Minimizing human interference in an online fully automated daily adaptive radiotherapy workflow for bladder cancer.

PURPOSE: The aim was to study the potential for an online fully automated daily adaptive radiotherapy (RT) workflow for bladder cancer, employing a focal boost and fiducial markers. The study focused on comparing the geometric and dosimetric aspects between the simulated automated online adaptive RT (oART) workflow and the clinically performed workflow. METHODS: Seventeen patients with muscle-invasive bladder cancer were treated with daily Cone Beam CT (CBCT)-guided oART. The bladder and pelvic lymph nodes (CTVelective) received a total dose of 40 Gy in 20 fractions and the tumor bed received an additional simultaneously integrated boost (SIB) of 15 Gy (CTVboost). During the online sessions a CBCT was acquired and used as input for the AI-network to automatically delineate the bladder and rectum, i.e. influencers. These influencers were employed to guide the algorithm utilized in the delineation process of the target. Manual adjustments to the generated contours are common during this clinical workflow prior to plan reoptimization and RT delivery. To study the potential for an online fully automated workflow, the oART workflow was repeated in a simulation environment without manual adjustments. A comparison was made between the clinical and automatic contours and between the treatment plans optimized on these clinical (Dclin) and automatic contours (Dauto). RESULTS: The bladder and rectum delineated by the AI-network differed from the clinical contours with a median Dice Similarity Coefficient of 0.99 and 0.92, a Mean Distance to Agreement of 1.9 mm and 1.3 mm and a relative volume of 100% and 95%, respectively. For the CTVboost these differences were larger, namely 0.71, 7 mm and 78%. For the CTVboost the median target coverage was 0.42% lower for Dauto compared to Dclin. For CTVelective this difference was 0.03%. The target coverage of Dauto met the clinical requirement of the CTV-coverage in 65% of the sessions for CTVboost and 95% of the sessions for the CTVelective. CONCLUSIONS: While an online fully automated daily adaptive RT workflow shows promise for bladder treatment, its complexity becomes apparent when incorporating a focal boost, necessitating manual checks to prevent potential underdosage of the target.

Three-in-One Nanozyme for Radiosensitization of Bladder Cancer.

Purpose: Bladder cancer is a common malignancy of the urinary system and the development of noninvasive therapeutic methods is imperative to avoid radical cystectomy, which results in a poor quality of life for patients. Methods: In this study, ultrasmall copper-palladium nanozymes decorated with cysteamine (CPC) nanoparticles (NPs) were synthesized to enhance the efficacy of radiotherapy (RT) in treating bladder cancer. CPC NPs react with intracellular overexpressed H2O2 in the tumor microenvironment to produce large quantities of reactive oxygen species (ROS) and induce tumor cell apoptosis. Furthermore, the CPC nanozymes can generate ample oxygen within tumors by utilizing H2O2, addressing hypoxia conditions, and mitigating radioresistance. Additionally, CPC facilitates the oxidation of glutathione (GSH) into oxidized glutathione disulfide (GSSG), blocking the self-repair mechanisms of tumor cells post-treatment. Simultaneously, CPC enhances the ionization energy deposition effect on tumor cells. Results: The results demonstrate an increased level of ROS and an elevation in oxygen content at the tumor site. Importantly, tumor growth was restrained without apparent systemic toxicity during the combined treatment. Conclusion: In summary, this study highlights the potential of CPC nanozyme-mediated radiotherapy as a promising avenue for the effective treatment of bladder cancer and demonstrates its potential for future clinical applications in the synergistic therapy of bladder cancer.

High-dose radiation-induced immunogenic cell death of bladder cancer cells leads to dendritic cell activation.

Radiotherapy is a commonly used method in the treatment of bladder cancers (BC). Radiation-induced immunogenic cell death (ICD) is related to the immune response against cancers and their prognoses. Even though dendritic cells (DC) act as powerful antigen-presenting cells in the body, their precise role in this ICD process remains unclear. Accordingly, an in vitro study was undertaken to ascertain whether high-dose radiation-induced ICD of BC cells could regulate the immune response of DC. The results indicated that high-dose radiation treatments of BC cells significantly increased their levels of apoptosis, blocked their cell cycle in the G2/M phase, increased their expression of ICD-related proteins, and upregulated their secretion of CCL5 and CCL21 which control the directed migration of DC. It was also noted that expression of CD80, CD86, CCR5, and CCR7 on DC was upregulated in the medium containing the irradiated cells. In conclusion, the present findings illustrate that high-dose radiation can induce the occurrence of ICD within BC cells, concomitantly resulting in the activation of DC. Such findings could be of great significance in increasing the understanding how radiotherapy of BC may work to bring about reductions in cell activity and how these processes in turn lead to immunoregulation of the function of DC.

Poor Prognosis among Radiation-Associated Bladder Cancer Is Defined by Clinicogenomic Features.

Radiotherapy (RT) for prostate cancer has been associated with an increased risk for the development of bladder cancer. We aimed to integrate clinical and genomic data to better understand the development of RT-associated bladder cancer. A retrospective analysis was performed to identify control patients (CTRL; n = 41) and patients with RT-associated bladder cancer (n = 41). RT- and CTRL-specific features were then identified through integration and analysis of the genomic sequencing data and clinical variables. RT-associated bladder tumors were significantly enriched for alterations in KDM6A and ATM, whereas CTRL tumors were enriched for CDKN2A mutation. Globally, there were an increased number of variants within RT tumors, albeit at a lower variant allele frequency. Mutational signature analysis revealed three predominate motif patterns, with similarity to SBS2/13 (APOBEC3A), SBS5 (ERCC2/smoking), and SBS6/15 (MMR). Poor prognostic factors in the RT cohort include a short tumor latency, smoking status, the presence of the smoking and X-ray therapy mutational signatures, and CDKN2A copy number loss. Based on the clinical and genomic findings, we suggest at least two potential pathways leading to RT-associated bladder cancer: The first occurs in the setting of field cancerization related to smoking or preexisting genetic alterations and leads to the development of more aggressive bladder tumors, and the second involves RT initiating the oncogenic process in otherwise healthy urothelium, leading to a longer latency and less aggressive disease. SIGNIFICANCE: Clinicogenomic analysis of radiation-associated bladder cancer uncovered mutational signatures that, in addition to a short tumor latency, smoking, and CDKN2A loss, are associated with a poor outcome. These clinical and genomic features provide a potential method to identify patients with prostate cancer who are at an increased risk for the development of aggressive bladder cancer following prostate RT.

Impact of on-trial IGRT quality assurance in an international adaptive radiotherapy trial for participants with bladder cancer.

BACKGROUND AND PURPOSE: Radiotherapy trial quality assurance (RT QA) is crucial for ensuring the safe and reliable delivery of radiotherapy trials, and minimizing inter-institutional variations. While previous studies focused on outlining and planning quality assurance (QA), this work explores the process of Image-Guided Radiotherapy (IGRT), and adaptive radiotherapy. This study presents findings from during-accrual QA in the RAIDER trial, evaluating concordance between online and offline plan selections for bladder cancer participants undergoing adaptive radiotherapy. RAIDER had two seamless stages; stage 1 assessed adherence to dose constraints of dose escalated radiotherapy (DART) and stage 2 assessed safety. The RT QA programme was updated from stage 1 to stage 2. MATERIALS AND METHODS: Data from all participants in the adaptive arms (standard dose adaptive radiotherapy (SART) and DART) of the trial was requested (33 centres across the UK, Australia and New Zealand). Data collection spanned September 2015 to December 2022 and included the plans selected online, on Cone-Beam Computed Tomography (CBCT) data. Concordance with the plans selected offline by the independent RT QA central reviewer was evaluated. RESULTS: Analysable data was received for 72 participants, giving a total of 884 CBCTs. The overall concordance rate was 83% (723/884). From stage 1 to stage 2 the concordance in the plans selected improved from 75% (369/495) to 91% (354/389). CONCLUSION: During-accrual IGRT QA positively influenced plan selection concordance, highlighting the need for ongoing support when introducing a new technique. Overall, it contributes to advancing the understanding and implementation of QA measures in adaptive radiotherapy trials.

The Impact of Histologic Subtypes on Clinical Outcomes After Radiation-Based Therapy for Muscle-Invasive Bladder Cancer.

PURPOSE: Outcomes of radiation-based therapy (RT) for muscle-invasive bladder cancer (MIBC) with histologic subtypes of urothelial cancer (HS-UC) are lacking. Our objective was to compare survival outcomes of pure urothelial carcinoma (PUC) to HS-UC after RT. MATERIALS AND METHODS: A multicenter retrospective study of 864 patients with MIBC who underwent curative-intent RT to the bladder for MIBC (clinical T2-T4aN0-2M0) between 2001 and 2018 was conducted. Regression models were used to test the association between HS-UC and complete response (CR) and survival outcomes after RT. RESULTS: In total, 122 patients (14%) had HS-UC. Seventy-five (61%) had HS-UC with squamous and/or glandular differentiation. A CR was confirmed in 69% of patients with PUC and 63% with HS-UC. There were 207 (28%) and 31 (25%) patients who died of metastatic bladder cancer in the PUC and HS-UC groups, respectively. There were 361 (49%) and 58 (48%) patients who died of any cause in the PUC and HS-UC groups, respectively. Survival outcomes were not statistically different between the groups. The HS-UC status was not associated with survival outcomes in multivariable Cox regression analyses. CONCLUSIONS: In our study, HS-UC responded to RT with no significant difference in CR and survival outcomes compared to PUC. The presence of HS-UC in MIBC does not seem to confer resistance to RT, and patients should not be withheld from bladder preservation therapy options. Due to low numbers, definitive conclusions cannot be drawn for particular histologic subtypes.

Stereotactic body radiation therapy for multiple lung cancers in a patient with six primary cancers: a case report.

BACKGROUND: Surgery is the standard care for patients with early-stage lung cancer, and stereotactic body radiation therapy is an option for those who are medically inoperable or refuse surgery. Medical developments in diagnostic and therapeutic strategies would prolong prognosis of patients with cancer. The number of patients with multiple cancers has also increased. Duplex primary malignant neoplasms are the most common, and triple or more primary malignant neoplasms were extremely rare. This is the first case of sextuple primary malignant neoplasms with lung cancer. CASE PRESENTATION: We report a case of two courses of stereotactic body radiation therapy for an 88-year-old Japanese male patient with six primary cancers in five organs. Cancers were detected in the thyroid, prostate, esophagus, bladder, and lungs. He also had a history of angina pectoris and had undergone percutaneous coronary intervention. Although he was capable of undergoing surgery for lung cancers, he refused it because he had experienced many invasive treatments, such as surgeries and percutaneous coronary intervention. In January 2020, the first stereotactic body radiation therapy was performed for the adenocarcinoma in the right lung. In March 2022, the second stereotactic body radiation therapy was performed for the nodule of the left lung. Although he complained of mild dyspnea after the first stereotactic body radiation therapy, we did not use steroids because his peripheral oxygen saturation was within the normal range. He had pleural effusion, cardiac dilatation, and pericardial effusion 2 months after the second stereotactic body radiation therapy, which improved with the use of compression stockings. CONCLUSION: A total of 43 and 17 months have passed since the first and second stereotactic body radiation therapy, respectively, there is no local recurrence and the patient can walk independently. We safely performed stereotactic body radiation therapy twice for our older patient with metachronous early-stage lung cancers. If another new tumor is detected, stereotactic body radiation therapy would be a good treatment option for the functional preservation of organs.

Prospective non-randomized comparison of transurethral laser en bloc resection vs. conventional resection of bladder tumors larger than 3 cm.

BACKGROUND: En bloc resection of bladder tumor (ERBT) is an established surgical treatment method for patients with non-muscle invasive bladder cancer (NMIBC) in tumors less than 3 cm. Data regarding the efficacy and safety of ERBT on larger than 3 cm tumors are sparse and its efficacy compared to conventional transurethral resection (TURBT) remains unclear. The aim of this study was to prospectively compare the feasibility, safety and oncological outcomes of laser (Tm-fiber) ERBT and TURBT in patients with primary bladder lesions ≥3 cm. METHODS: A cohort of 45 patients who underwent surgery for primary NMIBC between February 2018 and March 2022 was collected prospectively. There was no randomization. All procedures were performed by two experienced surgeons. Inclusion criteria were as follows: age >18 years, primary Ta or T1 bladder tumor with a diameter of ≥3 cm, no more than 3 tumors and no history of upper tract urothelial carcinoma. Exclusion criteria were carcinoma in situ or invasion into muscle layer (≥T2). ERBT was performed with thulium fiber laser (IPG, Russia). Primary endpoints included efficacy with recurrence-free survival (RFS) at 3, 6 and 12 months. Secondary endpoints were safety parameters, perioperative data and specimen quality (the presence of muscle layer in specimens). RESULTS: Twenty-eight patients underwent laser ERBT and 17 conventional TURBT. The location and size of the tumors were comparable in both groups. The success rate was 93.3% in the ERBT group with two cases of conversion from ERBT to TURBT. Detrusor muscle was present in 92.8% patients in the ERBT group versus 70.5% in the TURBT group (P=0.04). Obturator nerve reflex was observed only in the TURBT group: 17.6% vs. 0.0% (P=0.02). The frequency of other complications was comparable between the two groups. RFS was not statistically different between the two methods at 3 (93.9% vs. 94.1%, P=0.87), 6 (89.3% vs. 82.3%, P=0.5) and 12 months (89.3% vs. 70.6%, P=0.11). CONCLUSIONS: Laser ERBT is a feasible and safe procedure to manage bladder tumors larger than 3 cm. While it seems safer than TURBT, its effect on efficacy remains to be assessed in larger trials.

Adaptive radiotherapy for muscle invasive bladder cancer: a retrospective audit of two bladder filling protocols.

BACKGROUND: Radical radiotherapy for muscle-invasive bladder cancer (MIBC) is challenging due to large variations in bladder shape, size and volume during treatment, with drinking protocols often employed to mitigate geometric uncertainties. Utilising adaptive radiotherapy together with CBCT imaging to select a treatment plan that best fits the bladder target and reduce normal tissue irradiation is an attractive option to compensate for anatomical changes. The aim of this retrospective study was to compare a bladder empty (BE) protocol to a bladder filling (BF) protocol with regards to variations in target volumes, plan of the day (PoD) selection and plan dosimetry throughout treatment. METHODS: Forty patients were included in the study; twenty were treated with a BE protocol and twenty with a BF protocol to a total prescribed dose of 55 Gy in 20 fractions. Small, medium and large bladder plans were generated using three different CTV to PTV margins. Bladder (CTV) volumes were delineated on planning CTs and online pre-treatment CBCTs. Differences in CTV volumes throughout treatment, plan selection, PTV volumes and resulting dose metrics were compared for both protocols. RESULTS: Mean bladder volume differed significantly on both the planning CTs and online pre-treatment CBCTs between the protocols (p < 0.05). Significant differences in bladder volumes were observed between the planning CT and pre-treatment CBCTs for BF (p < 0.05) but not for BE (p = 0.11). Both protocols saw a significant decrease in bladder volume between first and final treatment fractions (p < 0.05). Medium plans were preferentially selected for BE whilst when using the BF protocol the small plan was chosen most frequently. With no significant change to PTV coverage between the protocols, the volume of body receiving 25.0-45.8 Gy was found to be significantly smaller for BE patients (p < 0.05). CONCLUSIONS: This work provides evidence in favour of a BE protocol compared to a BF protocol for radical radiotherapy for MIBC. The smaller treatment volumes observed in the BE protocol led to reduced OAR and total body doses and were also observed to be more consistent throughout the treatment course. These results highlight improvements in dosimetry for patients who undergo a BE protocol for MIBC.

The Value and Safety of Adjuvant Radiation Therapy After Radical Cystectomy in Locally Advanced Urothelial Bladder Cancer: A Controlled Randomized Study.

PURPOSE: Adjuvant radiation therapy (ART) after radical cystectomy in locally advanced bladder cancer was revived after the advancement in precise radiation therapy that decreased the normal pelvic tissue radiation hazards. However, there are still scarce controlled randomized studies addressing this issue. METHODS AND MATERIALS: One hundred thirty-one cystectomized urothelial bladder cancer patients were enrolled; 122 were randomized to receive ART of 50 Gy/25 fractions 4 weeks after cystectomy or cystectomy alone (CY). Sixty-two were included in the ART arm and 60 in the CY arm. Twenty-four ART and 30 CY patients received neoadjuvant chemotherapy. Eleven patients (9%) had cotenant neobladder diversion, 6 in ART, and 5 in CY arms. All ART patients were treated with intensity modulated radiation therapy with daily verification cone beam computed tomography. The median follow-up was 42.7 months. RESULTS: The 3-year adjusted locoregional recurrence-free survival rate was higher in the ART arm, measuring 81% (95% CI, 69%-94%) compared with 71% (95% CI, 60%-80%; p = .0457). ART significantly improved the locoregional relapse-free rate in the cystectomy bed and the pelvic side wall (p = .016 and p = .001, respectively). The overall, event-free, and distant metastasis-free survival did not rank to the level of statistical significance in the 2 arms. Even though the acute side effects were slightly higher in ART, the late toxicities were almost equal in the 2 groups. CONCLUSIONS: ART is safe and quite tolerable after radical cystectomy when using precise radiation techniques. These techniques significantly improved the locoregional recurrence-free survival but had insignificant improvement on the overall survival. ART did not affect the distant metastasis-free survival. Similar studies are performed in different centers around the world to confirm the value of ART in urothelial bladder cancer.

Stereotactic body radiation therapy is beneficial for a subgroup of patients with urothelial cancer and solitary metastatic disease: a single institution real-world experience.

BACKGROUND: Standard treatment options for patients with metastatic urothelial cancer (mUC) include systemic platinum-based chemotherapy, immunotherapy, antibody-drug-conjugates, and targeted therapy. Oligometastatic disease (OMD) may be an intermediate state between localized and generalized cancer. The best treatment strategy for OMD and oligoprogressive (OPD) disease is poorly studied in mUC but local stereotactic body radiation therapy (SBRT) could be an option to avoid or delay systemic treatment. The aim of this study was to assess the efficacy and feasibility of SBRT given in a real-world patient population. METHODS: All patients with mUC treated with SBRT at Karolinska University Hospital, Stockholm, Sweden between 2009 and 2022 were included in this study. Baseline clinical characteristics, treatment data, SBRT dosimetry data and treatment outcome were collected retrospectively. The study endpoints were local control rate (LCR), progression-free-survival (PFS), overall survival (OS) and feasibility of SBRT. RESULTS: In total 39 patients were treated with SBRT. The median follow-up was 25.6 months. The LCR was 82%. PFS and OS were 4.1 and 26.2 months, respectively. Treatment was well tolerated; all patients but one (treatment related pain) completed the planned SBRT. Number of metastases irradiated with SBRT was significantly associated with outcome; patients with only one irradiated lesion had more favourable PFS compared to individuals with 2 or more metastases (HR 4.12, 95% CI: 1.81-9.38, p = 0.001). A subgroup of patients (15%) achieved a sustained long-term survival benefit and never required systemic treatments after SBRT. CONCLUSIONS: SBRT was well tolerated and associated with high LCR. A subpopulation of patients with single metastatic lesion achieved long-term OS and never required subsequent systemic treatment after SBRT. Prospective randomized studies are warranted to discover treatment predictive biomarkers and to investigate the role of SBRT in oligometastatic UC.

[Does radiation therapy for prostate cancer increase the risk of second cancers?] / La radiothérapie du cancer de la prostate augmente-t-elle le risque de seconds cancers ?

PURPOSE: The increased risk of second cancer after prostate radiotherapy is a debated clinical concern. The objective of the study was to assess the risk of occurrence of second cancers after prostate radiation therapy based on the analysis the literature, and to identify potential factors explaining the discrepancies in results between studies. MATERIALS AND METHODS: A review of the literature was carried out, comparing the occurrence of second cancers in patients all presenting with prostate cancer, treated or not by radiation. RESULTS: This review included 30 studies reporting the occurrence of second cancers in 2,112,000 patients treated or monitored for localized prostate cancer, including 1,111,000 by external radiation therapy and 103,000 by brachytherapy. Regarding external radiation therapy, the average follow-up was 7.3years. The majority of studies (80%) involving external radiation therapy, compared to no external radiation therapy, showed an increased risk of second cancers with a hazard ratio ranging from 1.13 to 4.9, depending on the duration of the follow-up. The median time to the occurrence of these second cancers after external radiotherapy ranged from 4 to 6years. An increased risk of second rectal and bladder cancer was observed in 52% and 85% of the studies, respectively. Considering a censoring period of more than 10 years after irradiation, 57% and 100% of the studies found an increased risk of rectal and bladder cancer, without any impact in overall survival. Studies of brachytherapy did not show an increased risk of second cancer. However, these comparative studies, most often old and retrospective, had many methodological biases. CONCLUSION: Despite numerous methodological biases, prostate external radiation therapy appears associated with a moderate increase in the risk of second pelvic cancer, in particular bladder cancer, without impacting survival. Brachytherapy does not increase the risk of a second cancer.

Effects of combined radiotherapy with immune checkpoint blockade on immunological memory in luminal-like subtype murine bladder cancer model.

MIBC is a highly lethal disease, and the patient survival rate has not improved significantly over the last decades. UPPL is a cell line that can be used to recapitulate the luminal-like molecular subtype of bladder cancer and to discover effective treatments to be translated in patients. Here, we investigate the effects of combinational treatments of radiotherapy and immunotherapy in this recently characterized UPPL tumor-bearing mice. We first characterized the baseline tumor microenvironment and the effect of radiation, anti-PD-L1, and combinatorial treatments. Then, the mice were re-challenged with a second tumor (rechallenged tumor) in the contralateral flank of the first tumor to assess the immunological memory. Radiation slowed down the tumor growth. All treatments also decreased the neutrophil population and increased the T cell population. Anti-PD-L1 therapy was not able to synergize with radiation to further delay tumor growth. Furthermore, none of the treatments were able to generate immune memory. The treatments were not sufficient to induce a significant and lasting pool of memory cells. We show here that anti-PD-L1 treatment added to radiotherapy was not enough to achieve T cell-mediated memory in UPPL tumors. Stronger T cell activation signals may be required to enhance radiation efficacy in luminal-like bladder cancer.

Muscle-invasive bladder cancer in elderly and frail people: Is hypofractionated radiotherapy a feasible approach when no other local options are available?

AIM: The study aims to report the feasibility and safety of palliative hypofractionated radiotherapy targeting macroscopic bladder tumors in a monocentric cohort of frail and elderly bladder cancer patients not eligible for curative treatments. METHODS: Patients who underwent hypofractionated radiotherapy to the gross disease or to the tumor bed after transurethral resection of bladder tumor from 2017 to 2021 at the European Institute of Oncology IRCCS, were retrospectively considered. Schedules of treatment were 30 and 25 Gy in 5 fractions (both every other day, and consecutive days). Treatment response was evaluated with radiological investigation and/or cystoscopy. Toxicity assessment was carried out according to RTOG/EORTC v2.0 criteria. RESULTS: A total of 16 patients were included in the study, of these 11 received hypofractionated radiotherapy on the macroscopic target volume and five on the tumor bed after transurethral resection of bladder tumor. No grade (G) >2 acute toxicities were described after treatment for both groups. Only one patient in the group receiving radiotherapy on the macroscopic disease reported G4 GU late toxicity. Ten patients had available follow-up status (median FU time 18 months), of them six had complete response, one had stable disease, and three had progression of disease. The overall response rate and disease control rate were 60% and 70%, respectively. CONCLUSION: Our preliminary data demonstrate that palliative hypofractionated radiotherapy for bladder cancer in a frail and elderly population is technically feasible, with an acceptable toxicity profile. These outcomes emphasize the potential of this approach in a non-radical setting and could help to provide more solid indications in this underrepresented setting of patients.

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.

Radiotherapy Combined with a Radiosensitizer for Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Carcinoma In Situ Bladder Cancer: An Open-label, Single-arm, Multicenter, Phase 2 European Organisation for Research and Treatment of Cancer Trial.

Radical cystectomy with pelvic lymph node dissection and urinary diversion is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). However, many patients are unwilling or unable to undergo such major surgery associated with high morbidity and a negative impact on quality of life. Chemoradiotherapy is an established treatment option for muscle-invasive bladder cancer. However, it has not been investigated adequately in NMIBC until now. The European Organisation for Research and Treatment of Cancer (EORTC) 2235 study (NCT06310369) is designed as a multicenter, prospective, international, phase 2 trial of moderate hypofractionated radiotherapy combined with a radiosensitizer in BCG-unresponsive NMIBC patients with carcinoma in situ (CIS) who are not eligible for or declined to undergo radical cystectomy. Patients who have received nadofaragene firadenovec or TAR-200 are eligible. The primary endpoint is the 6-mo complete response (CR) rate defined by the absence of CIS proven by a control biopsy of the bladder. The secondary endpoints include overall survival, progression-free survival, durability of CR, grade 3-4 adverse events rate, patients' quality of life, and organ preservation rate. PATIENT SUMMARY: Intravesical instillation of bacillus Calmette-Guérin is the standard treatment of non-muscle-invasive, also coined as superficial, bladder cancer. In case the cancer recurs, even superficially, there is no other proven treatment than a radical cystectomy-the surgical removal of the bladder. Although the surgical technique has improved dramatically over the past few years, it remains contraindicated in patients with severe comorbidities. In addition, because it affects the quality of life, patients may reject this option. This study will assess the efficacy of external beam radiotherapy, a robust alternative to surgery in muscle-invasive bladder cancer. Radiotherapy will be administered 5 d a week for 4 wk. It will be associated with a "radiosensitizer," an intravenous or oral drug, during the radiotherapy treatment. The study will measure the proportion of patients remaining recurrence free at 6 mo and thereafter. It will also evaluate the safety of the treatment and its impact on quality of life.

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.