.

Propensity matched comparative analysis of survival following chemoradiation or radical cystectomy for muscle-invasive bladder cancer.

OBJECTIVE: To compare survival outcome between chemoradiation therapy (CRT) and radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: We conducted a retrospective analysis of patients with MIBC (≥cT2, N0, M0) in the National Cancer Database (2004-2013). CRT was defined as a radiation dose of ≥40 Gy and chemotherapy within 90 days of radiation. Descriptive statistics were used to compare groups. RC and CRT patients were propensity matched. Kaplan-Meier analysis was used to compare overall survival (OS). Multivariable Cox regression was used to determine predictors of survival. RESULTS: In all, 8 379 (6 606 RC and 1 773 CRT) patients met the inclusion criteria and 1 683 patients in each group were propensity matched. On multivariable extended Cox analysis, significant predictors of decreased OS were age, Charlson-Deyo Comorbidity score of 1, Charlson-Deyo Comorbidity score of 2, stage cT3-4, and urothelial histology. CRT was associated with decreased mortality at year 1 (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.74-0.96; P = 0.01), but at 2 years (HR 1.4, 95% CI 1.2-1.6; P < 0.001) and 3 years onward (HR 1.5, 95% CI 1.2-1.8; P < 0.001) CRT was associated with increased mortality. The 5-year OS was greater for RC than for CRT (38% vs 30%, P = 0.004). CONCLUSIONS: Initially after treatment for MIBC the risk of mortality is lower with CRT compared to RC. However, at ≥2 years after treatment the mortality risk favours RC. Patients who are suitable surgical candidates, with a low risk of morbidity, may be better served by RC.

Curative radiation therapy for very elderly bladder cancer patients with localized disease.

PURPOSE: To report the outcomes of a cohort of very elderly muscle-invasive bladder cancer (MIBC) patients treated with contemporary 3D-conformal radiation therapy (3D-CRT) with or without concurrent chemotherapy, after transurethral resection of bladder tumor (TURBT). METHODS: From February 2010 to January 2014, a total of 41 patients older than 75 years, with T2-3 N0-1 high-grade MIBC, a Karnofsky index (KI) of at least 90% and/or a Barthel scale score of at least 95, were treated with TURBT followed by radiotherapy (RT) with or without chemotherapy, and were prospectively followed-up. RESULTS: The mean age of patients was 82 years (range 76-88). Median follow-up was 47 months for surviving patients. Mean Charlson Comorbidity Index (CCI) score was 5 points. 28 patients (68.29%) were T2N0. All received 3D-CRT to a mean dose of 60 Gy (range 48.6-66 Gy), and chemotherapy was delivered to 34 patients (83%). Cause-specific survival (CSS) was 86 and 78.8% at 1 and 5 years, respectively. Patients achieving a complete response lived longer (48 vs 14 m, p = 0.036) than those with a progressive disease, who were more likely to die from cancer than from other causes (HR 3.865, IC95% 1.562-9.562). Dead patients had a longest treatment time (mean 56.78 vs 48.91 days, p = 0.019) than survivors. CONCLUSION: RT with contemporary 3D-CRT techniques after TURBT for MIBC in elderly patients is feasible and well-tolerated. Achieving a maximal response and shortening the total radiation treatment time may improve outcomes and quality of life.

Solitary biceps muscle metastasis from breast cancer.

Although direct muscle invasion by carcinoma is well recognised, skeletal muscle metastases are rare. Breast cancer very rarely metastasises to skeletal muscles. We present a case of breast cancer that metastasised to the biceps muscle. The woman developed breast cancer in 1990 and then developed axillary subcutaneous metastasis in 2001. In 2015, she presented with pain in the left forearm extending to the hand. Initial imaging showed no abnormalities, but the positron emission tomography-CT scanning revealed a hot spot in the left biceps muscle. Additionally, the nerve conduction study showed feature of carpal tunnel syndrome. The hot spot was deemed inconclusive in the view of normal CT and MRI scans, and the patient was treated with carpal tunnel decompression. A few months later, the patient developed a lump in the left biceps muscle, which appeared to be a metastatic lesion from her primary breast cancer. The patient was treated with radiotherapy and responded satisfactorily.

Electron Paramagnetic Resonance pO2 Image Tumor Oxygen-Guided Radiation Therapy Optimization.

Modern standards for radiation treatment do not take into account tumor oxygenation for radiation treatment planning. Strong correlation between tumor oxygenation and radiation treatment success suggests that oxygen-guided radiation therapy (OGRT) may be a promising enhancement of cancer radiation treatment. We have developed an OGRT protocol for rodents. Electron paramagnetic resonance (EPR) imaging is used for recording oxygen maps with high spatial resolution and excellent accuracy better than 1 torr. Radiation is delivered with an animal intensity modulated radiation therapy (IMRT) XRAD225Cx micro-CT/ therapy system. The radiation plan is delivered in two steps. First, a uniform 15% tumor control dose (TCD15) is delivered to the whole tumor. In the second step, an additional booster dose amounting to the difference between TCD98 and TCD15 is delivered to radio-resistant, hypoxic tumor regions. Delivery of the booster dose is performed using a multiport conformal beam protocol. For radiation beam shaping we used individual radiation blocks 3D-printed from tungsten infused ABS polymer. Calculation of beam geometry and the production of blocks is performed next to the EPR imager, immediately after oxygen imaging. Preliminary results demonstrate the sub-millimeter precision of the radiation delivery and high dose accuracy. The efficacy of the radiation treatment is currently being tested on syngeneic FSa fibrosarcoma tumors grown in the legs of C3H mice.

Extramedullary plasmacytoma of the lateral rectus muscle.

Plasmacytoma is an uncommon presentation of plasma cell malignancy, especially in the absence of multiple myeloma. Orbital plasmacytomas generally originate from bone, although few cases in the literature report orbital extramedullary plasmacytomas. We present the case of a 68-year-old man found to have a solitary extramedullary plasmacytoma in the lateral rectus muscle without further evidence of multiple myeloma. This case demonstrates a rare presentation for such a malignancy, and a review of the literature highlights the importance of proper workup and close monitoring to rule out multiple myeloma to guide management.

Cavity theory applications for kilovoltage cellular dosimetry.

Relationships between macroscopic (bulk tissue) and microscopic (cellular) dose descriptors are investigated using cavity theory and Monte Carlo (MC) simulations. Small, large, and multiple intermediate cavity theory (SCT, LCT, and ICT, respectively) approaches are considered for 20 to 370 keV incident photons; ICT is a sum of SCT and LCT contributions weighted by parameter d. Considering µm-sized cavities of water in bulk tissue phantoms, different cavity theory approaches are evaluated via comparison of [Formula: see text] (where D w,m is dose-to-water-in-medium and D m,m is dose-to-medium-in-medium) with MC results. The best overall agreement is achieved with an ICT approach in which [Formula: see text], where L is the mean chord length of the cavity and ß is given by [Formula: see text] (R CSDA is the continuous slowing down approximation range of an electron of energy equal to that of incident photons). Cell nucleus doses, D nuc, computed with this ICT approach are compared with those from MC simulations involving multicellular soft tissue models considering a representative range of cell/nucleus sizes and elemental compositions. In [Formula: see text] of cases, ICT and MC predictions agree within [Formula: see text]; disagreement is at most 8.8%. These results suggest that cavity theory may be useful for linking doses from model-based dose calculation algorithms (MBDCAs) with energy deposition in cellular targets. Finally, based on the suggestion that clusters of water molecules associated with DNA are important radiobiological targets, two approaches for estimating dose-to-water by application of SCT to MC results for D m,m or D nuc are compared. Results for these two estimates differ by up to [Formula: see text], demonstrating the sensitivity of energy deposition within a small volume of water in nucleus to the geometry and composition of its surroundings. In terms of the debate over the dose specification medium for MBDCAs, these results do not support conversion of D m,m to D w,m using SCT.

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.

Very elderly (>80 years), frail patients with muscle-invasive bladder cancer and comorbidities: is curative irradiation feasible?

PURPOSE: To evaluate clinical results in elderly and frail patients with bladder cancer treated with curative conformal irradiation alone. METHODS: The records of ambulatory frail elderly patients, age >80 years, Charlson Comorbidity Index (CCI) >5, with invasive bladder cancer, were retrospectively analyzed. The patients were irradiated with curative intent. Acute and late toxicities were evaluated. RESULTS: A total of 27 ambulatory patients were treated. Median age was 84.5 years and a median CCI of 6.5 was recorded. Median delivered radiation dose was 64 Gy. All patients completed the planned treatment. Grade 1-2 gastrointestinal (GI) and genitourinary (GU) toxicities were observed in 55.5% of patients (15/27). At the last follow-up, no late G3+ toxicities have been observed, with G1-2 toxicities reported in 11.1% of patients (3/27). Higher values of CCI were associated with higher acute GU/GI toxicities; there was a correlation between CCI and acute GU toxicity (r = 0.43, p = 0.027). The mean survival time was 23.5 months (95% confidence interval 20.9-26.1) and no median was reached. Locoregional disease-free events and metastasis-free survival showed a 2-year actuarial rate of 90% and 87%, respectively, with an actuarial 2-year overall survival of 84.5%. CONCLUSIONS: Our results demonstrate safety and feasibility of curative radiation therapy in very elderly and frail patients with bladder cancer using 3D conformal radiation therapy.