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Abstract Background Biliary tract cancers (BTC) are rare and aggressive malignancies originating from intrahepatic and extrahepatic bile ducts and the gallbladder. Surgery is the only curative option, but due to late-stage diagnosis, is frequently not feasible, leaving chemotherapy as the primary treatment. Radiotherapy (RT) can be an effective alternative for patients with unresectable, non-metastatic BTC despite the generally poor prognosis and significant variability. To help manage patients with unresectable BTC who receive RT, we aimed to identify prognostic markers that could aid in predicting overall survival (OS). Methods A retrospective cohort study was conducted at the University of Pennsylvania, involving seventy-eight patients with unresectable BTC treated with definitive intent RT. Comprehensive demographic, clinical, and treatment-related data were extracted from the electronic medical records. Univariate and multivariate Cox regressions were employed to identify predictors of OS after RT. A biomarker model was developed for refined survival prediction. Results The cohort primarily comprised patients with good performance status without significant hepatic dysfunction at presentation. The predominant treatment approach involved hypofractionated RT or concurrent 5FU-based chemoRT. Median OS after RT was 12.3 months, and 20 patients (15.6%) experienced local progression with a median time of 30.1 months. Univariate and multivariate analyses identified CA19-9 (above median) and higher albumin-bilirubin (ALBI) grades at presentation as significant predictors of poor OS. Median OS after RT was 24 months for patients with no risk factors and 6.3 months for those with both. Conclusions Our study demonstrates generally poor but significantly heterogeneous OS in patients with unresectable BTC treated with RT. We have developed a biomarker model based on CA19-9 and ALBI grade at presentation that can distinguish sub-populations with markedly diverse prognoses. This model can aid the clinical management of this challenging disease.

During the years of widespread use of radiotherapy in cancer patients, the incidence of local radiation damage to soft tissues (of varying severity) reached 30–40% or more. The experience of the radiation injury treatment department in the 70s and 80s indicates that every 2–3 beds were occupied by patients with this pathology. With the development of radiology, the introduction of new sources and techniques, the frequency of formation of such changes in the zone of irradiation fields has significantly decreased and currently stands at about 2%. The purpose of the proposed study is to demonstrate the possibilities of skin plastic surgery in this contingent of people who, as a rule, do not receive qualified care for a long time. As part of the work carried out, the time elapsed from the moment of formation of pathological changes to hospitalization in the department, on average, was 3–5 years, and was filled with ineffective conservative measures. Over the past 4 years, 60 reconstructive plastic surgeries have been performed in the radiation injury treatment department using musculoskeletal (21), skin fascial (21), skin (10) flaps, as well as plasty with local tissues (8). In the early postoperative period, the most common complication was marginal necrosis of the flap (13) which in 11 patients caused repeated operations in the form of secondary sutures or, in the case when it was not possible to perform this, plastic surgery of the defect with insular skin flaps was applied to the granulating wound. Subsequently, complete healing of the postoperative wound was noted in such patients. Thus, the proposed options for the reconstruction of radiation ulcers that developed after combined and radiation treatment of malignant neoplasms are highly effective methods that can get rid of disfiguring defects, improve the quality of life and restore social activity in almost 100% of patients.

Abstract Background Radiation therapy is the standard of care for central nervous system tumours. Despite the success of radiation therapy in reducing tumour mass, irradiation (IR)-induced vasculopathies and neuroinflammation contribute to late-delayed complications, neurodegeneration, and premature ageing in long-term cancer survivors. Mesenchymal stromal cells (MSCs) are adult stem cells that facilitate tissue integrity, homeostasis, and repair. Here, we investigated the potential of the iPSC-derived MSC (iMSC) secretome in immunomodulation and vasculature repair in response to radiation injury utilizing human cell lines. Methods We generated iPSC-derived iMSC lines and evaluated the potential of their conditioned media (iMSC CM) to treat IR-induced injuries in human monocytes (THP1) and brain vascular endothelial cells (hCMEC/D3). We further assessed factors in the iMSC secretome, their modulation, and the molecular pathways they elicit. Results Increasing doses of IR disturbed endothelial tube and spheroid formation in hCMEC/D3. When IR-injured hCMEC/D3 (IR ≤ 5 Gy) were treated with iMSC CM, endothelial cell viability, adherence, spheroid compactness, and proangiogenic sprout formation were significantly ameliorated, and IR-induced ROS levels were reduced. iMSC CM augmented tube formation in cocultures of hCMEC/D3 and iMSCs. Consistently, iMSC CM facilitated angiogenesis in a zebrafish model in vivo. Furthermore, iMSC CM suppressed IR-induced NFκB activation, TNF-α release, and ROS production in THP1 cells. Additionally, iMSC CM diminished NF-kB activation in THP1 cells cocultured with irradiated hCMEC/D3, iMSCs, or HMC3 microglial lines. The cytokine array revealed that iMSC CM contains the proangiogenic and immunosuppressive factors MCP1/CCL2, IL6, IL8/CXCL8, ANG (Angiogenin), GROα/CXCL1, and RANTES/CCL5. Common promoter regulatory elements were enriched in TF-binding motifs such as androgen receptor (ANDR) and GATA2. hCMEC/D3 phosphokinome profiling revealed increased expression of pro-survival factors, the PI3K/AKT/mTOR modulator PRAS40 and β-catenin in response to CM. The transcriptome analysis revealed increased expression of GATA2 in iMSCs and the enrichment of pathways involved in RNA metabolism, translation, mitochondrial respiration, DNA damage repair, and neurodevelopment. Conclusions The iMSC secretome is a comodulated composite of proangiogenic and immunosuppressive factors that has the potential to alleviate radiation-induced vascular endothelial cell damage and immune activation.

Abstract Background The planification of radiation therapy (RT) for pancreatic cancer (PC) requires a dosimetric computed tomography (CT) scan to define the gross tumor volume (GTV). The main objective of this study was to compare the inter-observer variability in RT planning between the arterial and the venous phases following intravenous contrast. Methods PANCRINJ was a prospective monocentric study that included twenty patients with non-metastatic PC. Patients underwent a pre-therapeutic CT scan at the arterial and venous phases. The delineation of the GTV was performed by one radiologist (gold standard) and two senior radiation oncologists (operators). The primary objective was to compare the Jaccard conformity index (JCI) for the GTVs computed between the GS (gold standard) and the operators between the arterial and the venous phases with a Wilcoxon signed rank test for paired samples. The secondary endpoints were the geographical miss index (GMI), the kappa index, the intra-operator variability, and the dose-volume histograms between the arterial and venous phases. Results The median JCI for the arterial and venous phases were 0.50 (range, 0.17–0.64) and 0.41 (range, 0.23–0.61) (p = 0.10) respectively. The median GS-GTV was statistically significantly smaller compared to the operators at the arterial (p

Background: Colorectal cancer ranks as the third most prevalent cancer type globally. In addition to surgery, chemotherapy, and radiation therapy, being the foremost efficacious and all-encompassing treatment modalities for cancer, pelvic chemoradiotherapy is known to precipitate adverse effects, notably intestinal inflammation. This study delves into assessing the impact of curcumin on the prophylaxis and amelioration of chemoradiotherapy-induced enterocolitis in colorectal cancer patients. Method: This randomized study encompassed 44 colorectal cancer patients undergoing standard pelvic chemoradiotherapy, allocated to either curcumin treatment (22 patients) or placebo (22 patients) groups. Patients were administered oral curcumin capsules at a daily dosage of 500 mg commencing one week before baseline and extending throughout the standard treatment regimen, adhering to the same schedule. Subsequently, patients were subjected to biweekly evaluations encompassing demographics, clinical characteristics, and manifestations of enterocolitis, with statistical analysis employing Mann-Whitney and chi-square tests. A significance threshold of P < 0.05 was employed in the study for statistical significance. Results: The incidence of complications exhibited no statistically significant disparity between the two cohorts across diverse disease stages. Furthermore, there were no discernible discrepancies in the manifestation of varying grades of intestinal complications between the curcumin-treated and placebo groups. Predominantly, both groups experienced the most pronounced side-effects during the initial two weeks of treatment. Additionally, there was no statistically significant distinction in the prevalence of adverse drug reactions between the two groups, with figures standing at 31% versus 40% (P = 0.17). Conclusion: Even though 500 mg/day of curcumin over a six-week duration did not engender a statistically significant reduction in the adverse effects of chemoradiotherapy, it was well-tolerated and deemed safe in this patient cohort.

Abstract Background Radiation-induced fibrosis (RIF) is an important late complication of radiation therapy, and the resulting damaging effects of RIF can significantly impact reconstructive outcomes. There is currently a paucity of effective treatment options available, likely due to the continuing knowledge gap surrounding the cellular mechanisms involved. In this study, detailed analyses of irradiated and non-irradiated human skin samples were performed incorporating histological and single-cell transcriptional analysis to identify novel features guiding development of skin fibrosis following radiation injury. Methods Paired irradiated and contralateral non-irradiated skin samples were obtained from six female patients undergoing post-oncologic breast reconstruction. Skin samples underwent histological evaluation, immunohistochemistry, and biomechanical testing. Single-cell RNA sequencing was performed using the 10X single cell platform. Cells were separated into clusters using Seurat in R. The SingleR classifier was applied to ascribe cell type identities to each cluster. Differentially expressed genes characteristic to each cluster were then determined using non-parametric testing. Results Comparing irradiated and non-irradiated skin, epidermal atrophy, dermal thickening, and evidence of thick, disorganized collagen deposition within the extracellular matrix of irradiated skin were readily appreciated on histology. These histologic features were associated with stiffness that was higher in irradiated skin. Single-cell RNA sequencing revealed six predominant cell types. Focusing on fibroblasts/stromal lineage cells, five distinct transcriptional clusters (Clusters 0–4) were identified. Interestingly, while all clusters were noted to express Cav1, Cluster 2 was the only one to also express Cav2. Immunohistochemistry demonstrated increased expression of Cav2 in irradiated skin, whereas Cav1 was more readily identified in non-irradiated skin, suggesting Cav1 and Cav2 may act antagonistically to modulate fibrotic cellular responses. Conclusion In response to radiation therapy, specific changes to fibroblast subpopulations and enhanced Cav2 expression may contribute to fibrosis. Altogether, this study introduces a novel pathway of caveolin involvement which may contribute to fibrotic development following radiation injury.

Introduction: Grenz ray therapy popular in dermatology decades ago causes multiple and recalcitrant skin cancer in the treated field many years later. The treatment of choice is surgical excision, but limitations especially disfiguring scarring are a major challenge. We introduce 20 MHz high-intensity focused ultrasound (HIFU) as a new therapy overcoming the limitations of excisional surgery. Case Presentation: A 66-year-old female, who in the 1980s had received several grenz ray treatments of the scalp, developed multiple basal cell carcinomas in the field. She had over 30 excisional surgeries including Mohs surgery in the past with many local complications but, nevertheless, recurrent cancers. HIFU treatments applied to eight basal cell carcinomas and two precancerous lesions resulted in complete clearing at 12-month control, but one recurrence after 15 months. Conclusion: The HIFU treatment is convenient, with very few complications, and applicable to field eradication of skin premalignancies and malignancies. HIFU may fill out a hitherto unmet need of both preventive and curative treatment with better long-term control of patients with recalcitrant skin cancer after grenz ray given in the past. HIFU is a new potentially important therapeutic modality in skin oncology, combining curative treatment, field eradication, and prevention in one procedure through treatment of lesions in different states of progression.

Background: Interest in the oligometastatic prostate cancer (OMPC) is increasing, and various clinical studies have reported the benefits of metastasis-directed radiation therapy (MDRT) in OMPC. However, the recognition regarding the adopted definitions, methodologies of assessment, and therapeutic approaches is diverse among radiation oncologists. This study aims to evaluate the level of agreement for issues in OMPC among radiation oncologists. Methods: We generated 15 key questions (KQs) for OMPC relevant to definition, diagnosis, local therapies, and endpoints. Additionally, three clinical scenarios representing synchronous metastatic prostate cancer (mPC) (case 1), metachronous mPC with visceral metastasis (case 2), and metachronous mPC with castration-resistance and history of polymetastasis (case 3) were developed. The 15 KQs were adapted according to each scenario and transformed into 23 questions with 6–9 per scenario. The survey was distributed to 80 radiation oncologists throughout the Republic of Korea. Answer options with 0.0–29.9%, 30–49.9%, 50–69.9%, 70–79.9%, 80–89.9%, and 90–100% agreements were considered as no, minimal, weak, moderate, strong, and near perfect agreement, respectively. Results: Forty-five candidates voluntarily participated in this study. Among 23 questions, near perfect (n = 4), strong (n = 3), or moderate (n = 2) agreements were shown in nine. For the case recognized as OMPC with agreements of 93% (case 1), near perfect agreements on the application of definitive radiation therapy (RT) for whole metastatic lesions were achieved. While ≥70% agreements regarding optimal dose-fractionation for metastasis-directed RT (MDRT) has not been achieved, stereotactic body RT (SBRT) is favored by clinicians with higher clinical volume. Conclusion: For the case recognized as OMPC, near perfect agreement for the application of definitive RT for whole metastatic lesions was reached. SBRT was more favored as a MDRT by clinicians with a higher clinical volume.

Abstract Background Patients undergoing radiation therapy (RT) often experience anxiety, which may jeopardize the treatment success. The efficacy of music interventions in reducing anxiety remains contentious. This randomized trial aimed to evaluate the impact of music listening on anxiety symptoms in patients undergoing initial RT. Methods First-time RT patients were randomly allocated to experimental and control groups. The Brief Symptom Rating Scale (BSRS-5), Distress Thermometer (DT), and Beck Anxiety Inventory (BAI-C) were administered pre- and post-RT. Changes in physiological anxiety symptoms were monitored over 10 consecutive days starting from the first day of RT. The experimental group received music during RT; the control group did not. The generalized linear mixed model was used to estimate the pre–post difference in the BSRS-5, DT, and BAI-C scores between the music intervention and control group. Results This study included 50 patients each in the experimental and control groups. BSRS-5 and DT scores were significantly reduced in the experimental group post-RT (p = 0.0114 and p = 0.0023, respectively). When music listening was discontinued, these scores rebounded. While the posttest BAI-C score was significantly lower in the experimental group (p

Abstract Introduction Surface‐guided radiation therapy (SGRT) has emerged as a powerful tool to improve patient setup accuracy in radiation therapy (RT). Combined with the goal of increasing RT accuracy is an ongoing effort to decrease RT side effects. The application of a prophylactic skin dressing to the treatment site is a well‐documented method of reducing skin‐related side effects from RT. This paper aims to investigate whether the application of Mepitel, a prophylactic skin dressing, has an impact on the accuracy of surface‐guided patient setups in chest wall RT. Methods A retrospective analysis of daily image‐guided Online Corrections (OLCs) from patients undergoing chest wall irradiation with SGRT was performed. Translational (superior–inferior, lateral, and anterior–posterior) OLC magnitude and direction were compared between patients treated with Mepitel applied and those treated without. Systematic and random errors were calculated and compared between groups. Results OLCs from 275 fractions were analysed. Mean OLCs were larger for patients with Mepitel applied in the superior_inferior axis (0.34 vs. 0.22 cm, P = 0.049) and for the combined translational vector (0.54 vs. 0.43 cm, P = 0.043). Combined translational systematic error was slightly larger for patients with Mepitel applied (0.15 vs. 0.09 cm). Conclusion Mepitel can impact the accuracy of SGRT patient‐positioning in chest wall RT. The variation however is small and unlikely to have any clinical impact if SGRT is coupled with image guidance and appropriate PTV margins. Further investigation is required to assess the effect of Mepitel on SGRT accuracy in other treatment sites, as well as any potential dosimetric impacts.

Abstract Background Primary testicular lymphoma (PTL) is relatively rare. The contralateral testis is a common site of PTL relapse; therefore, once complete remission is achieved, radiation therapy (RT) is administered to the contralateral testis to prevent relapse. Case presentation A 76-year-old man was diagnosed with PTL and received RT as described above. However, despite achieving and maintaining complete remission, a mass diagnosed as diffuse large B-cell lymphoma by tissue biopsy developed in the glans penis 6.5 years after prophylactic RT. We investigated whether the glans penile lymphoma was PTL relapse or a new malignancy by genomic analysis using next-generation sequencing of DNA extracted from two histopathological specimens. Conclusions We found the same variant allele fraction in four somatic genes (MYD88, IL7R, BLNK, and FLT3) at similar frequencies, indicating that the glans penile lymphoma had the same origin as the PTL. To the best of our knowledge, this is the first case report of PTL relapse in the glans penis.

Abstract Background Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation. Experimental design We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization. Results EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy. Conclusion Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.

Urinary dysfunction following treatment for rectal adenocarcinoma is a common and complex complication. We present a case of a 69-year-old male who underwent laparoscopic-assisted left hemicolectomy and loop ileostomy after receiving chemotherapy and radiation therapy for rectal adenocarcinoma. Postoperatively, it was incidentally discovered the patient had urinary frequency and urgency. Cystoscopy revealed radiation changes to the bladder walls and a bladder leak was confirmed by cystogram. The patient underwent successful repair of the urinary bladder leak, with challenges posed by prior radiation therapy. Effective prevention and management strategies for urinary dysfunction require a comprehensive preoperative risk assessment, consideration of nerve-preserving surgical techniques, and prompt identification and repair of postoperative complications.

Prostate cancer brain metastases are rare but increasingly recognized with prostate-specific membrane antigen (PSMA) PET/CT. Distinguishing tumor response from postradiation changes are challenging on MRI. PSMA PET/CT may clarify equivocal brain lesions after radiotherapy.A 71-year-old man with metastatic prostate cancer developed 2 new brain lesions on PSMA PET/CT. Lesions were high PSMA-avid and MRI follow up showed enhancing masses with edema, consistent with metastases. He underwent whole-brain radiation. Follow-up PSMA PET/CT after radiotherapy demonstrated significantly decreased lesion size and activity, with activity lower than blood pool, indicating a treatment response. MRI also showed near-resolution of the lesions.This case highlights the potential utility of PSMA PET/CT for detecting prostate cancer brain metastases and monitoring treatment response. PSMA PET/CT provides valuable complementary information to MRI for managing irradiated prostate cancer brain metastases.

Background: This study aims to identify trends, research gaps, leading journals, institutions, countries, and authors by examining the top 100 cited Yttrium-90 Radioembolization (Y90) research articles. The insights gained will assist funding and collaboration efforts in Y90 research. The team analyzed 981 articles from 36 peer-reviewed journals, gathering data on authors, publication year, journal, citations, affiliations, keywords, and references. Author affiliations were scrutinized to pinpoint institutions and countries. p values < 0.05 were deemed statistically significant. The most cited paper (703 citations) was authored by Salem et al. (2010), and the journal with the most publications (16) was Journal of Vascular and Interventional Radiology. There was no significant correlation between journal impact factor and citation metrics. A decreasing trend in the number of top 100 articles was observed since the peak period (2008–2013). Most papers were published in high-impact factor (IF > 3, n = 31/35) and SCImago Q1 journals (86/100), with Northwestern University, Clínica Universidad de Navarra, and Ludwig Maximilian University of Munich being the leading institutions. The most prolific authors were Salem, R., Lewandowski, R.J., and Mulcahy, M.F., with Salem, R. as the most influential. A statistically significant positive correlation between collaborative links and published articles was also discovered. Short conclusion: The top 100 cited articles were primarily published in high-impact journals, and Northwestern University and the USA showed greater productivity and collaboration. These findings have crucial implications for researchers, policymakers, and institutions, aiding in the improvement of Y90 application and understanding in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Radiation therapy (RT) is one of the primary treatment options for early-stage non-small cell lung cancer (ES-NSCLC). Therefore, accurately predicting the overall survival (OS) rate following radiotherapy is crucial for implementing personalized treatment strategies. This work aims to develop a dual-radiomics (DR) model to (1) predict 3-year OS in ES-NSCLC patients receiving RT using pre-treatment CT images, and (2) provide explanations between feature importanceand model prediction performance. Methods: The publicly available TCIA Lung1 dataset with 132 ES-NSCLC patients received RT were studied: 89/43 patients in the under/over 3-year OS group. For each patient, two types of radiomic features were examined: 56 handcrafted radiomic features (HRFs) extracted within gross tumor volume, and 512 image deep features (IDFs) extracted using a pre-trained U-Net encoder. They were combined as inputs to an explainable boosting machine (EBM) model for OS prediction. The EBM's mean absolute scores for HRFs and IDFs were used as feature importance explanations. To evaluate identified feature importance, the DR model was compared with EBM using either (1) key or (2) non-key feature type only. Comparison studies with other models, including supporting vector machine (SVM) and random forest (RF), were also included. The performance was evaluated by the area under the receiver operating characteristic curve (AUCROC), accuracy, sensitivity, and specificity with a 100-fold Monte Carlo cross-validation. Results: The DR model showed highestperformance in predicting 3-year OS (AUCROC=0.81 ± 0.04), and EBM scores suggested that IDFs showed significantly greater importance (normalized mean score=0.0019) than HRFs (score=0.0008). The comparison studies showed that EBM with key feature type (IDFs-only demonstrated comparable AUCROC results (0.81 ± 0.04), while EBM with non-key feature type (HRFs-only) showed limited AUCROC (0.64 ± 0.10). The results suggested that feature importance score identified by EBM is highly correlated with OS prediction performance. Both SVM and RF models were unable to explain key feature type while showing limited overall AUCROC=0.66 ± 0.07 and 0.77 ± 0.06, respectively. Accuracy, sensitivity, and specificity showed a similar trend. Discussion: In conclusion, a DR model was successfully developed to predict ESNSCLC OS based on pre-treatment CT images. The results suggested that the feature importance from DR model is highly correlated to the model prediction power. [ABSTRACT FROM AUTHOR]

The addition of metastasis-directed radiotherapy (MDRT) to immunotherapy in patients with advanced urothelial carcinoma (aUC) has shown promising results. We report the real-world data from the ARON-2 study (NCT05290038) on the impact of conventional (CRT) or stereotactic body radiotherapy (SBRT) on the outcome of aUC patients receiving pembrolizumab after platinum-based-chemotherapy. Medical records of 837 patients were reviewed from 60 institutions in 20 countries. Two hundred and sixty-two patients (31%) received radiotherapy (cohort A), of whom 193 (23%) received CRT and 69 (8%) received SBRT. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. With a median follow-up of 22.7 months, the median OS was 10.2 months, 6.8 months and 16.0 months in no RT, CRT and SBRT subgroups (p = 0.005), with an 1y-OS rates of 47%, 34% and 61%, respectively (p < 0.001). The 1y-OS rate in the SBRT subgroup were significantly higher for both lower (63%) and upper tract UC (68%), for pure urothelial histology (63%) and variant histologies (58%), and for patients with bone (40%) and lymph-node metastases (61%). Median PFS was 4.8 months, 9.6 months and 5.8 months in the CRT, SBRT and no RT subgroups, respectively (p = 0.060). The 1y-PFS rate was significantly higher (48%) in the SBRT population and was confirmed in all patient subsets. The difference in terms of ORR was in favour of SBRT. Our real-world analysis showed that the use of SBRT/pembrolizumab combination may play a role in a subset of aUC patients to increase disease control and possibly overall survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Glutamine (Gln) plays a critical role in the development and progression of prostate cancer (PCa). Non-malignant prostate cells are not addicted to Gln, but PCa cells become Gln-dependent due to the low levels of the Gln-producing enzyme glutamine synthetase. Gln metabolism in PCa is controlled by oncogenes such as MYC, AR, and mTOR, which contribute to therapy resistance and more aggressive forms of the disease. Studies have shown that depriving PCa cells of Gln can inhibit their growth and survival and make them more sensitive to radiotherapy. Targeting Gln metabolism is, therefore, a promising approach for PCa treatment. Clinical trials are currently testing the safety and efficacy of drugs that inhibit Gln metabolism in combination with other therapies for different types of cancer, including PCa. Understanding of how tumor cells metabolically interact with their environment may help improve these treatments and patient outcomes. In this review, we present the latest advances in Gln research in PCa and insights into the current clinical trials. Glutamine (Gln) is a non-essential amino acid that is involved in the development and progression of several malignancies, including prostate cancer (PCa). While Gln is non-essential for non-malignant prostate epithelial cells, PCa cells become highly dependent on an exogenous source of Gln. The Gln metabolism in PCa is tightly controlled by well-described oncogenes such as MYC, AR, and mTOR. These oncogenes contribute to therapy resistance and progression to the aggressive castration-resistant PCa. Inhibition of Gln catabolism impedes PCa growth, survival, and tumor-initiating potential while sensitizing the cells to radiotherapy. Therefore, given its significant role in tumor growth, targeting Gln metabolism is a promising approach for developing new therapeutic strategies. Ongoing clinical trials evaluate the safety and efficacy of Gln catabolism inhibitors in combination with conventional and targeted therapies in patients with various solid tumors, including PCa. Further understanding of how PCa cells metabolically interact with their microenvironment will facilitate the clinical translation of Gln inhibitors and help improve therapeutic outcomes. This review focuses on the role of Gln in PCa progression and therapy resistance and provides insights into current clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: To enhance the accuracy of real-time four-dimensional cone beam CT (4D-CBCT) imaging by incorporating spatiotemporal correlation from the sequential projection image into the single projection-based 4D-CBCT estimation process. Methods: We first derived 4D deformation vector fields (DVFs) from patient 4DCT. Principal component analysis (PCA) was then employed to extract distinctive feature labels for each DVF, focusing on the first three PCA coefficients. To simulate a wide range of respiratory motion, we expanded the motion amplitude and used random sampling to generate approximately 900 sets of PCA labels. These labels were used to produce 900 simulated 4D-DVFs, which in turn deformed the 0% phase 4D-CT to obtain 900 CBCT volumes with continuous motion amplitudes. Following this, the forward projection was performed at one angle to get all of the digital reconstructed radiographs (DRRs). These DRRs and the PCA labels were used as the training data set. To capture the spatiotemporal correlation in the projections, we propose to use the convolutional LSTM (ConvLSTM) network for PCA coefficient estimation. For network testing, when several online CBCT projections (with different motion amplitudes that cover the full respiration range) are acquired and sent into the network, the corresponding 4D-PCA coefficients will be obtained and finally lead to a full online 4D-CBCT prediction. A phantom experiment is first performed with the XCAT phantom; then, a pilot clinical evaluation is further conducted. Results: Results on the XCAT phantom and the patient data show that the proposed approach outperformed other networks in terms of visual inspection and quantitative metrics. For the XCAT phantom experiment, ConvLSTM achieves the highest quantification accuracy with MAPE(Mean Absolute Percentage Error), PSNR (Peak Signal-to-Noise Ratio), and RMSE(Root Mean Squared Error) of 0.0459, 64.6742, and 0.0011, respectively. For the patient pilot clinical experiment, ConvLSTM also achieves the best quantification accuracy with that of 0.0934, 63.7294, and 0.0019, respectively. The quantification evaluation labels that we used are 1) the Mean Absolute Error (MAE), 2) the Normalized Cross Correlation (NCC), 3)the Structural Similarity Index Measurement(SSIM), 4)the Peak Signal-to-Noise Ratio (PSNR), 5)the Root Mean Squared Error(RMSE), and 6) the Absolute Percentage Error (MAPE). Conclusion: The spatiotemporal correlation-based respiration motion modeling supplied a potential solution for accurate real-time 4D-CBCT reconstruction. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): To evaluate rates of clinical complete response (cCR), surgery-free survival, permanent ostomy-free survival, and factors associated with these outcomes in patients treated with total neoadjuvant therapy (TNT) with intent for non-operative management of rectal adenocarcinoma. Methods: A retrospective review was conducted of patients treated with TNT for stage II-IV rectal adenocarcinoma (n=45) at our institution between 2013 - 2022 with curative intent. All patients received radiation with concurrent capecitabine and additional chemotherapy, either prior to or following chemoradiation (CRT), with intent for non-operative management. Response rates were determined based on post-treatment MRI and endoscopy. Kaplan-Meier method was utilized to estimate the 1- and 2-year surgery- and permanent ostomy-free survivals. Cox regression was used to evaluate associations between surgery- and permanent ostomy-free survivals and various factors of interest, including patient and tumor characteristics and clinical response. Chi-squared analysis compared rates of cCR and surgery by sequence of TNT modality and cell count ratios. Results: Of the 45 patients treated with TNT, most patients had low-lying rectal tumors with a median distance of 4.1 cm from the anal verge (range, 0.0 - 12.0). Overall, 64.4% (n=29) achieved cCR after TNT. 13 patients (28.9%) underwent surgical resection following TNT, 12 of whom had incomplete response and one who elected to undergo surgery after reaching cCR. At median follow up of 32.0 months (range, 7.1 - 86.1), 22.2% (n=10) of patients had a permanent colostomy, with only 2 of these completed for tumor regrowth after cCR. At one and two years, respectively, surgery-free survival was 77.3% and 66.2%, and permanent ostomy-free survival was 90.9% and 78.2%. Rates of cCR were higher in patients who received CRT first compared to those who received chemotherapy first (72.2% vs. 33.3%, p=0.029) and rates of surgery were also lower in patients who received CRT first compared to those who received chemotherapy first (19.4% vs. 66.7%, p=0.005). On Cox regression model, cCR on 6 month post-CRT endoscopy was associated with surgery-free survival (p=0.006) and permanent ostomy-free survival (p=0.033). Clinical response at earlier follow up points did not predict surgery-nor permanent ostomy-free survival. Conclusion: These results support evidence that TNT may be a non-surgical option for select patients with rectal adenocarcinoma who desire organ preservation. In this investigation at a single institution, the treatment response on 6-month post-CRT endoscopy was the best predictor of surgery- and permanent ostomy-free survival, which are outcomes that are important to patient quality of life. CRT followed by consolidation chemotherapy was associated with higher rates of cCR and lower rates of surgery compared to those treated with induction chemotherapy. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) continues to be the primary approach for treating cancer, and numerous cancer biomarkers associated with oncological outcomes have been investigated in the context of RT. The serum platelet-to-lymphocyte ratio (PLR) is one of the emerging landmark biomarker in the oncologic field. Mounting evidence indicates that an elevated serum PLR may function as a marker of unfavorable tumor characteristics, adverse treatment outcomes and treatment-related toxicities among individuals undergoing RT. However, the findings of these investigations have revealed a few disparities among researchers, highlighting the need for further meticulously planned studies to draw conclusive results. This article provides a comprehensive literature review and in-depth discussion regarding the clinical implications of the serum PLR in the modern RT era. [ABSTRACT FROM AUTHOR]

Introduction: Primary vitreoretinal lymphoma (PVRL) is a rare malignant tumor that typically involves the retina, vitreous, or optic nerve head. PVRL often occurs concurrently with central nervous system lymphoma. Here, we present the first report of a patient with biopsy-confirmed PVRL presenting solely with asymptomatic peripheral drusenoid lesions. Case Presentation: A woman in her 70s presented with new elevated amelanotic yellow lesions with overlying pigment in both of her eyes not previously seen prior to cataract surgery. Over the next 4 months, there was waxing and waning of lesions which resolved and first appeared in the right eye and then the left. A diagnostic vitrectomy of the left eye revealed B-cell lymphoma. The patient elected for initial treatment with radiation therapy of both orbits. A new lesion was identified in her right eye nearly 18 months after starting maintenance therapy with ibrutinib, following which systemic chemotherapy with methotrexate was initiated. Conclusion: Elevated clinical suspicion for a malignant process is needed for patients with progressive new retinal lesions in older age. Local radiation therapy to the orbits alone may not be sufficient to prevent progression despite initial presentation showing confinement of disease to the intraocular space. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of various frequencies of bolus use on the superficial dose of volumetric modulated arc therapy after modified radical mastectomy for breast cancer. Methods: Based on the computed tomography images of a female anthropomorphic breast phantom, a 0.5 cm silicone-based 3D-printed bolus was created. Nine points evenly distributed on the breast skin were selected for assessing the skin dose, and a volume of subcutaneous lymphatic drainage of the breast (noted as ROI2-3) was delineated for assessing the chest wall dose. The treatment plans with and without bolus (plan_wb and plan_nb) were separately designed using the prescription of 50 Gy in 25 fractions following the standard dose constraints of the adjacent organ at risk. To characterize the accuracy of treatment planning system (TPS) dose calculations, the doses of the nine points were measured five times by thermoluminescence dosimeters (TLDs) and then were compared with the TPS calculated dose. Results: Compared with Plan_nb (144.46 ± 10.32 cGy), the breast skin dose for plan_wb (208.75 ± 4.55 cGy) was significantly increased (t = −18.56, P < 0.001). The deviation of skin dose was smaller for Plan_wb, and the uniformity was significantly improved. The calculated value of TPS was in good agreement with the measured value of TLD, and the maximum deviation was within 5%. Skin and ROI2-3 doses were significantly increased with increasing frequencies of bolus applications. The mean dose of the breast skin and ROI2-3 for 15 and 23 times bolus applications were 45.33 Gy, 50.88 Gy and 50.36 Gy, 52.39 Gy, respectively. Conclusion: 3D printing bolus can improve the radiation dose and the accuracy of the planned dose. Setting Plan_wb to 15 times for T1-3N+ breast cancer patients and 23 times for T4N+ breast cancer patients can meet the clinical need. Quantitative analysis of the bolus application frequency for different tumor stages can provide a reference for clinical practice. [ABSTRACT FROM AUTHOR]

Using the MTT 3-(4, 5-dimethylthiazol-2yl-2, 5-diphenyltetrazolium bromide) assay induced by hydrogen peroxide (H2O2) and the ability to increase the cytotoxicity of doxorubicin in HepG2 and MDA-MB-231 cells, the protective effects of ethanolic extract of tamarillo were assessed in the current study. The cells were pre-treated with tamarillo ethanolic extract at 10 g/mL for 4 h before being exposed to 0.6 mM H2O2 for 3 h showed the greatest protection, with a significant increase (P 0.05) in cell viability of 79% compared to the control (57%). The results support a role that cyto-protective effect of tamarillo and doxorubicin which low in toxicity opens a new possible approach for possible future use in conventional chemotherapeutic drugs and radiation therapy. [ABSTRACT FROM AUTHOR]

Anal cancer is uncommon, comprising 2.2% of gastrointestinal cancers. Squamous cell carcinoma (SCC) is the most common; while perianal basal cell carcinoma (BCC) is rare, representing only 0.2% of anorectal malignancies. BCC, associated with sun exposure and immunosuppression, often resembles benign conditions and manifests as perianal ulcers or masses. Histologically, BCC exhibits basaloid tumor cells with distinct patterns. Despite its rarity, accurate diagnosis is crucial. We expose a case study of a 59-year-old male, previously healthy, that presented with hematochezia and perianal pain, leading to a diagnosis of lower gastrointestinal bleeding. Colonoscopy was needed, and a biopsy revealed an ulcerated, indurated lesion involving the left lateral hemorrhoidal bundle, diagnosed as pigmented basaloid carcinoma. Microscopic examination showed malignant nests of cells with peripheral nuclear palisading, melanocytes, and melanin pigment. Immunohistochemistry confirmed positivity for p63, CK5/6, and BCL2. Respect the treatment, due to the involvement of the anal sphincteric muscle, radiotherapy was chosen. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for over 85% of cases and poor prognosis in advanced stages. This study explored shifts in circulating metabolite levels in NSCLC patients versus healthy controls and examined the effects of conventionally fractionated radiation therapy (CFRT) and stereotactic body radiation therapy (SBRT). We enrolled 91 NSCLC patients (38 CFRT and 53 SBRT) and 40 healthy controls. Plasma metabolite levels were assessed using semi-targeted metabolomics, revealing 32 elevated and 18 reduced metabolites in patients. Key discriminatory metabolites included ethylmalonic acid, maltose, 3-phosphoglyceric acid, taurine, glutamic acid, glycocolic acid, and d-arabinose, with a combined Receiver Operating Characteristics curve indicating perfect discrimination between patients and controls. CFRT and SBRT affected different metabolites, but both changes suggested a partial normalization of energy and amino acid metabolism pathways. In conclusion, metabolomics identified distinct metabolic signatures in NSCLC patients with potential as diagnostic biomarkers. The differing metabolic responses to CFRT and SBRT reflect their unique therapeutic impacts, underscoring the utility of this technique in enhancing NSCLC diagnosis and treatment monitoring. [ABSTRACT FROM AUTHOR]

Objectives: Olfactory dysfunction is an overlooked adverse effect of radiation therapy. This study is designed to find the effect of radiation therapy on olfactory function in head and neck malignancy excluding tumors of nose and nasopharynx and correlate the olfactory changes with the radiotherapy dose. Method: This prospective observational study was done over a 2-year period in 34 participants with head and neck malignancies who underwent radiation therapy (RT). The participants olfaction was evaluated subjectively with Italian Nose Obstruction Symptom Evaluation (I-NOSE) scale and objectively by a modified I-Smell test which included an olfactory identification score and an olfactory threshold score at 5 time points. The beginning of RT (T 0), at 2 weeks of RT(T 1), end of RT (T 2), 1 month follow-up (T 3), and 3-month follow-up (T 4). The near maximum dose to the nasal cavity (D 2%) and mean dose to the nasal cavity (D mean) were calculated for all participants and correlated with olfactory function. Results: A total of 34 patients with head neck malignancy were recruited. The median I-NOSE score reached maximum at the end of radiation and decreased to baseline at 3 months follow-up (P <.001). The olfactory identification score, olfactory threshold score, and median combined olfactory score showed a significant decrease at the end of radiation therapy compared to Pre-radiation therapy values. There was a significant but incomplete recovery in the 3-month follow-up period (P <.001). Conclusion: There was a significant deterioration in quality of life for olfaction, olfactory identification, and olfactory threshold at the completion of radiotherapy. At 3 months follow-up, though there was no complete recovery of olfaction, it did not have an adverse effect on the quality of life. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess if multicriteria optimization could limit interoperator variability in radiation therapy planning and assess if this method could contribute to target volume coverage and sparing of organ at risk for intensity-modulated curative radiation therapy of head and neck cancers. We performed a retrospective analysis on 20 patients treated for an oropharyngeal or oral cavity squamous cell carcinoma. We carried out a comparative dosimetric study of manual plans produced with Precision® software, compared with the plans proposed using the multicriteria optimization method (RayStation®). We assessed interoperator reproducibility on the first six patients, and dosimetric contribution in sparing organs at risk using the multicriteria optimization method. Median age was 69 years, most lesions were oropharyngeal carcinoma (65%), and 35% lesions were stage T3. First, we obtained a high degree of similarity between the four operator measurements for each patient at the level of each organ. Intraclass correlation coefficients were greater than 0.85. Second, we observed a significant dosimetric benefit for contralateral parotid gland, homolateral and contralateral masseter muscles, homolateral and contralateral pterygoid muscles and for the larynx (P < 0.05). For the contralateral parotid gland, the mean dose difference between the multicriteria optimization and manual plans was −2.0 Gy (P = 0.01). Regarding the larynx, the mean dose difference between the two plans was −4.6 Gy (P < 0.001). Multicriteria optimization is a reproducible technique and faster than manual optimization. It allows dosimetric advantages on organs at risk, especially for those not usually taken into consideration in manual dosimetry. This may lead to improved quality of life. [ABSTRACT FROM AUTHOR]

Simple Summary: Proton therapy has been shown to provide dosimetric benefits in comparison with IMRT when treating prostate cancer with whole pelvis radiation; however, the optimal proton beam arrangement has yet to be established. Twenty-three post-prostatectomy patients were planned using three different beam arrangements: two-field (opposed laterals), three-field (opposed laterals inferiorly matched to a posterior–anterior beam superiorly), and four-field (opposed laterals inferiorly matched to two posterior oblique beams superiorly) arrangements. CTV coverages were similar for all plans, while the four-field plan provided the lowest doses to several metrics for bladder, bowel, sigmoid, rectum, femoral head, bone, penile bulb, and skin. The data presented herein may help inform the future delivery of whole pelvis IMPT for prostate cancer. Background and purpose: Proton therapy has been shown to provide dosimetric benefits in comparison with IMRT when treating prostate cancer with whole pelvis radiation; however, the optimal proton beam arrangement has yet to be established. The aim of this study was to evaluate three different intensity-modulated proton therapy (IMPT) beam arrangements when treating the prostate bed and pelvis in the postoperative setting. Materials and Methods: Twenty-three post-prostatectomy patients were planned using three different beam arrangements: two-field (IMPT2B) (opposed laterals), three-field (IMPT3B) (opposed laterals inferiorly matched to a posterior–anterior beam superiorly), and four-field (IMPT4B) (opposed laterals inferiorly matched to two posterior oblique beams superiorly) arrangements. The prescription was 50 Gy radiobiological equivalent (GyE) to the pelvis and 70 GyE to the prostate bed. Comparisons were made using paired two-sided Wilcoxon signed-rank tests. Results: CTV coverages were met for all IMPT plans, with 99% of CTVs receiving ≥ 100% of prescription doses. All organ at risk (OAR) objectives were met with IMPT3B and IMPT4B plans, while several rectum objectives were exceeded by IMPT2B plans. IMPT4B provided the lowest doses to OARs for the majority of analyzed outcomes, with significantly lower doses than IMPT2B +/− IMPT3B for bladder V30–V50 and mean dose; bowel V15–V45 and mean dose; sigmoid maximum dose; rectum V40–V72.1, maximum dose, and mean dose; femoral head V37–40 and maximum dose; bone V40 and mean dose; penile bulb mean dose; and skin maximum dose. Conclusion: This study is the first to compare proton beam arrangements when treating the prostate bed and pelvis. four-field plans provided better sparing of the bladder, bowel, and rectum than 2- and three-field plans. The data presented herein may help inform the future delivery of whole pelvis IMPT for prostate cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: RCC has traditionally been considered radioresistant, with surgery being the gold standard for primary localized RCC. However, not all patients are suitable for surgery and percutaneous, non-surgical options are invasive, with significant limitations. SABR is a non-invasive advanced RT technique that delivers high doses accurately. Growing evidence supports SABR as a definitive alternative therapy for medically inoperable patients, those who decline surgery, are unfit for invasive ablation, or are at high-risk of requiring postoperative dialysis. SABR has shifted the renal radioresistance paradigm, widening the therapeutic window. Additionally, SABR is increasingly used for locally recurrent, oligoprogressive, and oligometastatic disease. This review aims to support the use of SABR across various stages of RCC disease and explore future directions. The overall landscape of RCC is promising, and we are confident that our update will stimulate further research in this field and contribute to the advancement of patient care. Renal cell cancer (RCC) has traditionally been considered radioresistant. Because of this, conventional radiotherapy (RT) has been predominantly relegated to the palliation of symptomatic metastatic disease. The implementation of stereotactic ablative radiotherapy (SABR) has made it possible to deliver higher ablative doses safely, shifting the renal radioresistance paradigm. SABR has increasingly been adopted into the multidisciplinary framework for the treatment of locally recurrent, oligoprogressive, and oligometastatic disease. Furthermore, there is growing evidence of SABR as a non-invasive definitive therapy in patients with primary RCC who are medically inoperable or who decline surgery, unsuited to invasive ablation (surgery or percutaneous techniques), or at high-risk of requiring post-operative dialysis. Encouraging outcomes have even been reported in cases of solitary kidney or pre-existing chronic disease (poor eGFR), with a high likelihood of preserving renal function. A review of clinical evidence supporting the use of ablative radiotherapy (SABR) in primary, recurrent, and metastatic RCC has been conducted. Given the potential immunogenic effect of the high RT doses, we also explore emerging opportunities to combine SABR with systemic treatments. In addition, we explore future directions and ongoing clinical trials in the evolving landscape of this disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma is the most common and aggressive brain tumor in adults. Despite surgery, radiation, and chemotherapy, survival rates remain low, which emphasizes the urgent need for improved therapies. Current preclinical models use untreated tumors, which do not reflect the clinical scenario where patients already receive initial treatments. This review examines the effects of current treatments on the properties of recurrent tumors and evaluates preclinical models that incorporate these standard treatments to better mimic real patient conditions. Improving these models could help to identify more effective treatments, potentially leading to better outcomes for glioblastoma patients. Glioblastoma (GBM) presents a significant public health challenge as the deadliest and most common malignant brain tumor in adults. Despite standard-of-care treatment, which includes surgery, radiation, and chemotherapy, mortality rates are high, underscoring the critical need for advancing GBM therapy. Over the past two decades, numerous clinical trials have been performed, yet only a small fraction demonstrated a benefit, raising concerns about the predictability of current preclinical models. Traditionally, preclinical studies utilize treatment-naïve tumors, failing to model the clinical scenario where patients undergo standard-of-care treatment prior to recurrence. Recurrent GBM generally exhibits distinct molecular alterations influenced by treatment selection pressures. In this review, we discuss the impact of treatment—surgery, radiation, and chemotherapy—on GBM. We also provide a summary of treatments used in preclinical models, advocating for their integration to enhance the translation of novel strategies to improve therapeutic outcomes in GBM. [ABSTRACT FROM AUTHOR]

Purpose: To examine demographic and clinical characteristics and their association with survival in grade 2 and 3 pediatric meningiomas in a large cohort using the National Cancer Database (NCDB). Methods: We conducted a comprehensive analysis using data from NCDB between 2004 to 2018. Tumor-specific data included tumor grade and size. Treatment details, including surgical resection, extent of resection, and radiotherapy, were gathered. Our analytic approach incorporated logistic and Poisson regression, Kaplan-Meier survival estimates, and Cox proportional hazards models. Results: Among the included 239 patients aged 0–21 years, age category distribution was significantly different between grade 2 and grade 3 tumors (p = 0.018). For grade 2 meningiomas, 51.5% of patients were female, and 76.7% were white. 85.3% of patients with grade 2 meningiomas underwent surgical resection, of which 67% underwent gross total resection. Overall survival (OS) was significantly different between resected and non-resected patients (p = 0.048). Uninsured patients were over seven times as likely to have prolonged length of stay (LOS) versus those with private insurance (OR = 7.663, p = 0.014). For grade 3 meningiomas, 51.4% of patients were male, and 82.9% were white. 91.4% of patients with grade 3 meningiomas underwent surgical resection, of which 53.3% underwent subtotal resection. OS was not significantly different between resected and non-resected patients (p = 0.659). Conclusion: In summary, there were significant differences in age, maximum tumor dimension, unplanned readmission, radiotherapy, and treatment combinations between grade 2 and 3 meningiomas. These findings highlight the intricacies of managing pediatric meningiomas and emphasize the necessity for tailored therapeutic approaches to enhance outcomes in the future. [ABSTRACT FROM AUTHOR]

Background: Biliary tract cancers (BTC) are rare and aggressive malignancies originating from intrahepatic and extrahepatic bile ducts and the gallbladder. Surgery is the only curative option, but due to late-stage diagnosis, is frequently not feasible, leaving chemotherapy as the primary treatment. Radiotherapy (RT) can be an effective alternative for patients with unresectable, non-metastatic BTC despite the generally poor prognosis and significant variability. To help manage patients with unresectable BTC who receive RT, we aimed to identify prognostic markers that could aid in predicting overall survival (OS). Methods: A retrospective cohort study was conducted at the University of Pennsylvania, involving seventy-eight patients with unresectable BTC treated with definitive intent RT. Comprehensive demographic, clinical, and treatment-related data were extracted from the electronic medical records. Univariate and multivariate Cox regressions were employed to identify predictors of OS after RT. A biomarker model was developed for refined survival prediction. Results: The cohort primarily comprised patients with good performance status without significant hepatic dysfunction at presentation. The predominant treatment approach involved hypofractionated RT or concurrent 5FU-based chemoRT. Median OS after RT was 12.3 months, and 20 patients (15.6%) experienced local progression with a median time of 30.1 months. Univariate and multivariate analyses identified CA19-9 (above median) and higher albumin-bilirubin (ALBI) grades at presentation as significant predictors of poor OS. Median OS after RT was 24 months for patients with no risk factors and 6.3 months for those with both. Conclusions: Our study demonstrates generally poor but significantly heterogeneous OS in patients with unresectable BTC treated with RT. We have developed a biomarker model based on CA19-9 and ALBI grade at presentation that can distinguish sub-populations with markedly diverse prognoses. This model can aid the clinical management of this challenging disease. [ABSTRACT FROM AUTHOR]

Background: Structured exercise has an important role in mitigating the extensive side effects caused by ongoing prostate cancer treatments, specifically androgen deprivation therapy (ADT) and radiation therapy (RT). Little is known about men's experiences of, and preferences for, structured exercise programmes during active cancer treatment. This study aimed to inform the acceptability of a 6-month supervised intervention that emphasised increasing and varied intensities of aerobic and resistance exercise, by exploring the experiences of men who participated. Methods: Individual semi-structured interviews were conducted with an interviewer independent of the exercise study and data was analysed using a descriptive qualitative design. Results: Twelve prostate cancer patients were interviewed including participants who completed (n = 9) and withdrew from (n = 3) the intervention. Four main themes captured how men experienced the intervention: (1) Navigating the Unknown: Building confidence amidst vulnerability (subtheme- pushing the limits), (2) Building Trust: The credibility and approach of the exercise instructor (subtheme- appropriateness of supervised vs. independent exercise), (3) Flexibility in Delivery, (4) Finding Purpose: Exercise as a means of escapism and regaining control during treatment. Conclusion: While an initial lack of self-confidence can be a barrier to exercise participation, exercise programmes have the potential to provide psychosocial benefits, rebuild confidence and empower men throughout their cancer treatment and into recovery. Structured exercise is acceptable during treatment including RT and can offer a form of escapism and sense of control for men navigating their cancer journey. Trust building, flexible delivery and credibility alongside a challenging exercise prescription are important facilitators of acceptability for men. Strategies to embed exercise from the point of diagnosis through ADT and RT should reflect men's experiences of exercise during treatment. Trial registration: The trial has been registered on ClinicalTrials.gov as of the 14th of December 2021 (NCT05156424). [ABSTRACT FROM AUTHOR]

The evidence in the field of diagnosis, staging, and treatment of localised prostate cancer (PCa) is evolving rapidly. The 2024 European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Urological Pathology (ISUP)-International Society of Geriatric Oncology (SIOG) guidelines on PCa summarise the most recent findings and advice for their use in clinical practice. These PCa guidelines reflect the multidisciplinary nature of PCa management. The European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Urological Pathology (ISUP)-International Society of Geriatric Oncology (SIOG) guidelines provide recommendations for the management of clinically localised prostate cancer (PCa). This paper aims to present a summary of the 2024 version of the EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on the screening, diagnosis, and treatment of clinically localised PCa. The panel performed a literature review of all new data published in English, covering the time frame between May 2020 and 2023. The guidelines were updated, and a strength rating for each recommendation was added based on a systematic review of the evidence. A risk-adapted strategy for identifying men who may develop PCa is advised, generally commencing at 50 yr of age and based on individualised life expectancy. The use of multiparametric magnetic resonance imaging in order to avoid unnecessary biopsies is recommended. When a biopsy is considered, a combination of targeted and regional biopsies should be performed. Prostate-specific membrane antigen positron emission tomography imaging is the most sensitive technique for identifying metastatic spread. Active surveillance is the appropriate management for men with low-risk PCa, as well as for selected favourable intermediate-risk patients with International Society of Urological Pathology grade group 2 lesions. Local therapies are addressed, as well as the management of persistent prostate-specific antigen after surgery. A recommendation to consider hypofractionation in intermediate-risk patients is provided. Patients with cN1 PCa should be offered a local treatment combined with long-term intensified hormonal treatment. The evidence in the field of diagnosis, staging, and treatment of localised PCa is evolving rapidly. These PCa guidelines reflect the multidisciplinary nature of PCa management. This article is the summary of the guidelines for "curable" prostate cancer. Prostate cancer is "found" through a multistep risk-based screening process. The objective is to find as many men as possible with a curable cancer. Prostate cancer is curable if it resides in the prostate; it is then classified into low-, intermediary-, and high-risk localised and locally advanced prostate cancer. These risk classes are the basis of the treatments. Low-risk prostate cancer is treated with "active surveillance", a treatment with excellent prognosis. For low-intermediary-risk active surveillance should also be discussed as an option. In other cases, active treatments, surgery, or radiation treatment should be discussed along with the potential side effects to allow shared decision-making. [ABSTRACT FROM AUTHOR]

• History of cancer treatments. • The current landscape of cancer treatments. • Potential future cancer therapies. There is a rich history of cancer treatments which provides a number of important lessons for present and future cancer therapies. We outline this history by looking in the past, reviewing the current landscape of cancer treatments, and by glancing at the potential future cancer therapies. [ABSTRACT FROM AUTHOR]

Before introducing new treatment techniques, an investigation of hazards due to unintentional radiation exposures is a reasonable activity for proactively increasing patient safety. As dedicated software is scarce, we developed a tool for risk assessment to design a quality management program based on best practice methods, i.e., process mapping, failure modes and effects analysis and fault tree analysis. Implemented as a web database application, a single dataset was used to describe the treatment process and its failure modes. The design of the system and dataset allowed failure modes to be represented both visually as fault trees and in a tabular form. Following the commissioning of the software for our department, previously conducted risk assessments were migrated to the new system after being fully re-assessed which revealed a shift in risk priorities. Furthermore, a weighting factor was investigated to bring risk levels of the migrated assessments into perspective. The compensation did not affect high priorities but did re-prioritize in the midrange of the ranking. We conclude that the tool is suitable to conduct multiple risk assessments and concomitantly keep track of the overall quality management activities. [ABSTRACT FROM AUTHOR]

MRI is widely used in radiation therapy planning, particularly in stereotactic radiosurgery for brain metastases. The article addresses the geometric distortion of MRI images, which can lead to errors in radiation therapy planning. A series of experiments with a simple phantom were conducted on two MRI scanners with 0.5 and 1.5 T magnetic fields. Deviations in the positions of the phantom objects from their actual locations were observed. The detected deviations can reach up to 5 mm. A theoretical dependence of the magnetic field gradient on the distance to the center of homogeneity was calculated, which agrees well with the approximation of experimental data. An assessment was made of the dependence of the image area distortion of objects located at the center of the field homogeneity on their actual sizes. It was found that the area deviation can reach up to 20 . [ABSTRACT FROM AUTHOR]

In radiation therapy, patient setup is important for improving treatment accuracy. The six-axis couch semi-automatically adjusts the patient's position; however, adjusting the patient to twist is difficult. In this study, we developed and evaluated a virtual reality setup training tool for medical students to understand and improve their patient setup skills for radiation therapy. First, we set up a simulated patient in a virtual space to reproduce the radiation treatment room. A gyro sensor was attached to the patient phantom in real space, and the twist of the phantom was linked to the patient in the virtual space. Training was conducted for 24 students, and their operation records were analyzed and evaluated. The training's efficacy was also evaluated through questionnaires provided at the end of the training. The total time required for patient setup tests before and after training decreased significantly from 331.9 s to 146.2 s. As a result of the questionnaire regarding the usability of training to the trainee, most were highly evaluated. We found that training significantly improved students' understanding of the patient setup. With the proposed system, trainees can experience a simulated setup that can aid in deepening their understanding of radiation therapy treatments. [ABSTRACT FROM AUTHOR]

Purpose: Prior data have demonstrated relationships between patient characteristics, the use of surgery to treat lung cancer, and the timeliness of treatment. Our study examines whether these relationships were observable in 2019 in patients with Medicare Advantage health plans being treated for lung cancer. Methods: Claims data pertaining to patients with Medicare Advantage health plans who had received radiation therapy (RT) or surgery to treat lung cancer within 90 days of diagnostic imaging were extracted. Other databases were used to determine patients' demographics, comorbidities, the urbanicity of their ZIP code, the median income of their ZIP code, and whether their treatment was ordered by a physician at a hospital. Multivariable logistic and Cox Proportional Hazards models were used to assess the association between patient characteristics, receipt of surgery, and time to non-systemic treatment (surgery or RT), respectively. Results: A total of 2,682 patients were included in the analysis. In an adjusted analysis, patients were significantly less likely to receive surgery if their first ordering physician was based in a hospital, if they were older, if they had a history of congestive heart failure (CHF), if they had a history of chronic obstructive pulmonary disease, or if they had stage III lung cancer. Likewise, having stage III cancer was associated with significantly shorter time to treatment. Conclusions: Within a Medicare Advantage population, patient demographics were found to be significantly associated with the decision to pursue surgery, but factors other than stage were not significantly associated with time to non-systemic treatment. [ABSTRACT FROM AUTHOR]

Purpose of Review: The goal is to describe the evolution of radiation therapy (RT) utilization in the management of localized and metastatic prostate cancer. Recent Findings: Long term data for a variety of hypofractionated definitive RT dose-fractionation schemes has matured, allowing patients and providers many standard-of-care options to choose from. Post-prostatectomy, adjuvant RT has largely been replaced by an early salvage approach. Multiparametric MRI and PSMA PET have enabled increasingly targeted RT delivery to the prostate and oligometastatic tumors. Areas of active investigation include determining the value of proton beam therapy and perirectal spacers, and optimally incorporate genomic tumor profiling and next generation hormonal therapies with RT in the curative setting. Summary: The use of radiation therapy to treat prostate cancer is rapidly evolving. In the coming years, there will be continued improvements in a variety of areas to enhance the value of RT in multidisciplinary prostate cancer management. [ABSTRACT FROM AUTHOR]

Background This study assessed the influence of age, co-morbidity and frailty on 5-year survival outcomes after breast conservation surgery (BCS) with radiotherapy (RT) versus mastectomy (with or without RT) in women with early invasive breast cancer. Methods Women aged over 50 years with early invasive breast cancer diagnosed in England (2014–2019) who had breast surgery were identified from Cancer Registry data. Survival estimates were calculated from a flexible parametric survival model. A competing risk approach was used for breast cancer–specific survival (BCSS). Standardized survival probabilities and cumulative incidence functions for breast cancer death were calculated for each treatment by age. Results Among 101 654 women, 72.2% received BCS + RT and 27.8% received mastectomy. Age, co-morbidity and frailty were associated with overall survival (OS), but only age and co-morbidity were associated with BCSS. Survival probabilities for OS were greater for BCS + RT (90.3%) versus mastectomy (87.0%), and the difference between treatments varied by age (50 years: 1.9% versus 80 years: 6.5%). Cumulative incidence functions for breast cancer death were higher after mastectomy (5.1%) versus BCS + RT (3.9%), but there was little change in the difference by age (50 years: 0.9% versus 80 years: 1.2%). The results highlight the change in baseline mortality risk by age for OS compared to the stable baseline for BCSS. Conclusion For OS, the difference in survival probabilities for BCS + RT and mastectomy increased slightly with age. The difference in cumulative incidence functions for breast cancer death by surgery type was small regardless of age. Evidence on real-world survival outcomes among older populations with breast cancer is informative for treatment decision-making. [ABSTRACT FROM AUTHOR]

Background: Radiation has a huge impact on wound healing with progressive and irreversible impairment at the cellular level, making it very challenging for surgeons in terms of wound healing after salvage surgery in previously radiated patients. CO2 LASER helps in wound healing by its combined effect yielding a better result. Our study aims to retrospectively evaluate the healing outcome in a series of patients post-radiation, diagnosed with head and neck neoplasm recurrence, undergoing CO2 LASER treatment for non-healing surgical wounds, post salvage surgery having a previous history of radiotherapy in Head and Neck cancers. Methodology: A total of seven patients from January 2018 to June 2021 who underwent CO2 LASER treatment in non-healing surgical wounds, post salvage surgery having a previous history of radiotherapy in Head and Neck cancers were included in this study. Clinical assessment of healing in terms of complete healing, the appearance of the scar, and patient satisfaction, with a follow-up for 18 months. Results: This series included a total of seven patients, five men and two women, aged between 27 and 62 years with a mean age of 47 years. Three patients had a previous history of radiation, and four patients had a previous history of chemoradiation (CT + RT). Successful healing was noted in all the seven patients. Post-healing all patient's scars were soft, flat, and clinically acceptable. One patient presented with hypopigmentation. Conclusion: CO2 LASER therapy speeds up the healing process with minimal discomfort to the patient. CO2 LASER therapy can be used as an alternative for non-healing surgical wounds after salvage surgery in previously radiated patients with an unhealthy wound bed where split-thickness skin graft uptake is unpredictable. [ABSTRACT FROM AUTHOR]

Objective: To determine differences in post‐treatment QoL across treatment settings in patients receiving adjuvant radiation therapy for head and neck squamous cell carcinoma (HNSCC). Methods: This was a prospective observational cohort study of patients with HNSCC initially evaluated in a head and neck surgical oncologic and reconstructive clinic at an academic medical center (AMC). Participants were enrolled prior to treatment in a prospective registry collecting demographic, social, and clinical data. Physical and social–emotional QoL (phys‐QoL and soc‐QoL, respectively) was measured using the University of Washington‐QoL questionnaire at pre‐treatment and post‐treatment visits. Results: A cohort of 177 patients, primarily male and White with an average age of 61.2 ± 11.2 years, met inclusion criteria. Most patients presented with oral cavity tumors (n = 132, 74.6%), had non‐HPV‐mediated disease (n = 97, 61.8%), and were classified as Stage IVa (n = 72, 42.8%). After controlling for covariates, patients treated at community medical centers (CMCs) reported a 7.15‐point lower phys‐QoL compared with those treated at AMCs (95% CI: −13.96 to −0.35, p = 0.040) up to 12 months post‐treatment. Additionally, patients who were treated at CMCs had a 5.77‐point (−11.86–0.31, p = 0.063) lower soc‐QoL score compared with those treated at an AMC, which was not statistically significant. Conclusion: This study revealed that HNSCC patients treated with radiation at AMCs reported significantly greater phys‐QoL in their first‐year post‐treatment compared to those treated at CMCs, but soc‐QoL did not differ significantly. Further observational studies are needed to explore potential factors, including treatment planning and cancer resource engagement, behind disparities between AMCs and CMCs. Level of Evidence: 3 Laryngoscope, 134:3645–3655, 2024 [ABSTRACT FROM AUTHOR]

Background: Radiation therapy is the standard of care for central nervous system tumours. Despite the success of radiation therapy in reducing tumour mass, irradiation (IR)-induced vasculopathies and neuroinflammation contribute to late-delayed complications, neurodegeneration, and premature ageing in long-term cancer survivors. Mesenchymal stromal cells (MSCs) are adult stem cells that facilitate tissue integrity, homeostasis, and repair. Here, we investigated the potential of the iPSC-derived MSC (iMSC) secretome in immunomodulation and vasculature repair in response to radiation injury utilizing human cell lines. Methods: We generated iPSC-derived iMSC lines and evaluated the potential of their conditioned media (iMSC CM) to treat IR-induced injuries in human monocytes (THP1) and brain vascular endothelial cells (hCMEC/D3). We further assessed factors in the iMSC secretome, their modulation, and the molecular pathways they elicit. Results: Increasing doses of IR disturbed endothelial tube and spheroid formation in hCMEC/D3. When IR-injured hCMEC/D3 (IR ≤ 5 Gy) were treated with iMSC CM, endothelial cell viability, adherence, spheroid compactness, and proangiogenic sprout formation were significantly ameliorated, and IR-induced ROS levels were reduced. iMSC CM augmented tube formation in cocultures of hCMEC/D3 and iMSCs. Consistently, iMSC CM facilitated angiogenesis in a zebrafish model in vivo. Furthermore, iMSC CM suppressed IR-induced NFκB activation, TNF-α release, and ROS production in THP1 cells. Additionally, iMSC CM diminished NF-kB activation in THP1 cells cocultured with irradiated hCMEC/D3, iMSCs, or HMC3 microglial lines. The cytokine array revealed that iMSC CM contains the proangiogenic and immunosuppressive factors MCP1/CCL2, IL6, IL8/CXCL8, ANG (Angiogenin), GROα/CXCL1, and RANTES/CCL5. Common promoter regulatory elements were enriched in TF-binding motifs such as androgen receptor (ANDR) and GATA2. hCMEC/D3 phosphokinome profiling revealed increased expression of pro-survival factors, the PI3K/AKT/mTOR modulator PRAS40 and β-catenin in response to CM. The transcriptome analysis revealed increased expression of GATA2 in iMSCs and the enrichment of pathways involved in RNA metabolism, translation, mitochondrial respiration, DNA damage repair, and neurodevelopment. Conclusions: The iMSC secretome is a comodulated composite of proangiogenic and immunosuppressive factors that has the potential to alleviate radiation-induced vascular endothelial cell damage and immune activation. [ABSTRACT FROM AUTHOR]

Objective: In external radiotherapy, dose boluses and compensators are used for treatment of irregular facial topography surfaces. In such cases, skewed isodose curves need to be addressed using a bolus that gives the deep dose distribution a shape adapted to the anatomical structures to be protected or irradiated. The combination of 3D modeling and printing technologies is a promising alternative to the conventional inaccurate and uncomfortable bolus fabrication technique. In this work, the proposed technologies will be used in the design and fabrication of high-performance and high-accuracy boluses that respond to the main constraints on metrology, adhesion to the patient's surface, comfort, and dose delivery. Methods: As a first phase in the implementation of the proposed solution, 3D printing materials, to be used in the fabrication of radiotherapy boluses, were selected and characterized to check how they respond to the required criteria on functionality, safety, and quality. Results: The obtained results show that among the studied materials, thermoplastic polyurethane (TPU) was found to be slightly more suitable than polylactic acid (PLA) for the fabrication of 3D printing boluses but for some kinds of treatments, PLA may be preferred despite its relative rigidity. Conclusion: In this work, procedures for dose bolus fabrication were proposed, and necessary data were obtained for some available 3D printing materials (TPU and PLA) that can be used for targeted applications. This achievement is a major step toward the final implementation of 3D modeling and printing technologies for the efficient fabrication of radiotherapy dose boluses. [ABSTRACT FROM AUTHOR]

Background: The planification of radiation therapy (RT) for pancreatic cancer (PC) requires a dosimetric computed tomography (CT) scan to define the gross tumor volume (GTV). The main objective of this study was to compare the inter-observer variability in RT planning between the arterial and the venous phases following intravenous contrast. Methods: PANCRINJ was a prospective monocentric study that included twenty patients with non-metastatic PC. Patients underwent a pre-therapeutic CT scan at the arterial and venous phases. The delineation of the GTV was performed by one radiologist (gold standard) and two senior radiation oncologists (operators). The primary objective was to compare the Jaccard conformity index (JCI) for the GTVs computed between the GS (gold standard) and the operators between the arterial and the venous phases with a Wilcoxon signed rank test for paired samples. The secondary endpoints were the geographical miss index (GMI), the kappa index, the intra-operator variability, and the dose-volume histograms between the arterial and venous phases. Results: The median JCI for the arterial and venous phases were 0.50 (range, 0.17–0.64) and 0.41 (range, 0.23–0.61) (p = 0.10) respectively. The median GS-GTV was statistically significantly smaller compared to the operators at the arterial (p < 0.0001) and venous phases (p < 0.001), respectively. The GMI were low with few tumors missed for all patients with a median GMI of 0.07 (range, 0-0.79) and 0.05 (range, 0-0.39) at the arterial and venous phases, respectively (p = 0.15). There was a moderate agreement between the radiation oncologists with a median kappa index of 0.52 (range 0.38–0.57) on the arterial phase, and 0.52 (range 0.36–0.57) on the venous phase (p = 0.08). The intra-observer variability for GTV delineation was lower at the venous phase than at the arterial phase for the two operators. There was no significant difference between the arterial and the venous phases regarding the dose-volume histogram for the operators. Conclusions: Our results showed inter- and intra-observer variability in delineating GTV for PC without significant differences between the arterial and the venous phases. The use of both phases should be encouraged. Our findings suggest the need to provide training for radiation oncologists in pancreatic imaging and to collaborate within a multidisciplinary team. [ABSTRACT FROM AUTHOR]

The authors report on the rare occurrence of dual synchronous primary brain tumors in a canine patient, successful treatment with radiation therapy, and medical therapy with patient stabilization for almost three years. A 12.5-year-old spayed mixed-breed female Labrador was referred to Purdue Veterinary Hospital to treat hyperadrenocorticism of suspected pituitary origin. During MRI imaging, the presence of two possible brain neoplasms was detected: a possible right olfactory bulb meningioma and a microadenoma of the pituitary gland. The patient was treated with a fractionated course of radiation in both tumors, 15 treatments of 3Gy, which limited the tumor growth. Mitotane therapy corrected the hormonal dysregulation. The dog had a normal life for nearly three years and recently passed. Cancer cells were not found at necropsy. No MEN1 germline mutations were identified in constitutional DNA (from blood) via high-coverage whole genome sequencing. [ABSTRACT FROM AUTHOR]

Featured Application: Importance of the evaluation of the physician's eye exposure to radiation during 198Au grain brachytherapy, given that the eye dose limit has been reduced drastically from 150 to 20 mSv/year. Brachytherapy is a practical, effective procedure for the local treatment of cancer; it delivers a high radiation dose to a limited tissue volume while sparing the surrounding normal tissues. Although the clinical benefit of brachytherapy is clear, there have been very few studies on the radiation dose received by physicians during the procedure. Furthermore, no study has investigated the eye radiation dose received by physicians performing 198Au grain (seed) brachytherapy, using an eye dosimeter. Recently, the International Commission on Radiological Protection (ICRP) recommended significantly reducing the occupational lens dose limit, from 150 to 20 mSv/yr (100 mSv/5 years). Therefore, it has become essential to evaluate the eye radiation doses of medical workers. We evaluated the eye radiation dose of a brachytherapy physician performing 198Au permanent grain implantation for tongue cancer; this is the first study on this topic. The maximum eye dose was ~0.1 mSv/procedure, suggesting that it is unlikely to exceed the ICRP limit (20 mSv/yr) for the lens, unless many procedures are performed with inappropriate radiation protection. To reduce the dose of radiation received by 198Au grain brachytherapy physicians, it is necessary to use additional lead shielding equipment when preparing the treatment needles, i.e., when loading the grains. This study provides useful information on radiation exposure of physicians conducting 198Au permanent grain brachytherapy. [ABSTRACT FROM AUTHOR]

The rate of obesity is increasing in the Australian population, and this also includes patients with cancer. The safety and dignity of this cohort of patients is paramount as well as the timely acquisition of equipment required to assist patients with obesity to complete a course of radiation therapy (RT). The design and manufacture of equipment used in most RT departments is not suitable for the weight or BMI of all patients presenting for treatment. RT also operates under a unique set of circumstances that differs from the routine hospital environment which prompted the design of an RT bariatric protocol for use in our department. The protocol is based on the mapping of a patient's pathway from simulation and treatment. Treatment technique and equipment limitations as well as information relating to a patient with high BMI are used as trigger points that direct a patient pathway. The bariatric protocol provides the RT team with decision‐making support for appropriate resource utilisation ensuring safe and efficient treatment delivery for both the patient and staff. This paper will outline how the RT bariatric protocol was developed and implemented in our department, highlighting areas that required more attention due to the RT‐specific environment. [ABSTRACT FROM AUTHOR]