Efficacy of stereotactic ablative radiotherapy in patients with oligometastatic hepatocellular carcinoma: A phase II study.

BACKGROUND & AIMS: Stereotactic ablative radiotherapy (SABR) can extend survival and offers the potential for cure in some patients with oligometastatic disease (OMD). However, limited evidence exists regarding its use in oligometastatic hepatocellular carcinoma (HCC). We aimed to prospectively investigate the efficacy and safety of SABR in patients with oligometastatic HCC. METHODS: We enrolled patients with controlled primary HCC and one to five metastatic lesions amenable to SABR. The primary endpoint was treatment efficacy defined as overall survival (OS) and progression-free survival (PFS). The secondary endpoints included time to local progression, objective response rate, disease control rate, toxicities, and quality of life (QOL), assessed using the EORTC QLQ-C30 before, and 0, 1, and 3 months after SABR. RESULTS: Overall, 40 consecutive patients received SABR on 62 lesions between 2021 and 2022. The most common locations for OMD were the lungs (48.4%), lymph nodes (22.6%), and bone (17.7%). After a median follow-up of 15.5 months, the 2-year OS was 80%. Median PFS was 5.3 months, with 1- and 2-year PFS rates of 21.2% and 0%, respectively. A shorter time to OMD from the controlled primary independently correlated with PFS (p = 0.039, hazard ratio 2.127) alongside age, Child-Pugh class, and alpha-fetoprotein (p = 0.002, 0.004, 0.019, respectively). The 2-year time to local progression, objective response rate, and disease control rate were 91.1%, 75.8%, and 98.4%, respectively. Overall, 10% of patients experienced acute toxicity, and 7.5% experienced late toxicity, with no grade 3+ toxicity. All QOL scores remained stable, whereas the patients without systemic treatments had improved insomnia and social functioning scores. CONCLUSIONS: SABR is an effective and feasible option for oligometastatic HCC that leads to excellent local tumor control and improves survival without adversely affecting QOL. IMPACT AND IMPLICATIONS: Stereotactic ablative radiotherapy (SABR) is a non-invasive treatment approach capable of efficiently ablating the target lesion; however, neither the oligometastatic disease concept nor the potential benefits of SABR have been well-defined in hepatocellular carcinoma (HCC). According to this study, SABR is an effective and safe treatment option for oligometastatic HCC, yielding excellent local tumor control and survival improvement without worsening patients' quality of life, regardless of tumor sites. We also demonstrated that patients with a later presentation of OMD from the controlled primary and lower alpha-fetoprotein levels achieved better survival outcomes. This is the first prospective study of SABR in oligometastatic HCC, providing insights for the development of novel strategies to improve oncologic outcomes. CLINICAL TRIAL NUMBER: NCT05173610.

Revisiting prognostic factors of gliomatosis cerebri in adult-type diffuse gliomas.

PURPOSE: There is lack of comprehensive analysis evaluating the impact of clinical, molecular, imaging, and surgical data on survival of patients with gliomatosis cerebri (GC). This study aimed to investigate prognostic factors of GC in adult-type diffuse glioma patients. METHODS: Retrospective chart and imaging review was performed in 99 GC patients from adult-type diffuse glioma (among 1,211 patients; 6 oligodendroglioma, 16 IDH-mutant astrocytoma, and 77 IDH-wildtype glioblastoma) from a single institution between 2005 and 2021. Predictors of overall survival (OS) of entire patients and IDH-wildtype glioblastoma patients were determined. RESULTS: The median OS was 16.7 months (95% confidence interval [CI] 14.2-22.2) in entire patients and 14.3 months (95% CI 12.2-61.9) in IDH-wildtype glioblastoma patients. In entire patients, KPS (hazard ratio [HR] = 0.98, P = 0.004), no 1p/19q codeletion (HR = 10.75, P = 0.019), MGMTp methylation (HR = 0.54, P = 0.028), and hemorrhage (HR = 3.45, P = 0.001) were independent prognostic factors on multivariable analysis. In IDH-wildtype glioblastoma patients, KPS (HR = 2.24, P = 0.075) was the only independent prognostic factor on multivariable analysis. In subgroup of IDH-wildtype glioblastoma with CE tumors, total resection of CE tumor did not remain as a significant prognostic factor (HR = 1.13, P = 0.685). CONCLUSIONS: The prognosis of GC patients is determined by its underlying molecular type and patient performance status. Compared with diffuse glioma without GC, aggressive surgery of CE tumor in GC patients does not improve survival.

Identification of prognostic imaging biomarkers in H3 K27-altered diffuse midline gliomas in adults: impact of tumor oxygenation imaging biomarkers on survival.

PURPOSE: To investigate prognostic markers for H3 K27-altered diffuse midline gliomas (DMGs) in adults with clinical, qualitative and quantitative imaging phenotypes, including tumor oxygenation characteristics. METHODS: Retrospective chart and imaging reviews were conducted on 32 adults with H3 K27-altered DMGs between 2017 and 2023. Clinical and qualitative imaging characteristics were analyzed. Quantitative imaging assessment was performed from the tumor mask via automatic segmentation to calculate normalized cerebral blood volume (nCBV), capillary transit time heterogeneity (CTH), oxygen extraction fraction (OEF), relative cerebral metabolic rate of oxygen (rCMRO2), and mean ADC values. Leptomeningeal metastases (LM) was diagnosed with imaging. Cox analyses were conducted to determine predictors of overall survival (OS) in entire patients and a subgroup of patients with contrast-enhancing (CE) tumor. RESULTS: The median patient age was 40.5 years (range 19.9-75.7), with an OS of 30.3 months (interquartile range 11.3-32.3). In entire patients, the presence of LM was the only independent predictor of OS (hazard ratio [HR] = 6.01, P = 0.009). In the subgroup of 23 (71.9%) patients with CE tumors, rCMRO2 of CE tumor (HR = 1.08, P = 0.019) and the presence of LM (HR = 5.92, P = 0.043) were independent predictors of OS. CONCLUSION: The presence of LM was independently associated with poor prognosis in adult patients with H3 K27-altered DMG. In patients with CE tumors, higher rCMRO2 of CE tumor, which may reflect higher metabolic activity in the tumor oxygenation microenvironment, may be a useful imaging biomarker to predict poor prognosis.

Revisiting oligodendroglioma grading in the 2021 WHO classification: calcification and larger contrast-enhancing tumor volume may predict higher oligodendroglioma grade.

PURPOSE: To investigate whether qualitative and quantitative imaging phenotypes can predict the grade of oligodendroglioma. METHODS: Retrospective chart and imaging reviews were conducted on 180 adults with oligodendroglioma (IDH-mutant and 1p/19q codeleted) between 2005 and 2021. Qualitative imaging characteristics including tumor location, calcification, gliomatosis cerebri, cystic change, necrosis, and infiltrative pattern were analyzed. Quantitative imaging assessment was performed from the tumor mask via automatic segmentation to calculate total, contrast-enhancing (CE), non-enhancing (NE), and necrotic tumor volumes. Logistic analyses were conducted to determine predictors of oligodendroglioma grade. RESULTS: This study included 180 patients (84 [46.7%] with grade 2 and 96 [53.3%] with grade 3 oligodendrogliomas), with a median age of 42 years (range 23-76 years), comprising 91 females and 89 males. On univariable analysis, calcification (odds ratio [OR] = 6.00, P < 0.001), necrosis (OR = 21.84, P = 0.003), presence of CE tumor (OR = 7.86, P < 0.001), larger total (OR = 1.01, P < 0.001), larger CE (OR = 2.22, P = 0.010), and larger NE (OR = 1.01, P < 0.001) tumor volumes were predictors of grade 3 oligodendroglioma. On multivariable analysis, calcification (OR = 3.79, P < 0.001) and larger CE tumor volume (OR = 2.70, P = 0.043) remained as independent predictors of grade 3 oligodendroglioma. The multivariable model exhibited an AUC, accuracy, sensitivity, specificity of 0.78 (95% confidence interval 0.72-0.84), 72.8%, 79.2%, 69.1%, respectively. CONCLUSION: Presence of calcification and larger CE tumor volume may serve as useful imaging biomarkers for prediction of oligodendroglioma grade. CLINICAL RELEVANCE STATEMENT: Assessment of intratumoral calcification and CE tumor volume may facilitate accurate preoperative estimation of oligodendroglioma grade. Presence of intratumoral calcification and larger contrast-enhancing tumor volume were the significant predictors of higher grade oligodendroglioma based on the 2021 WHO classification.

MRI radiomics may predict early tumor recurrence in patients with sinonasal squamous cell carcinoma.

OBJECTIVES: Sinonasal squamous cell carcinoma (SCC) follows a poor prognosis with high tendency for local recurrence. We aimed to evaluate whether MRI radiomics can predict early local failure in sinonasal SCC. METHODS: Sixty-eight consecutive patients with node-negative sinonasal SCC (January 2005-December 2020) were enrolled, allocated to the training (n = 47) and test sets (n = 21). Early local failure, which occurred within 12 months of completion of initial treatment, was the primary endpoint. For clinical features (age, location, treatment modality, and clinical T stage), binary logistic regression analysis was performed. For 186 extracted radiomic features, different feature selections and classifiers were combined to create two prediction models: (1) a pure radiomics model; and (2) a combined model with clinical features and radiomics. The areas under the receiver operating characteristic curves (AUCs) were calculated and compared using DeLong's method. RESULTS: Early local failure occurred in 38.3% (18/47) and 23.8% (5/21) in the training and test sets, respectively. We identified several radiomic features which were strongly associated with early local failure. In the test set, both the best-performing radiomics model and the combined model (clinical + radiomic features) yielded higher AUCs compared to the clinical model (AUC, 0.838 vs. 0.438, p = 0.020; 0.850 vs. 0.438, p = 0.016, respectively). The performances of the best-performing radiomics model and the combined model did not differ significantly (AUC, 0.838 vs. 0.850, p = 0.904). CONCLUSION: MRI radiomics integrated with a machine learning classifier may predict early local failure in patients with sinonasal SCC. CLINICAL RELEVANCE STATEMENT: MRI radiomics intergrated with machine learning classifiers may predict early local failure in sinonasal squamous cell carcinomas more accurately than the clinical model. KEY POINTS: • A subset of radiomic features which showed significant association with early local failure in patients with sinonasal squamous cell carcinomas was identified. • MRI radiomics integrated with machine learning classifiers can predict early local failure with high accuracy, which was validated in the test set (area under the curve = 0.838). • The combined clinical and radiomics model yielded superior performance for early local failure prediction compared to that of the radiomics (area under the curve 0.850 vs. 0.838 in the test set), without a statistically significant difference.

Risk of Lymphedema Following Contemporary Treatment for Breast Cancer: An Analysis of 7617 Consecutive Patients From a Multidisciplinary Perspective.

OBJECTIVE: The aim of this study was to identify the comprehensive risk factors for lymphedema, thereby enabling a more informed multidisciplinary treatment decision-making. SUMMARY BACKGROUND DATA: Lymphedema is a serious long-term complication in breast cancer patients post-surgery; however, the influence of multimodal therapy on its occurrence remains unclear. METHODS: We retrospectively collected treatment-related data from 5549 breast cancer patients who underwent surgery between 2007 and 2015 at our institution. Individual radiotherapy plans were reviewed for regional nodal irradiation (RNI) field design and fractionation type. We identified lymphedema risk factors and used them to construct nomograms to predict individual risk of lymphedema. Nomograms were validated internally using 100 bootstrap samples and externally using 2 separate datasets of 1877 Asian and 191 Western patients. RESULTS: Six hundred thirty-nine patients developed lymphedema during a median follow-up of 60 months. The 3-year lymphedema incidence was 10.5%; this rate increased with larger irradiation volumes (no RNI vs RNI excluding axilla I-II vs RNI including axilla I-II: 5.7% vs 16.8% vs 24.1%) and when using conventional fractionation instead of hypofractionation (13.5% vs 6.8%). On multivariate analysis, higher body mass index, larger number of dissected nodes, taxane-based regimen, total mastectomy, larger irradiation field, and conventional fractionation were strongly associated with lymphedema (all P < 0.001). Nomograms constructed based on these variables showed good calibration and discrimination internally (concordance index: 0.774) and externally (0.832 for Asian and 0.820 for Western patients). CONCLUSIONS: Trimodality breast cancer treatment factors interact to promote lymphedema. Lymphedema risk can be decreased by deintensifying node dissection, chemotherapy regimen, and field and dose of radiotherapy. Deescalation strategies on a multidisciplinary basis might minimize lymphedema risk.

Definitive radiotherapy for localized follicular lymphoma staged by 18F-FDG PET-CT: a collaborative study by ILROG.

Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40 to 50%. As 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography with computerized tomography (PET-CT) upstages 10 to 60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Inclusion criteria were: RT alone for untreated stage I to II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow-up ≥3 months. End points were freedom from progression (FFP), local control, and overall survival (OS). A total of 512 patients treated between 2000 and 2017 at 16 centers were eligible for analysis; median age was 58 years (range, 20-90); 410 patients (80.1%) had stage I disease; median RT dose was 30 Gy (24-52); and median follow-up was 52 months (3.2-174.6). Five-year FFP and OS were 68.9% and 95.7%. For stage I, FFP was 74.1% vs 49.1% for stage II (P < .0001). Eight patients relapsed in-field (1.6%). Four had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.44-3.10) and BCL2 expression (HR, 1.62; 95% CI, 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated.

Use of bevacizumab before or after radiotherapy increases the risk of fistula formation in patients with cervical cancer.

OBJECTIVE: Several reports have documented the risk of fistula formation after bevacizumab in patients previously treated with radiation therapy. The aim of this study was to investigate the risk of fistula formation with bevacizumab and radiotherapy compared with radiotherapy alone. METHODS: We retrospectively analyzed patients with stage I-IV cervical cancer between January 2013 and December 2018. Patients who had a history of pelvic radiotherapy, who were treated with intracavitary brachytherapy alone, received radiotherapy at another hospital, received concurrent bevacizumab and radiotherapy, or had missing follow-up data or a short follow-up period (<6 months) were excluded. The fistula rates were compared between the groups using the Cox proportional hazards model and propensity score analyses. RESULTS: A total of 302 patients were included in the study: 249 patients were treated with definitive or adjuvant radiotherapy, and 53 patients were treated with radiotherapy before or after bevacizumab. With a median follow-up of 35.9 (IQR 22.8-53.5) months, the 3 year cumulative fistula incidence rate was significantly higher in the radiotherapy + bevacizumab group than in the radiotherapy group (27.0% vs 3.0%, p<0.001). Bevacizumab administration was significantly associated with fistula formation in the multivariable adjusted model (HR 4.76, 95% CI 1.71 to 13.23) and three propensity score adjusted model (all p<0.05). Biologically equivalent dose in 2 Gy fractions for 2 cc of the rectum more than 76 Gy was also associated with fistula formation (HR 4.30, 95% CI 1.52 to 12.18). Additionally, a 10 month interval between radiotherapy and bevacizumab reduced the incidence of fistula formation in the radiotherapy + bevacizumab group (p=0.032). CONCLUSIONS: In patients with cervical cancer treated with pelvic radiotherapy, the addition of bevacizumab substantially increased the risk of fistula formation. Physicians should perform pelvic radiotherapy in combination with bevacizumab with caution; moreover, close monitoring for fistula formation is warranted in these patients.

Clinical safety and efficacy of salvage reirradiation for upper abdominal malignancies.

PURPOSE: Reirradiation has the potential to provide effective local control of upper abdominal malignancies. This study aimed to evaluate the safety and efficacy of reirradiation for upper abdominal malignancies. METHODS: A total of 42 patients with a history of prior radiotherapy (RT) received reirradiation for abdominal malignancies between 2005 and 2017. Each patient's medical records, contours, and dose distribution for both RT courses were reviewed. The median dose of the prior RT was 50.0 Gy (range, 30.0-60.0 Gy) and the median dose of reirradiation was 45.0 Gy (range, 15.0-75.0 Gy). RESULTS: With a median follow-up of 10.9 months, the median infield-failure-free survival (IFFS) rate was 9.2 months. Gross tumor volume (GTV) significantly related to IFFS in both the univariate (p = 0.009) and multivariate analyses (p = 0.024), and patients with a GTV of <60.0 mL had an improved IFFS (p = 0.001). Four patients experienced ≥grade 3 late toxicities. In the retrospective dose reconstruction analysis in these patients, the cumulative dose to the most exposed 2 cc (D2cc) of the duodenum was >60.0 Gy (range, 60.1-73.7 Gy). In the univariate analysis, the D2cc of the duodenum and a preexisting duodenal ulcer identified using endoscopy prior to reirradiation significantly correlated with late severe toxicity (p = 0.021 and 0.017, respectively). CONCLUSIONS: Reirradiation for upper abdominal malignancies could be safely performed for patients without preexisting gastrointestinal morbidity unless the duodenum received excessive radiation doses. Reirradiation could also provide substantial IFFS, especially for patients with a GTV of <60.0 mL.

Treatment outcomes of radiotherapy for primary spinal cord glioma.

PURPOSE: Spinal cord gliomas are rare, and there is no consensus on the optimal radiotherapy (RT) regimen. Herein, we investigated therapeutic outcomes in spinal cord gliomas to obtain clues for the optimal RT regimen. METHODS: We assessed 45 patients who received RT for primary spinal cord non-ependymoma gliomas between 2005 and 2017: 37 (82%) received postoperative RT, 6 (13%) underwent definitive RT without surgery, and 2 (5%) received salvage RT for recurrent tumors. Craniospinal irradiation (CSI; median, 40 Gy) was administered in 4 patients with seeding at diagnosis; all other patients received local RT only (median, 50.4 Gy). RESULTS: In all 23 failures occurred (20 in patients without initial seeding +3 in patients with initial seeding and CSI; median follow-up, 33 months). The 2­year overall survival and progression-free survival rates were 74 and 54%, respectively. Overall, 13 (32%) new seeding events outside the local RT field developed either first or subsequently. Tumor grade was significantly associated with survival endpoints (p = 0.009, 0.028) and overall seeding rates (p = 0.042). In grade II tumors, seeding developed in 23%, with a dismal prognosis (median, 10 months after RT). In grade III tumors, seeding developed in 45% with diverse prognosis. In grade IV tumors, seeding developed in 45%. The survival of patients with newly developed seeding was significantly worse than the others (2-year 50%, p < 0.001). CONCLUSION: To encompass a considerable rate of progressive disease seeding, aggressive treatment such as pre-emptive application of CSI needs to be considered for high-grade spinal cord gliomas with adverse features. Prophylactic CSI could be an option for survival prolongation and requires prospective validation.

Generation and analysis of expressed sequence tags (ESTs) of Camelina sativa to mine drought stress-responsive genes.

Camelina sativa is an oil-producing crop belonging to the family of Brassicaceae. Due to exceptionally high content of omega fatty acid, it is commercially grown around the world as edible oil, biofuel, and animal feed. A commonly referred 'false flax' or gold-of-pleasure Camelina sativa has been interested as one of biofuel feedstocks. The species can grow on marginal land due to its superior drought tolerance with low requirement of agricultural inputs. This crop has been unexploited due to very limited transcriptomic and genomic data. Use of gene-specific molecular markers is an important strategy for new cultivar development in breeding program. In this study, Illumina paired-end sequencing technology and bioinformatics tools were used to obtain expression profiling of genes responding to drought stress in Camelina sativa BN14. A total of more than 60,000 loci were assembled, corresponding to approximately 275 K transcripts. When the species was exposed to 10 kPa drought stress, 100 kPa drought stress, and rehydrated conditions, a total of 107, 2,989, and 982 genes, respectively, were up-regulated, while 146, 3,659, and 1189 genes, respectively, were down-regulated compared to control condition. Some unknown genes were found to be highly expressed under drought conditions, together with some already reported gene families such as senescence-associated genes, CAP160, and LEA under 100 kPa soil water condition, cysteine protease, 2OG, Fe(II)-dependent oxygenase, and RAD-like 1 under rehydrated condition. These genes will be further validated and mapped to determine their function and loci. This EST library will be favorably applied to develop gene-specific molecular markers and discover genes responsible for drought tolerance in Camelina species.

FDG-PET predicts outcomes of treated bone metastasis following palliative radiotherapy in patients with hepatocellular carcinoma.

AIMS: To determine the utility of FDG-PET in predicting long-term infield tumour control after RT in patients with metastatic hepatocellular carcinoma (HCC) to bone. METHODS: Among 223 patients with HCC skeletal metastases diagnosed, we reviewed 22 patients with 45 total sites treated with RT who had at least two FDG-PETs prior to and after RT. The median RT dose was 42 Gy (range, 22-48) with a median fraction of 3 Gy (range, 2-8). Helical tomotherapy was generally offered for lesions that received higher RT dose (36%). The intrahepatic control rate in all patients was 73% at the time of referral. The ratio of tumour SUV to blood-pool activity SUV (SUV-ratio) was calculated. The primary end-points were infield progression-free survival (infield-PFS) and infield event-free survival (infield-EFS; recurrent and intractable pain or skeletal-related events). RESULTS: Among 45 sites, 20 had tumour progression and 21 developed events in the previously treated area. A higher SUV-ratio before RT, SUV-ratio decline and higher radiation dose were independently and significantly correlated with better infield-PFS (both P<0.05). The tumours with a pre-RT SUV-ratio≥3.0 and SUV-ratio decline≥40% had significantly better infield-PFS and EFS than those with either a pre-RT SUV-ratio<3.0 or SUV-ratio decline<40% (both P<0.05). CONCLUSIONS: FDG-PET may help to predict outcomes of infield tumour control following palliative RT for treatment of HCC bone metastases. Tumours with low metabolic uptake before RT or with a minor decline in post-RT SUV-ratio showed poor long-term infield tumour control.

Clinical, qualitative imaging biomarkers, and tumor oxygenation imaging biomarkers for differentiation of midline-located IDH wild-type glioblastomas and H3 K27-altered diffuse midline gliomas in adults.

PURPOSE: To compare the clinical, qualitative and quantitative imaging phenotypes, including tumor oxygenation characteristics of midline-located IDH-wildtype glioblastomas (GBMs) and H3 K27-altered diffuse midline gliomas (DMGs) in adults. METHODS: Preoperative MRI data of 55 adult patients with midline-located IDH-wildtype GBM or H3 K27-altered DMG (32 IDH-wildtype GBM and 23 H3 K27-altered DMG patients) were included. Qualitative imaging assessment was performed. Quantitative imaging assessment including the tumor volume, normalized cerebral blood volume, capillary transit time heterogeneity (CTH), oxygen extraction fraction (OEF), relative cerebral metabolic rate of oxygen values, and mean ADC value were performed from the tumor mask via automatic segmentation. Univariable and multivariable logistic analyses were performed. RESULTS: On multivariable analysis, age (odds ratio [OR] = 0.92, P = 0.015), thalamus or medulla location (OR = 10.48, P = 0.013), presence of necrosis (OR = 0.15, P = 0.038), and OEF (OR = 0.01, P = 0.042) were independent predictors to differentiate H3 K27-altered DMG from midline-located IDH-wildtype GBM. The area under the curve, accuracy, sensitivity, and specificity of the multivariable model were 0.88 (95 % confidence interval: 0.77-0.95), 81.8 %, 82.6 %, and 81.3 %, respectively. CONCLUSIONS: Along with younger age, tumor location, less frequent necrosis, and lower OEF may be useful imaging biomarkers to differentiate H3 K27-altered DMG from midline-located IDH-wildtype GBM. Tumor oxygenation imaging biomarkers may reflect the less hypoxic nature of H3 K27-altered DMG than IDH-wildtype GBM and may contribute to differentiation.

Large institutional experience of early outcomes and dosimetric findings with postoperative stereotactic partial breast irradiation in breast cancer.

PURPOSE: To analyze the dosimetric and toxicity outcomes of patients treated with postoperative stereotactic partial breast irradiation (S-PBI). METHODS: We identified 799 women who underwent S-PBI at our institution between January 2016 and December 2022. The most commonly used dose-fraction and technique were 30 Gy in 5 fractions (91.7 %) and a robotic stereotactic radiation system with real-time tracking (83.7 %). The primary endpoints were dosimetric parameters and radiation-related toxicities. For comparison, a control group undergoing ultra-hypofractionated whole breast irradiation (UF-WBI, n = 468) at the same institution was selected. RESULTS: A total of 815 breasts from 799 patients, with a median planning target volume (PTV) volume of 89.6 cm3, were treated with S-PBI. Treatment plans showed that the mean and maximum doses received by the PTV were 96.2 % and 104.8 % of the prescription dose, respectively. The volume of the ipsilateral breast that received 50 % of the prescription dose was 32.3 ± 8.9 %. The mean doses for the ipsilateral lung and heart were 2.5 ± 0.9 Gy and 0.65 ± 0.39 Gy, respectively. Acute toxicity occurred in 175 patients (21.5 %), predominantly of grade 1. Overall rate of late toxicity was 4 % with a median follow-up of 31.6 months. Compared to the UF-WBI group, the S-PBI group had comparably low acute toxicity (21.5 % vs. 25.2 %, p = 0.12) but significantly lower dosimetric parameters for all organs-at-risks (all p < 0.05). CONCLUSION: In this large cohort, S-PBI demonstrated favorable dosimetric and toxicity profiles. Considering the reduced radiation exposure to surrounding tissues, external beam PBI with advanced techniques should at least be considered over traditional WBI-based approaches for PBI candidates.

Normal tissue complication probability models of hypothyroidism after radiotherapy for breast cancer.

Purpose: We aimed to develop Lyman-Kutcher-Burman (LKB) and multivariable normal tissue complication probability (NTCP) models to predict the risk of radiation-induced hypothyroidism (RIHT) in breast cancer patients. Materials and methods: A total of 1,063 breast cancer patients who underwent whole breast irradiation between 2009 and 2016 were analyzed. Individual dose-volume histograms were used to generate LKB and multivariable logistic regression models. LKB model was fit using the thyroid radiation dose-volume parameters. A multivariable model was constructed to identify potential dosimetric and clinical parameters associated with RIHT. Internal validation was conducted using bootstrapping techniques, and model performance was evaluated using the area under the curve (AUC) and Hosmer-Lemeshow (HL) goodness-of-fit test. Results: RIHT developed in 4 % of patients with a median follow-up of 77.7 months. LKB and multivariable NTCP models exhibited significant agreement between the predicted and observed results (HL P values > 0.05). The multivariable NTCP model outperformed the LKB model in predicting RIHT (AUC 0.62 vs. 0.54). In the multivariable model, systemic therapy, age, and percentage of thyroid volume receiving ≥ 10 Gy (V10) were significant prognostic factors for RIHT. The cumulative incidence of RIHT was significantly higher in patients who exceeded the cut-off values for all three risk predictors (systemic therapy, age ≥ 40 years, and thyroid V10 ≥ 26 %, P < 0.005). Conclusions: Systemic therapy, age, and V10 of the thyroid were identified as strong risk factors for the development of RIHT. Our NTCP models provide valuable insights to clinicians for predicting and preventing hypothyroidism by identifying high-risk patients.

Experience of Implementing Deep Learning-Based Automatic Contouring in Breast Radiation Therapy Planning: Insights From Over 2000 Cases.

PURPOSE: This study evaluated the impact and clinical utility of an auto-contouring system for radiation therapy treatments. METHODS AND MATERIALS: The auto-contouring system was implemented in 2019. We evaluated data from 2428 patients who underwent adjuvant breast radiation therapy before and after the system's introduction. We collected the treatment's finalized contours, which were reviewed and revised by a multidisciplinary team. After implementation, the treatment contours underwent a finalization process that involved manual review and adjustment of the initial auto-contours. For the preimplementation group (n = 369), auto-contours were generated retrospectively. We compared the auto-contours and final contours using the Dice similarity coefficient (DSC) and the 95% Hausdorff distance (HD95). RESULTS: We analyzed 22,215 structures from final and corresponding auto-contours. The final contours were generally larger, encompassing more slices in the superior or inferior directions. Among organs at risk (OAR), the heart, esophagus, spinal cord, and contralateral breast demonstrated significantly increased DSC and decreased HD95 postimplementation (all P < .05), except for the lungs, which presented inaccurate segmentation. Among target volumes, CTVn_L2, L3, L4, and the internal mammary node showed increased DSC and decreased HD95 postimplementation (all P < .05), although the increase was less pronounced than the OAR outcomes. The analysis also covered factors contributing to significant differences, pattern identification, and outlier detection. CONCLUSIONS: In our study, the adoption of an auto-contouring system was associated with an increased reliance on automated settings, underscoring its utility and the potential risk of automation bias. Given these findings, we underscore the importance of considering the integration of stringent risk assessments and quality management strategies as a precautionary measure for the optimal use of such systems.

Dose-toxicity surface histogram-based prediction of radiation dermatitis severity and shape.

Objective.This study aimed to develop a new approach to predict radiation dermatitis (RD) by using the skin dose distribution in the actual area of RD occurrence to determine the predictive dose by grade.Approach.Twenty-three patients with head and neck cancer treated with volumetric modulated arc therapy were prospectively and retrospectively enrolled. A framework was developed to segment the RD occurrence area in skin photography by matching the skin surface image obtained using a 3D camera with the skin dose distribution. RD predictive doses were generated using the dose-toxicity surface histogram (DTH) calculated from the skin dose distribution within the segmented RD regions classified by severity. We then evaluated whether the developed DTH-based framework could visually predict RD grades and their occurrence areas and shapes according to severity.Main results.The developed framework successfully generated the DTH for three different RD severities: faint erythema (grade 1), dry desquamation (grade 2), and moist desquamation (grade 3); 48 DTHs were obtained from 23 patients: 23, 22, and 3 DTHs for grades 1, 2, and 3, respectively. The RD predictive doses determined using DTHs were 28.9 Gy, 38.1 Gy, and 54.3 Gy for grades 1, 2, and 3, respectively. The estimated RD occurrence area visualized by the DTH-based RD predictive dose showed acceptable agreement for all grades compared with the actual RD region in the patient. The predicted RD grade was accurate, except in two patients.Significance. The developed DTH-based framework can classify and determine RD predictive doses according to severity and visually predict the occurrence area and shape of different RD severities. The proposed approach can be used to predict the severity and shape of potential RD in patients and thus aid physicians in decision making.

Assessment of deep learning-based auto-contouring on interobserver consistency in target volume and organs-at-risk delineation for breast cancer: Implications for RTQA program in a multi-institutional study.

PURPOSE: To quantify interobserver variation (IOV) in target volume and organs-at-risk (OAR) contouring across 31 institutions in breast cancer cases and to explore the clinical utility of deep learning (DL)-based auto-contouring in reducing potential IOV. METHODS AND MATERIALS: In phase 1, two breast cancer cases were randomly selected and distributed to multiple institutions for contouring six clinical target volumes (CTVs) and eight OAR. In Phase 2, auto-contour sets were generated using a previously published DL Breast segmentation model and were made available for all participants. The difference in IOV of submitted contours in phases 1 and 2 was investigated quantitatively using the Dice similarity coefficient (DSC) and Hausdorff distance (HD). The qualitative analysis involved using contour heat maps to visualize the extent and location of these variations and the required modification. RESULTS: Over 800 pairwise comparisons were analysed for each structure in each case. Quantitative phase 2 metrics showed significant improvement in the mean DSC (from 0.69 to 0.77) and HD (from 34.9 to 17.9 mm). Quantitative analysis showed increased interobserver agreement in phase 2, specifically for CTV structures (5-19 %), leading to fewer manual adjustments. Underlying IOV differences causes were reported using a questionnaire and hierarchical clustering analysis based on the volume of CTVs. CONCLUSION: DL-based auto-contours improved the contour agreement for OARs and CTVs significantly, both qualitatively and quantitatively, suggesting its potential role in minimizing radiation therapy protocol deviation.

Selective Inhibition of PI3K Isoforms in Brain Tumors Suppresses Tumor Growth by Increasing Radiosensitivity.

PURPOSE: Glioblastoma (GBM) is a malignant brain tumor with poor prognosis. Radioresistance is a major challenge in the treatment of brain tumors. The development of several types of tumors, including GBM, involves the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Upon activation, this pathway induces radioresistance. In this study, we investigated whether additional use of selective inhibitors of PI3K isoforms would enhance radiosensitivity in GBM. MATERIALS AND METHODS: We evaluated whether radiation combined with PI3K isoform selective inhibitors can suppress radioresistance in GBM. Glioma 261 expressing luciferase (GL261-luc) and LN229 were used to confirm the effect of combination of radiation and PI3K isoform inhibitors in vitro. Cell viability was confirmed by clonogenic assay, and inhibition of PI3K/AKT signaling activation was observed by Western blot. To confirm radiosensitivity, the expression of phospho-γ-H2AX was observed by immunofluorescence. In addition, to identify the effect of a combination of radiation and PI3K-α isoform inhibitor in vivo, an intracranial mouse model was established by implanting GL261-luc. Tumor growth was observed by IVIS imaging, and survival was analyzed using Kaplan-Meier survival curves. RESULTS: Suppression of the PI3K/AKT signaling pathway increased radiosensitivity, and PI3K-α inhibition had similar effects on PI3K-pan inhibition in vitro. The combination of radiotherapy and PI3K-α isoform inhibitor suppressed tumor growth and extended survival in vivo. CONCLUSION: This study verified that PI3K-α isoform inhibition improves radiosensitivity, resulting in tumor growth suppression and extended survival in GBM mice.

Effects of Saffron Extract (Affron®) with 100 mg/kg and 200 mg/kg on Hypothalamic-Pituitary-Adrenal Axis and Stress Resilience in Chronic Mild Stress-Induced Depression in Wistar Rats.

Stress-related symptoms are a global concern, impacting millions of individuals, yet effective and safe treatments remain scarce. Although multiple studies have highlighted the stress- alleviating properties of saffron extract, the underlying mechanisms remain unclear. This study employs the unpredictable chronic mild stress (CMS) animal model to investigate the impact of a standardized saffron extract, Affron® (AFN), on hypothalamic-pituitary-adrenal (HPA) axis regulation and neuroplasticity in Wistar rats following repeated oral administration. The research evaluates AFN's effects on various stress-related parameters, including hypothalamic gene expression, stress hormone levels, and the sucrose preference test. In animals subjected to continuous unpredictable CMS, repetitive administration of AFN at doses of 100 mg/kg and 200 mg/kg effectively normalized HPA axis dysregulation and enhanced neuroplasticity. Increased concentrations of AFN demonstrated greater efficacy. Following AFN oral administration, adrenocorticotropic and corticosterone hormone levels exhibited significant or nearly significant reductions in comparison to subjects exposed to stress only. These changes align with the alleviation of stress and the normalization of the HPA axis. These findings elucidate AFN's role in stress mitigation, affirm its health benefits, validate its potential as a treatment for stress-related symptoms, confirm its physiological effectiveness, and emphasize its therapeutic promise.