Dietary fibre supplementation enhances radiotherapy tumour control and alleviates intestinal radiation toxicity.

BACKGROUND: Non-toxic approaches to enhance radiotherapy outcomes are beneficial, particularly in ageing populations. Based on preclinical findings showing that high-fibre diets sensitised bladder tumours to irradiation by modifying the gut microbiota, along with clinical evidence of prebiotics enhancing anti-cancer immunity, we hypothesised that dietary fibre and its gut microbiota modification can radiosensitise tumours via secretion of metabolites and/or immunomodulation. We investigated the efficacy of high-fibre diets combined with irradiation in immunoproficient C57BL/6 mice bearing bladder cancer flank allografts. RESULT: Psyllium plus inulin significantly decreased tumour size and delayed tumour growth following irradiation compared to 0.2% cellulose and raised intratumoural CD8+ cells. Post-irradiation, tumour control positively correlated with Lachnospiraceae family abundance. Psyllium plus resistant starch radiosensitised the tumours, positively correlating with Bacteroides genus abundance and increased caecal isoferulic acid levels, associated with a favourable response in terms of tumour control. Psyllium plus inulin mitigated the acute radiation injury caused by 14 Gy. Psyllium plus inulin increased caecal acetate, butyrate and propionate levels, and psyllium alone and psyllium plus resistant starch increased acetate levels. Human gut microbiota profiles at the phylum level were generally more like mouse 0.2% cellulose profiles than high fibre profiles. CONCLUSION: These supplements may be useful in combination with radiotherapy in patients with pelvic malignancy. Video Abstract.

Taraxasterol enhanced bladder cancer cells radiosensitivity via inhibiting the COX-2/PGE2/JAK2/STAT3/MMP pathway.

PURPOSE: Radiotherapy with bladder preservation is highly acceptable among patients bearing bladder cancer (BCa), but the occurrence of secondary tolerance (ARR) during treatment is one of the important reasons for the failure of clinical radiotherapy. COX-2 has been frequently reported to be highly expressed and associated with radio-resistance in various cancers. In this study, the feasibility of Taraxasterol (Tara) as a radiosensitizer was investigated, and the target effect of Tara on COX-2 and its underlying mechanism were explored. METHODS AND MATERIALS: The toxicity of Tara toward BCa cells was detected with the MTT method and cells in response to IR or Tara + IR were compared by clone formation assay. Next, a small RNA interference system (siRNA) was employed to decrease endogenous COX-2 expression in BCa cells, and the stem cell-like features and motion abilities of BCa cells under different treatments were investigated using microsphere formation and transwell chamber assay, respectively. Meanwhile, the expression of a series of inflammation-related molecules and stem cell characteristic molecules was determined by qRT-PCR, western blot and ELISA method. In vivo studies, BCa cells were subcutaneously injected into the right flank of each male mouse. Those mice were then grouped and exposed to different treatment: Tara, IR, IR + Tara and untreated control. The volumes of each tumor were measured every two days and target proteins were detected with immunohistochemical (IHC) staining. RESULTS: The results show that COX-2 decline, due to COX-2 knocking-down or Tara treatment, could greatly enhance BCa cells' radiosensitivity and significantly decrease their migration, invasion and microsphere formation abilities, companied with the reduce of JAK2, phos-STAT3, MMP2 and MMP9 expression. However, Tara could not further reduce the expression of an above molecule of cells in COX-2-deficient BCa cells. Correspondingly, Tara treatment could not further enhance those siCOX-2 BCa cells response to IR. CONCLUSIONS: Our data support that Tara can improve the radiosensitivity of BCa cells by targeting COX-2/PGE2. The mechanism may involve regulating STAT3 phosphorylation, DNA damage response protein activation, and expression of MMP2/MMP9.

Radiotherapy and Anrotinib in Malignant Glomus Tumor of the Bladder: A Case Report and Literature Review.

Background: Malignant glomus tumors (MGTs) are rare malignancies, which grow rapidly and are aggressive. Surgical resection has been regarded as the standard management, but treatment options for those unresectable tumors are limited, resulting in a high recurrence rate and poor prognosis. Case Description: An 85-year-old man presented with gross hematuria and was diagnosed with MGTs of bladder. The patient achieved long-term local control after multimodal therapy comprising radiotherapy, iodine-125 seeds brachytherapy, transcatheter arterial chemoembolization, and antiangiogenic targeted therapy. Conclusion: MGTs occurring in the bladder are clinically rare and refractory. The case presented here highlights the importance of multidisciplinary diagnosis and treatment, providing evidence that radiotherapy and antiangiogenic therapy may play an important role in unresectable bladder MGT.

Radiotherapy in metastatic bladder cancer.

PURPOSE: To review available and emerging evidence of radiotherapy for symptom management and disease control in metastatic bladder cancer. METHODS: A literature search and subsequent cross-referencing were carried out for articles in the PubMed and Scopus databases using terms 'radiotherapy' OR 'palliative radiation therapy' with 'metastatic bladder cancer' OR 'advanced bladder cancer' between 1990 and 2023, excluding articles with no English translation. RESULTS: Palliative radiotherapy is an effective and accessible treatment for the alleviation of haematuria and pain due to the primary and metastatic disease. With growing recognition of oligometastatic disease state at diagnosis, response, or progression, radiotherapy can consolidate response by ablating residual or resistant lesions. Experience with other primary cancers supports positive impact of radiotherapy on disease control, quality of life, and survival in oligometastatic stage, without significant adverse effects. Alongside immune checkpoint inhibitors, fibroblast growth receptor inhibitors, and antibody-drug conjugates, the immunomodulatory potential of radiotherapy is being explored in combination with these systemic therapies for metastatic bladder cancer. CONCLUSION: Radiotherapy is an effective, safe, and accessible treatment modality for palliation as well as disease control in various clinical settings of metastatic bladder cancer. Its role in oligometastatic stage in combination with systemic therapy is expected to expand with emerging evidence.

Does intensity-modulated radiation therapy by helical tomotherapy for prostate cancer increase the subsequent risk of bladder cancer? A propensity score-matched analysis.

OBJECTIVES: This study aimed to evaluate the risk of bladder cancer after intensity-modulated radiation therapy (IMRT) using helical tomotherapy for prostate cancer in comparison to the risk post-radical prostatectomy (RP) using propensity score-matched analysis and to assess the risk factors for bladder cancer. METHODS: This retrospective study included 2067 patients with non-metastatic prostate cancer treated at our institution between June 2007 and December 2016. Of these, 1547 patients were treated with IMRT and 520 underwent RP. The propensity scores were calculated using age, National Comprehensive Cancer Network risk classification, prostate volume, Brinkman index, and follow-up time as matched covariates. A propensity score-matched patient cohort (n = 718; IMRT: 359, RP: 359) was created, and the risk of bladder cancer after treatment was compared. RESULTS: In total, bladder cancer was detected in 33 patients. Five patients in the IMRT group and one in the RP group died of bladder cancer. In the propensity score-matched analysis, the 5-year bladder cancer-free survival rate was significantly lower in the IMRT group than in the RP group (91.7% and 96.2%, respectively; p < 0.001). Multivariate analysis revealed that IMRT and the Brinkman index were the risk factors for bladder cancer in this cohort (odds ratio = 5.085, 95% confidence interval = 1.436-18.008, p = 0.012 and odds ratio = 1.001, 95% confidence interval = 1.000-1.001, p = 0.010, respectively). CONCLUSIONS: IMRT for prostate cancer using helical tomotherapy increases the subsequent risk of bladder cancer compared with RP and is an independent risk factor for bladder cancer similar to smoking.

Phase II Trial of Concurrent Nivolumab and Radiation Therapy for Muscle-Invasive Bladder Cancer of Older or Chemotherapy-Ineligible Patients.

PURPOSE: Bladder cancer is predominantly a disease of older individuals. Concurrent chemotherapy and radiation is a bladder-sparing strategy for management of muscle-invasive bladder cancer; however, many patients are not candidates for chemotherapy due to comorbidities or impaired performance status. We conducted a study in a chemotherapy-ineligible patient population with the objectives of evaluating the safety, efficacy, and quality-of-life effect of the combination of nivolumab and radiation therapy in patients with localized/locally advanced urothelial cancer. METHODS AND MATERIALS: Eligible patients had muscle-invasive bladder cancer and were not candidates for standard chemoradiation strategy due to at least one of the following: performance status of 2, creatinine clearance ≤60 mL/min, cardiac disease, neuropathy, and intolerance to previous treatment. Creatinine clearance ≥40 mL/min, normal marrow, and liver function were required. The primary endpoint was progression-free survival at 12 months. Nivolumab was started within 3 days of radiation therapy and administered at a dose of 240 mg intravenously every 2 weeks for a maximum of 6 months. Radiation therapy was per standard of care for bladder cancer. Imaging and cystoscopy and biopsy evaluation were required at months 3, 6, and 12 and then annually until progression. RESULTS: Twenty patients were enrolled, with a median age of 78.5 years (range, 58-95 years); 80% of patients were >70 years of age, and 8 (40%) were >80 years of age. Median creatinine clearance was 52 mL/min. Nine patients (48%) were progression free at 12 months. Median progression-free survival was 11.4 months (90% CI, 7.5-23.7 months), and median overall survival was 15.6 months (90% CI, 9.1-26.1 months). CONCLUSIONS: Concurrent nivolumab and radiation therapy is tolerable but demonstrated limited efficacy in an older population with multiple comorbidities. Immune correlates demonstrated that patients with baseline programmed cell death ligand 1 combined prognostic score ≥5% had numerically longer progression-free survival.

Online adaptive radiotherapy for bladder cancer using a simultaneous integrated boost and fiducial markers.

PURPOSE: The aim was to assess the feasibility of online adaptive radiotherapy (oART) for bladder cancer using a focal boost by focusing on the quality of the online treatment plan and automatic target delineation, duration of the workflow and performance in the presence of fiducial markers for tumor bed localization. METHODS: Fifteen patients with muscle invasive bladder cancer received daily oART with Cone Beam CT (CBCT), artificial intelligence (AI)-assisted automatic delineation of the daily anatomy and online plan reoptimization. The bladder and pelvic lymph nodes received a total dose of 40 Gy in 20 fractions, the tumor received an additional simultaneously integrated boost (SIB) of 15 Gy. The dose distribution of the reference plan was calculated for the daily anatomy, i.e. the scheduled plan. Simultaneously, a reoptimization of the plan was performed i.e. the adaptive plan. The target coverage and V95% outside the target were evaluated for both plans. The need for manual adjustments of the GTV delineation, the duration of the workflow and the influence of fiducial markers were assessed. RESULTS: All 300 adaptive plans met the requirement of the CTV-coverage V95%≥98% for both the boost (55 Gy) and elective volume (40 Gy). For the scheduled plans the CTV-coverage was 53.5% and 98.5%, respectively. Significantly less tissue outside the targets received 55 Gy in case of the adaptive plans as compared to the scheduled plans. Manual corrections of the GTV were performed in 67% of the sessions. In 96% of these corrections the GTV was enlarged and resulted in a median improvement of 1% for the target coverage. The median on-couch time was 22 min. A third of the session time consisted of reoptimization of the treatment plan. Fiducial markers were visible on the CBCTs and aided the tumor localization. CONCLUSIONS: AI-driven CBCT-guided oART aided by fiducial markers is feasible for bladder cancer radiotherapy treatment including a SIB. The quality of the adaptive plans met the clinical requirements and fiducial markers were visible enabling consistent daily tumor localization. Improved automatic delineation to lower the need for manual corrections and faster reoptimization would result in shorter session time.

Current trends in the promising immune checkpoint inhibition and radiotherapy combination for locally advanced and metastatic urothelial carcinoma.

Locally advanced and metastatic urothelial carcinoma (UC) remains a challenging malignancy, though several novel therapeutic drugs have been developed in recent years. Over the past decade, immune checkpoint inhibitors (ICI) have shifted the paradigm of therapeutic strategies for UC; however, only a limited number of patients respond to ICI. Since radiotherapy (RT) is widely known to induce systemic immune activation, it may boost the efficacy of ICI. Conversely, RT also causes exhaustion of cytotoxic T cells, and the activation and recruitment of immunosuppressive cells; ICI may help overcome these immunosuppressive effects. Therefore, the combination of ICI and RT has attracted attention in recent years. The therapeutic benefits of this combination therapy and its optimal regimen have not yet been determined through prospective studies. Therefore, this review article aimed to provide an overview of the current preclinical and clinical studies that illustrate the underlying mechanisms and explore the optimization of the RT regimen along with the ICI and RT combination sequence. We also analyzed ongoing prospective studies on ICI and RT combination therapies for metastatic UC. We noted that the tumor response to ICI and RT combination seemingly differs among cancer types. Thus, our findings highlight the need for well-designed prospective trials to determine the optimal combination of ICI and RT for locally advanced and metastatic UC.

Clinical and dosimetric outcomes of image-guided, dose-painted radiotherapy in muscle invasive bladder cancer.

PURPOSE/OBJECTIVE: Definitive radiotherapy (RT) is an alternative to radical cystectomy for select patients with muscle invasive bladder cancer (MIBC); however, there is limited data on dose-painted RT approaches. We report the clinical and dosimetric outcomes of a cohort of MIBC patients treated with dose-painted RT. MATERIAL/METHODS: This was a single institution retrospective study of cT2-4N0M0 MIBC patients treated with external beam radiotherapy (EBRT) to the bladder, and sequential or concomitant boost to the tumor bed. The target delineation was guided by either intravesical injection of Lipiodol or through fusion of the pre-treatment imaging. The majority were treated with daily image-guidance. Kaplan-Meier was used to characterize overall survival (OS) and progression-free survival (PFS). Cumulative incidence function (CIF) was used to estimate local (intravesical) recurrence (LR), regional recurrence (RR) and distant metastasis (DM). Univariable and multivariable cause-specific hazard model was used to assess factors associated with LR and OS. RESULTS: 117 patients were analyzed. The median age was 73 years (range 43, 95). The median EQD2 to the boost volume was 66 Gy (range 52.1, 70). Lipiodol injection was used in 64 patients (55%), all treated with IMRT/VMAT. 95 (81%) received concurrent chemotherapy, of whom, 44 (38%) received neoadjuvant chemotherapy. The median follow-up was 37 months (IQR 16.2, 83.3). At 5-year, OS and PFS were 79% (95% CI 70.5-89.2) and 46% (95% CI 36.5-57.5). Forty-five patients had bladder relapse, of which 30 patients (67%) were at site of the tumor bed. Nine patients underwent salvage-cystectomy. Late high-grade (G3-G4) genitourinary and gastrointestinal toxicity were 3% and 1%. CONCLUSION: Partial boost RT in MIBC is associated with good local disease control and high rates of cystectomy free survival. We observed a pattern of predominantly LR in the tumor bed, supporting the use of a dose-painted approach/de-escalation strategy to the uninvolved bladder. Prospective trials are required to compare oncological and toxicity outcomes between dose-painted and homogeneous bladder RT techniques.

Cox Regression Analysis of Prognostic Factors of Intensity-Modulated Radiotherapy in Patients with Bladder Cancer.

OBJECTIVE: This paper aims to explore the prognostic factors of intensity-modulated radiotherapy (IMRT) in patients with bladder cancer by Cox regression analysis and to provide evidence for prolonging the survival of patients and improving the treatment status. METHODS: A total of 153 cases of patients with bladder cancer who received IMRT were selected as research objects, and their clinical data were retrospectively analyzed and followed up. Kaplan-Meier survival analysis was conducted to calculate the median survival period, univariate and multivariate Cox regression were used to analyze the prognostic factors of IMRT in patients with bladder cancer, and receiver operating characteristic curve was adopted to evaluate the prediction efficiency of influencing factors. RESULTS: Patients were followed up for 9-40 months, and 55 patients died by the end of the follow-up. The median survival time was 30 months, and the 3-year survival rate was 64.05% (98/153). Univariate analysis showed that T stage, total cystectomy, lymph node, pathological type and hydronephrosis influenced the prognosis of IMRT for patients with bladder cancer (p < 0.05). Multivariate Cox regression analysis showed T3 stage (odds ratio (OR) = 0.149, 0.068-0.327), T4 stage (OR = 27.639, 3.677-207.758), lymph node presence (OR = 0.152, 0.050-0.467), pathological type (OR = 0.086, 0.025-0.296) and hydronephrosis (OR = 7.402, 1.161-47.192) were independent factors affecting the prognosis of IMRT in patients with bladder cancer (p < 0.05), while total cystectomy (OR = 1.037, 0.171-6.301) was not an independent factor affecting the prognosis of IMRT in patients with bladder cancer (p > 0.05). CONCLUSIONS: T stage, lymph nodes, nontransitional cell carcinoma with pathological type and hydronephrosis can influence the prognostic effect of IMRT in patients with bladder cancer.

Cox Regression Analysis of Prognostic Factors of Intensity-Modulated Radiotherapy in Patients with Bladder Cancer

Objective: This paper aims to explore the prognostic factors of intensity-modulated radiotherapy (IMRT) in patients with bladder cancer by Cox regression analysis and to provide evidence for prolonging the survival of patients and improving the treatment status. Methods: A total of 153 cases of patients with bladder cancer who received IMRT were selected as research objects, and their clinical data were retrospectively analyzed and followed up. Kaplan–Meier survival analysis was conducted to calculate the median survival period, univariate and multivariate Cox regression were used to analyze the prognostic factors of IMRT in patients with bladder cancer, and receiver operating characteristic curve was adopted to evaluate the prediction efficiency of influencing factors. Results: Patients were followed up for 9–40 months, and 55 patients died by the end of the follow-up. The median survival time was 30 months, and the 3-year survival rate was 64.05% (98/153). Univariate analysis showed that T stage, total cystectomy, lymph node, pathological type and hydronephrosis influenced the prognosis of IMRT for patients with bladder cancer (p < 0.05). Multivariate Cox regression analysis showed T3 stage (odds ratio (OR) = 0.149, 0.068–0.327), T4 stage (OR = 27.639, 3.677–207.758), lymph node presence (OR = 0.152, 0.050–0.467), pathological type (OR = 0.086, 0.025–0.296) and hydronephrosis (OR = 7.402, 1.161–47.192) were independent factors affecting the prognosis of IMRT in patients with bladder cancer (p < 0.05), while total cystectomy (OR = 1.037, 0.171–6.301) was not an independent factor affecting the prognosis of IMRT in patients with bladder cancer (p > 0.05). Conclusions: T stage, lymph nodes, nontransitional cell carcinoma with pathological type and hydronephrosis can influence the prognostic effect of IMRT in patients with bladder cancer (AU)

Clinical characteristics of secondary bladder cancer developing after low-/high-dose-rate brachytherapy to treat localized prostate cancer.

BACKGROUND: To explore correlations between the clinical attributes of secondary bladder cancer and brachytherapy, we retrospectively reviewed our institutional database on patients with localized prostate cancer who underwent low-dose-rate brachytherapy (LDR-BT) or high-dose-rate brachytherapy (HDR-BT) with or without external beam radiation therapy (EBRT) or radical prostatectomy (RP). METHODS: From October 2003 to December 2014, 2551 patients with localized prostate cancer were treated at our institution. Of these, data on 2163 were available (LDR-BT alone: n = 953; LDR-TB with EBRT: n = 181; HDR-BT with EBRT: n = 283; RP without EBRT: n = 746). The times of secondary bladder cancer development subsequent to radical treatment, and their clinical characteristics, were studied. RESULTS: Age-adjusted Cox's regression analyses indicated that brachytherapy did not significantly impact the incidence of secondary bladder cancer. However, the pathological characteristics of such cancer differed between patients treated via brachytherapy and RP without EBRT; invasive bladder cancer was more common in such patients. CONCLUSION: The risk for secondary bladder cancer was not significantly increased after brachytherapy compared to non-irradiation therapy. However, brachytherapy patients exhibited a higher incidence of invasive bladder cancer. Therefore, meticulous follow-up is crucial for early detection and treatment of bladder cancer in such patients.

Use of Perirectal Hyaluronic Acid Spacer Prior to Radiotherapy in a Pediatric Patient With Bladder Rhabdomyosarcoma: A Case Report.

Rhabdomyosarcoma (RMS) treatment involves surgery, chemotherapy, and radiotherapy. A radioprotective space between the bladder/prostate and rectum reduces postradiation complications, as reported in adult patients. Describe pediatric preradiotherapy perirectal hyaluronic acid (HA) spacer injection for bladder/prostate RMS. We present a case of a 17-month-old male with bladder/prostate RMS. Before radiotherapy, an HA spacer was injected peri-rectally. Under general anesthesia, a transrectal ultrasound was positioned and 1mL of HA spacer was injected into the perirectal space. No complications were reported at 6-month follow-up. This is the first report of pre-radiation therapy spacer injection for pediatric bladder/prostate RMS.

Bladder-Sparing Treatment With Radical Dose Radiotherapy Is an Effective Alternative to Radical Cystectomy in Patients With Clinically Node-Positive Nonmetastatic Bladder Cancer.

PURPOSE: Bladder-sparing trimodal therapy (TMT) is an alternative to radical cystectomy (RC) according to international guidelines. However, there are limited data to guide management of nonmetastatic clinically node-positive bladder cancer (cN+ M0 BCa). We performed a multicenter retrospective analysis of survival outcomes in node-positive patients to inform practice. METHODS: Data from patients diagnosed with cN+ M0 BCa were collected from participating UK Oncology centers offering both TMT and RC. Overall survival (OS) and progression-free survival (PFS) outcomes were collected with details of treatment and clinical factors. RESULTS: A total of 287 patients with cN+ M0 BCa were included in the survival analysis. Median OS across all patients was 1.55 years (95% CI, 1.35 to 1.82 years). Receiving radical treatments was associated with improved OS (hazard ratio [HR], 0.32; 95% CI, 0.23 to 0.44; P < .001) compared with receiving palliative treatment. Radically treated patients (n = 163) received RC (n = 76) or radical dose radiotherapy (RT, n = 87); choice of radical treatment showed no association with OS (HR, 0.94; 95% CI, 0.63 to 1.41; P = .76) or PFS (HR, 0.74; 95% CI, 0.50 to 1.08; P = .12) on multivariable analysis. CONCLUSION: Patient cohorts with cN+ M0 BCa had equivalent survival outcomes whether treated with surgery or radical RT. Given the known morbidities of RC-in a patient group with poor survival-this study confirms that bladder-sparing TMT treatment should be a treatment option available to all patients with cN+ M0 BCa.

Delineating and sparing the ileal conduit in adjuvant radiotherapy for bladder cancer with modulated radiotherapy.

Purpose: We undertook a prospective planning study to describe the delineation of ileal conduit (IC) loop on radiotherapy planning computed tomography (RTP CT) scan as an organ at risk (OAR) and its sparing using volumetric modulated arc therapy (VMAT) during adjuvant irradiation of bladder malignancies. Materials and Methods: Fifteen patients with bladder malignancy needing adjuvant radiotherapy postoperatively and having normal renal function underwent delayed phase RTP CT from June 2020 to March 2021, with certain modifications (Foley's catheter through stoma, additional delayed scans). We identified the course of ureters, external stoma, IC, and uretero-ileal (right and left) anastomotic sites. VMAT plans were generated. Results: A step-by-step description is given. Genitourinary OARs include kidneys, ureters, uretero-ileal anastomoses, and IC. The contrast on delayed scan opacifies ureters and IC. IC can be seen three-dimensionally as a structure with two fixed ends (blind proximal end anterior to the right sacroiliac joint and the open distal end over the right anterior abdominal wall in parasagittal location) and a 15-20 cm hanging intraabdominal loop that lies adjacent to the right iliac vessels. For prescription doses (PD) of 50.4 gray and 54 gray, respectively, VMAT plan achieved IC dose maximum to less than PD and V50 lower than 10 cc. Stoma sparing traditionally used as a surrogate for IC sparing is insufficient due to the variable intraabdominal location of IC loop. Conclusions: Delineation of IC as an OAR is feasible with slight modifications in the RTP protocols. VMAT (or other forms of intensity modulated radiation therapy) can help IC sparing and should be considered when it lies in close proximity to target volumes and the risk of additional morbidity is considerable.

Reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti-PD-1/PD-L1.

Despite breakthroughs in immune checkpoint inhibitors (ICI), the majority of tumors, including those poorly infiltrated by CD8+ T cells or heavily infiltrated by immunosuppressive immune effector cells, are unlikely to result in clinically meaningful tumor responses. Radiation therapy (RT) has been combined with ICI to potentially overcome this resistance and improve response rates but reported clinical trial results have thus far been disappointing. Novel approaches are required to overcome this resistance and reprogram the immunosuppressive tumor microenvironment (TME) and address this major unmet clinical need. Using diverse preclinical tumor models of prostate and bladder cancer, including an autochthonous prostate tumor (Pten-/-/trp53-/-) that respond poorly to radiation therapy (RT) and anti-PD-L1 combinations, the key drivers of this resistance within the TME were profiled and used to develop rationalized combination therapies that simultaneously enhance activation of anti-cancer T cell responses and reprogram the immunosuppressive TME. The addition of anti-CD40mAb to RT resulted in an increase in IFN-y signaling, activation of Th-1 pathways with an increased infiltration of CD8+ T-cells and regulatory T-cells with associated activation of the CTLA-4 signaling pathway in the TME. Anti-CTLA-4mAb in combination with RT further reprogrammed the immunosuppressive TME, resulting in durable, long-term tumor control. Our data provide novel insights into the underlying mechanisms of the immunosuppressive TME that result in resistance to RT and anti-PD-1 inhibitors and inform therapeutic approaches to reprogramming the immune contexture in the TME to potentially improve tumor responses and clinical outcomes.

Increased Burden of Second Bladder Cancer and Rectal Cancer in Prostate Cancer Treated With Radiotherapy: Results From Surveillance, Epidemiology, and End Results.

BACKGROUND: Previous studies have confirmed the higher risk of bladder cancer (BC) and rectal cancer (RC) development among prostate cancer (PCa) patients receiving radiotherapy. In this study, we intend to explore the long-term trend in second BC and RC incidence among PCa patients undergoing radiotherapy. METHOD: We identified first primary PCa patients diagnosed between 1975 and 2014 from the Surveillance, Epidemiology, and End Results (SEER)-9 cancer registries. Standardized incidence ratios (SIRs) were calculated by calendar year of diagnosis among PCa patients receiving radiotherapy and not. P trends were evaluated using Poisson regression. 10-year cumulative incidence of BC and RC was calculated utilizing competing risk regression model. RESULT: Of PCa patients treated with radiotherapy, SIRs of BC increased from .82 (95% CI: .35- 1.61) in 1980-1984 to 1.58 (95% CI: 1.48-1.68) in 2010-2014 (Ptrend=.003). SIRs of RC increased from 1.01 (95% CI: .27-2.58) in 1980-1984 to 1.54 (95% CI: 1.31-1.81) in 2010-2014 (Ptrend=.025). No statistically significant change in both BC and RC incidence was observed. The 10-year cumulative incidence of BC increased from 1975-1984 (.04%) to 2005-2014 (.15%) among PCa treated with radiotherapy. Simultaneously, the 10-year cumulative incidence of RC was demonstrated to range from 1975-1984 (.02%) to 2005-2014 (.11%). CONCLUSION: we have observed an increasing trend in second BC and RC incidence in PCa patients receiving radiotherapy. There was no significant change in the incidence of second BC and RC in PCa without radiotherapy. These results reflect the increasing clinical burden of second malignant tumors in PCa patients undergoing radiotherapy.