Association of Skin Microbiome Dynamics With Radiodermatitis in Patients With Breast Cancer.

Importance: The interindividual differences in severity of acute radiation dermatitis are not well understood. To date, the pathomechanism and interplay of microbiome and radiodermatitis before and during treatment remain largely unknown. Objective: To assess the association of skin microbiome baseline composition and dynamics with severity of radiodermatitis in patients undergoing adjuvant radiotherapy for breast cancer. Design, Setting, and Participants: A longitudinal prospective pilot observational study was conducted between January 2017 and January 2019. Sequencing results were received in March 2021, and the data were analyzed from August 2021 to March 2023. This study was performed at an urban academic university cancer center. A total of 21 female patients with breast cancer after surgery were consecutively approached, of which 1 patient withdrew consent before the study started. Exposure: Adjuvant radiotherapy for breast cancer for 7 weeks. Main Outcomes and Measures: The main outcome was the association of baseline skin microbiome composition and its dynamics with the severity of radiodermatitis. A total of 360 skin microbiome samples from patients were analyzed, taken before, during, and after radiotherapy, from both the treated and contralateral healthy sides. The skin microbiome samples were analyzed using 16S (V1-V3) amplicon sequencing and quantitative polymerase chain reaction bacterial enumeration. Results: Twenty female patients with breast cancer after surgery who underwent radiotherapy enrolled in the study had a median (range) age of 61 (37-81) years. The median (range) body mass index of the patients was 24.2 (17.6-38.4). The 16S sequencing revealed that low (<5%) relative abundance of commensal skin bacteria (Staphylococcus epidermidis, Staphylococcus hominis, Cutibacterium acnes) at baseline composition was associated with the development of severe radiodermatitis with an accuracy of 100% (sensitivity and specificity of 100%, P < .001). Furthermore, in patients with severe radiodermatitis, quantitative polymerase chain reaction bacterial enumeration revealed a general non-species-specific overgrowth of skin bacterial load before the onset of severe symptoms. Subsequently, the abundance of commensal bacteria increased in severe radiodermatitis, coinciding with a decline in total bacterial load. Conclusions and Relevance: The findings of this observational study indicated a potential mechanism associated with the skin microbiome for the pathogenesis of severe radiodermatitis, which may be a useful biomarker for personalized prevention of radiodermatitis in patients undergoing adjuvant radiotherapy for breast cancer.

Outcome of patients with soft tissue sarcomas of the extremities and trunk treated by (neo)adjuvant intensity modulated radiation therapy with curative intent.

BACKGROUND: Soft tissue sarcomas (STS) are a relatively rare group of malignant tumors. Currently, there is very little published clinical data, especially in the context of curative multimodal therapy with image-guided, conformal, intensity-modulated radiotherapy. METHODS: Patients who received preoperative or postoperative intensity-modulated radiotherapy for STS of the extremities or trunk with curative intent were included in this single centre retrospective analysis. A Kaplan-Meier analysis was performed to evaluate survival endpoints. Multivariable proportional hazard models were used to investigate the association between survival endpoints and tumour-, patient-, and treatment-specific characteristics. RESULTS: 86 patients were included in the analysis. The most common histological subtypes were undifferentiated pleomorphic high-grade sarcoma (UPS) (27) and liposarcoma (22). More than two third of the patients received preoperative radiation therapy (72%). During the follow-up period, 39 patients (45%) suffered from some type of relapse, mainly remote (31%). The two-years overall survival rate was 88%. The median DFS was 48 months and the median DMFS was 51 months. Female gender (HR 0.460 (0.217; 0.973)) and histology of liposarcomas compared to UPS proved to be significantly more favorable in terms of DFS (HR 0.327 (0.126; 0.852)). CONCLUSION: Conformal, intensity-modulated radiotherapy is an effective treatment modality in the preoperative or postoperative management of STS. Especially for the prevention of distant metastases, the establishment of modern systemic therapies or multimodal therapy approaches is necessary.

Relevance of tumor boards for the inclusion of patients in oncological clinical trials.

INTRODUCTION: Major national and international oncological societies generally recommend treating a significant proportion of oncological patients in clinical trials to improve therapy strategies for cancer patients. At cancer centers, the recommendation about the appropriate therapy for the individual tumor patient is usually made in interdisciplinary case discussions in multidisciplinary tumor boards (MDT). In this study, we examined the impact of MDTs for the inclusion of patients in therapy trials. METHODOLOGY: A prospective, explorative study of the Comprehensive Cancer Center Munich (CCCM) was conducted at both university hospitals in 2019. In the first phase, various MDTs' case discussions about oncological situations and their decisions regarding possible therapy trials were recorded in a structured manner. In the second phase, the actual inclusion rates of patients in therapy trials and reasons for non-inclusion were examined. Finally, the data of the respective university hospitals were anonymized, pooled and analyzed. RESULTS: A total of 1797 case discussions were reviewed. Therapy recommendations were made in 1527 case presentations. 38 (2.5%) of 1527 patients were already included in a therapy trial at the time of case presentation. The MDTs recommended inclusion of an additional 107 cases (7%), for a therapy trial. Of these patients, 41 were finally enrolled in a therapy trial which resulted in a total recruitment rate of 5.2%. Despite MDTs' recommendations, 66 patients were not included in a therapy trial. The main reason for non-inclusion was insufficient inclusion or existing exclusion criteria (n = 18, 28%). In 48% of all cases (n = 31), the reason for non-inclusion could not be determined. CONCLUSION: The potential of MDTs as an instrument for the inclusion of patients in therapy trials is high. To increase the enrollment of patients in oncological therapy trials, structural measures such as the central use of trial administration and MTB software in addition to standardized tumor board discussions must be established to ensure a seamless flow of information about actual recruiting trials and the current status of trial participation of patients.

Teaching in radiation oncology: now and 2025-results of a focus group with medical students.

PURPOSE: In Germany, the new Licensing Regulations for Physicians 2025 (Ärztliche Approbationsordnung, ÄApprO) define a binding legal framework on the basis of which medical faculties modernize their curricula. Since 2015, the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog 2.0., NKLM) formulates competencies and learning objectives to be achieved in the course of studies as curriculum orientation for the medical faculties. In addition, about 80% of the areas of a new core curriculum are to be made compulsory. A needs analysis in the target group of students has not yet taken place for the subject of radiation therapy (RT) or radiation oncology (RO). This study therefore surveys the experiences and requirements of students regarding medical education in RT. METHODS: Qualitative single-center study using a semistructured in-depth focus group with 11 medical students (20-26 years; 6 female, 5 male) was conducted. Brainstorming sessions were conducted in small groups and individually; oral contributions were recorded, transcribed, and analyzed using qualitative content analysis according to Mayring. Results were compared with the content of the future curriculum and reviewed for congruence with current expert recommendations of the German Society of Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO). RESULTS: The plans to develop a longitudinal and practice-oriented curriculum was positively received by students. Specifically, students wanted to introduce the basics of RT as an early link to practice in preclinical teaching units. The necessary acquisition of communicative skills should also be taught by lecturers in RO. Methodologically, regular digital survey tools for self-monitoring, discussion rooms, and problem-based learning were named. In the perception of students, the subject appears underrepresented in relation to its relevance in the multimodal therapy of oncological diseases. CONCLUSION: Results of the needs analysis for the subject of RT are consistent with ÄApprO, NKLM, and DEGRO. Moreover, they complement them and should be considered in the curriculum development of Masterplan Medical Education 2020 (Masterplan Medizinstudium 2020). The results contribute to high-quality and target-group-oriented medical training in the subject of RT, increased visibility, and thus early bonding of future physicians to RO in Germany.

Influence of radiation treatment technique (IMRT vs. 3D-RT) on acute toxicity and prognostic factors for survival for anal cancer.

We compared our institutional experience with intensity-modulated radiotherapy (IMRT) and 3D-conformal radiotherapy (3D-RT) for definitive treatment of primary anal cancer. We performed a single-institution retrospective review of all patients with anal squamous cell carcinoma treated with definitive (chemo) radiotherapy with curative intent from 2004 through 2018. We assessed several prognostic factors in respect to relevant survival endpoints. In addition, acute toxicities were determined and compared between IMRT and 3D-RT patients. This study included 94 patients (58 IMRT, 36 3D-RT). Mean follow up for all patients, for IMRT and 3D-RT patients was 61 months (range 6-176), 46 months (range 6-118), and 85 months (range 6-176), respectively. 5-year overall survival (OS) was 86%, disease-free survival (DFS) was 72%, and colostomy-free survival (CFS) was 75% in the IMRT cohort. In the 3D-RT cohort, OS was 87%, DFS was 71%, and CFS was 81% (all p > 0.05). Male gender and Karnofsky Index (KI) were revealed as independent prognostic factors for 5-year OS (p = 0.017; p = 0.023). UICC stage was an independent prognostic factor for DFS and CFS (p = 0.023; p = 0.042). In addition, the pre-treatment leukocyte count was an independent prognostic factor for CFS (p = 0.042). Acute grade ≥ 3 toxicity was not significantly different between IMRT and 3D-RT patients, but the IMRT cohort had favorable outcomes. This study confirmed IMRT as the primary definitive treatment of anal cancer. With similar survival rates, IMRT had the potential to reduce acute toxicity by sparing organs at risk. Promising prognostic factors such as BMI, KI, and leucocyte and hemoglobin levels should be further investigated.

Quality of life in patients treated with radiochemotherapy for primary diagnosis of anal cancer.

Anal cancer and the related treatment are generally known to affect patients' quality of life. The aim of this study was to assess self-reported quality of life (QoL) of anal cancer patients after combined radiation and chemotherapy, and to identify patient-, disease-, and therapy-related factors associated with QoL. A total of 94 patients treated with definitive chemoradiation for anal cancer at our institution in the period from 2004 to 2018 were identified from our database. QoL was assessed in the remaining 52 patients using the EORTC QLQ-C30 questionnaire (cancer-specific QoL) and the newly developed anal cancer module QLQ-ANL27 (site-specific QoL). Differences in QoL between anal cancer patients and a German age and sex adjusted reference population were examined. The median follow-up was 71 months (range, 7-176). In the cancer-specific QoL module, the anal cancer cohort presented with significantly lower scores in role (- 12.2 points), emotional (- 6.6 points), and social functioning (- 6.8 points), but higher scores in diarrhea (+ 36.3 points) and constipation (+ 13.3 points) than the German reference population. There were no significant differences in disease- or therapy-related factors, but age greater than 70 years and a follow-up time greater than 71 months had a negative impact on global QoL. As for the site-specific QoL, patients with a tumor relapse showed significantly higher symptom scores than patients with a complete clinical remission in all scales except of micturition frequency. Compared to 3D conformal radiotherapy, IMRT treatment seemed to improve non-stoma bowel function (+ 23.3 points), female sexual functioning (+ 24.2 points), and came along with less scores in the symptom scales pain (- 35.9 points), toilet proximity (- 28.6 points), and cleanliness (- 26.2 points). Most of the functional scores of anal cancer patients were lower compared to the general German population, but did not seem to affect the general QoL. Fatigue, physical, and role functioning had the strongest impact on global QoL causing psychological symptoms as important as physical.

MRI-based delta-radiomics predicts pathologic complete response in high-grade soft-tissue sarcoma patients treated with neoadjuvant therapy.

PURPOSE: In high-grade soft-tissue sarcomas (STS) the standard of care encompasses multimodal therapy regimens. While there is a growing body of evidence for prognostic pretreatment radiomic models, we hypothesized that temporal changes in radiomic features following neoadjuvant treatment ("delta-radiomics") may be able to predict the pathological complete response (pCR). METHODS: MRI scans (T1-weighted with fat-saturation and contrast-enhancement (T1FSGd) and T2-weighted with fat-saturation (T2FS)) of patients with STS of the extremities and trunk treated with neoadjuvant therapy were gathered from two independent institutions (training: 103, external testing: 53 patients). pCR was defined as <5% viable cells. After segmentation and preprocessing, 105 radiomic features were extracted. Delta-radiomic features were calculated by subtraction of features derived from MRI scans obtained before and after neoadjuvant therapy. After feature reduction, machine learning modeling was performed in 100 iterations of 3-fold nested cross-validation. Delta-radiomic models were compared with single timepoint models in the testing cohort. RESULTS: The combined delta-radiomic models achieved the best area under the receiver operating characteristic curve (AUC) of 0.75. Pre-therapeutic tumor volume was the best conventional predictor (AUC 0.70). The T2FS-based delta-radiomic model had the most balanced classification performance with a balanced accuracy of 0.69. Delta-radiomic models achieved better reproducibility than single timepoint radiomic models, RECIST or the peri-therapeutic volume change. Delta-radiomic models were significantly associated with survival in multivariate Cox regression. CONCLUSION: This exploratory analysis demonstrated that MRI-based delta-radiomics improves prediction of pCR over tumor volume and RECIST. Delta-radiomics may one day function as a biomarker for personalized treatment adaptations.

Impact of CBCT frequency on target coverage and dose to the organs at risk in adjuvant breast cancer radiotherapy.

The current study aims to assess the effect of cone beam computed tomography (CBCT) frequency during adjuvant breast cancer radiotherapy with simultaneous integrated boost (SIB) on target volume coverage and dose to the organs at risk (OAR). 50 breast cancer patients receiving either non-hypofractionated or hypofractionated radiotherapy after lumpectomy including a SIB to the tumor bed were selected for this study. All patients were treated in volumetric modulated arc therapy (VMAT) technique and underwent daily CBCT imaging. In order to estimate the delivered dose during the treatment, the applied fraction doses were recalculated on daily CBCT scans and accumulated using deformable image registration. Based on a total of 2440 dose recalculations, dose coverage in the clinical target volumes (CTV) and OAR was compared depending on the CBCT frequency. The estimated delivered dose (V95%) for breast-CTV and SIB-CTV was significantly lower than the planned dose distribution, irrespective of the CBCT-frequency. Between daily CBCT and CBCT on alternate days, no significant dose differences were found regarding V95% for both, breast-CTV and SIB-CTV. Dose distribution in the OAR was similar for both imaging protocols. Weekly CBCT though led to a significant decrease in dose coverage compared to daily CBCT and a small but significant dose increase in most OAR. Daily CBCT imaging might not be necessary to ensure adequate dose coverage in the target volumes while efficiently sparing the OAR during adjuvant breast cancer radiotherapy with SIB.

Development and External Validation of Deep-Learning-Based Tumor Grading Models in Soft-Tissue Sarcoma Patients Using MR Imaging.

BACKGROUND: In patients with soft-tissue sarcomas, tumor grading constitutes a decisive factor to determine the best treatment decision. Tumor grading is obtained by pathological work-up after focal biopsies. Deep learning (DL)-based imaging analysis may pose an alternative way to characterize STS tissue. In this work, we sought to non-invasively differentiate tumor grading into low-grade (G1) and high-grade (G2/G3) STS using DL techniques based on MR-imaging. METHODS: Contrast-enhanced T1-weighted fat-saturated (T1FSGd) MRI sequences and fat-saturated T2-weighted (T2FS) sequences were collected from two independent retrospective cohorts (training: 148 patients, testing: 158 patients). Tumor grading was determined following the French Federation of Cancer Centers Sarcoma Group in pre-therapeutic biopsies. DL models were developed using transfer learning based on the DenseNet 161 architecture. RESULTS: The T1FSGd and T2FS-based DL models achieved area under the receiver operator characteristic curve (AUC) values of 0.75 and 0.76 on the test cohort, respectively. T1FSGd achieved the best F1-score of all models (0.90). The T2FS-based DL model was able to significantly risk-stratify for overall survival. Attention maps revealed relevant features within the tumor volume and in border regions. CONCLUSIONS: MRI-based DL models are capable of predicting tumor grading with good reproducibility in external validation.

Excluding Lung Tissue from the PTV during Internal Mammary Irradiation. A Safe Technique for OAR-Sparing?

The current study aims to determine whether exclusion of lung tissue from planning treatment volume (PTV) is a valid organ at risk (OAR)-sparing technique during internal mammary irradiation (IMNI). Twenty patients with left-sided breast cancer undergoing adjuvant radiotherapy including IMNI after mastectomy or lumpectomy with daily ConeBeam CT (CBCT; median n = 28) were enrolled in the current study. The daily dose distribution of the patients was estimated by recalculating treatment plans on CBCT-scans based on a standard PTV (PTV margin: 5mm-STD) and a modified PTV, which excluded overlapping lung tissue (ExLung). Using 3D-deformable dose accumulation, the dose coverage in the target volume was estimated in dependence of the PTV-margins. The estimated delivered dose in the IMN-CTV was significantly lower for the ExLung PTV compared to the STD PTV: ExLung: V95%: 76.6 ± 22.9%; V90%: 89.6 ± 13.2%, STD: V95%: 95.6 ± 7.4%; V90%: 99.1 ± 2.7%. Daily CBCT imaging cannot sufficiently compensate the anatomic changes and intrafraction movement throughout the treatment. Therefore, to ensure adequate delivery of the prescribed dose to the IMN-CTV, exclusion of lung tissue from the PTV to spare the OARs is not recommended.

Prognostic Assessment in High-Grade Soft-Tissue Sarcoma Patients: A Comparison of Semantic Image Analysis and Radiomics.

BACKGROUND: In patients with soft-tissue sarcomas of the extremities, the treatment decision is currently regularly based on tumor grading and size. The imaging-based analysis may pose an alternative way to stratify patients' risk. In this work, we compared the value of MRI-based radiomics with expert-derived semantic imaging features for the prediction of overall survival (OS). METHODS: Fat-saturated T2-weighted sequences (T2FS) and contrast-enhanced T1-weighted fat-saturated (T1FSGd) sequences were collected from two independent retrospective cohorts (training: 108 patients; testing: 71 patients). After preprocessing, 105 radiomic features were extracted. Semantic imaging features were determined by three independent radiologists. Three machine learning techniques (elastic net regression (ENR), least absolute shrinkage and selection operator, and random survival forest) were compared to predict OS. RESULTS: ENR models achieved the best predictive performance. Histologies and clinical staging differed significantly between both cohorts. The semantic prognostic model achieved a predictive performance with a C-index of 0.58 within the test set. This was worse compared to a clinical staging system (C-index: 0.61) and the radiomic models (C-indices: T1FSGd: 0.64, T2FS: 0.63). Both radiomic models achieved significant patient stratification. CONCLUSIONS: T2FS and T1FSGd-based radiomic models outperformed semantic imaging features for prognostic assessment.

Radiation oncology as part of medical education-current status and possible digital future prospects.

PURPOSE: Education as part of medical education is currently changing rapidly. Not least because of the corona crisis, more and more digital teaching formats and innovative teaching concepts such as the flipped classroom model are finding their way into teaching. We analyzed the acceptance and effectiveness of traditional teaching methods as well as the interest in innovative e­learning methods among medical students in the field of radiation oncology at the medical school of the Technical University of Munich. METHODS: We carried out an online-based survey as well as a knowledge test on all students from two terms who had completed the seminar series of radiation oncology. The survey comprised seven questions on the frequency of participation, acceptance, and judgment of the effectiveness in terms of learning and on a potential use of e­learning methods using a six-point Likert scale. The test consisted of 10 multiple-choice questions. RESULTS: Traditional teaching methods are largely accepted by students and most students consider the current learning format to be effective in terms of the teaching effect in the field of radiation oncology. However, only about 50% of all knowledge questions were answered correctly. The possible use of e­learning methods was judged critically or desired in roughly equal parts among the students. CONCLUSION: Traditional seminars enjoy a high level of acceptance among students. Effectiveness with regard to the internalization of content taught, however, should be increased. After all, the future seems to lie in the integration of e­learning in the form of educational videos and practical seminars.

Dual-energy CT parameters in correlation to MRI-based apparent diffusion coefficient: evaluation in rectal cancer after radiochemotherapy.

BACKGROUND: Rectal cancer (RC) is a frequent malignancy for which magnetic resonance imaging (MRI) is the most common and accurate imaging. Iodine concentration (IC) can be quantified with spectral dual-layer computed tomography CT (DL-CT), which could improve imaging of RC, especially for evaluation of response to radiochemotherapy (RCT). PURPOSE: To compare a DL-CT system to MRI as the non-invasive imaging gold standard for imaging of RC to evaluate the possibility of a response evaluation with DL-CT. MATERIAL AND METHODS: Eleven patients who received DL-CT as well as MRI before and after RCT of RC were retrospectively included into this study. For each examination, a region of interest (ROI) was placed within the tumor. For MRI, the mean apparent diffusion coefficient (ADC) was assessed. For DL-CT, IC, z-effective, and Hounsfield Units (HU) were measured. IC, z-effective, and HU were normalized to the aorta. ADC was correlated to absolute and relative normalized IC, z-effective, and HU with Spearman's ρ. Differences before and after treatment were tested with Wilcoxon signed-rank test. RESULTS: HU, IC, and Z-effective values in DL-CT images decreased significantly after RCT (P<0.01 for each comparison). The mean ADC increased significantly after RCT. Spearman's ρ of the absolute IC difference and the absolute ADC (both before and after RCT) is high and significant (ρ = 0.73; P = 0.01), whereas the ρ-value for z-effective (ρ = 0.56) or HU (ρ = 0.45) to ADC was lower and non-significant. CONCLUSION: Response evaluation of RC after RCT could be possible with DL-CT via the measurement of IC.

Impact of 18F-FDG-PET/CT on the identification of regional lymph node metastases and delineation of the primary tumor in esophageal squamous cell carcinoma patients.

PURPOSE: In patients undergoing chemoradiation for esophageal squamous cell carcinoma (ESCC), the extent of elective nodal irradiation (ENI) is still discussed controversially. This study aimed to analyze patterns of lymph node metastases and their correlation with the primary tumor using 18F­fludeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scans. METHODS: 102 ESCC patients with pre-treatment FDG-PET/CT scans were evaluated retrospectively. After exclusion of patients with low FDG uptake and patients without FDG-PET-positive lymph node metastases (LNM), 76 patients were included in the final analysis. All LNM were assigned to 16 pre-defined anatomical regions and classified according to their position relative to the primary tumor (above, at the same height, or below the primary tumor). In addition, the longitudinal distance to the primary tumor was measured for all LNM above or below the primary tumor. The craniocaudal extent (i.e., length) of the primary tumor was measured using FDG-PET imaging (LPET) and also based on all other available clinical and imaging data (endoscopy, computed tomography, biopsy results) except FDG-PET (LCT/EUS). RESULTS: Significantly more LNM were identified with 18F­FDG-PET/CT (177 LNM) compared to CT alone (131 LNM, p < 0.001). The most common sites of LNM were paraesophageal (63% of patients, 37% of LNM) and paratracheal (33% of patients, 20% of LNM), while less than 5% of patients had supraclavicular, subaortic, diaphragmatic, or hilar LNM. With regard to the primary tumor, 51% of LNM were at the same height, while 25% and 24% of lymph node metastases were above and below the primary tumor, respectively. For thirty-three LNM (19%), the distance to the primary tumor was larger than 4 cm. No significant difference was seen between LCT/EUS (median 6 cm) and LPET (median 6 cm, p = 0.846) CONCLUSION: 18F­FDG-PET can help to identify subclinical lymph node metastases which are located outside of recommended radiation fields. PET-based involved-field irradiation might be the ideal compromise between small treatment volumes and decreasing the risk of undertreatment of subclinical metastatic lymph nodes and should be further evaluated.

Dosimetric comparison of organs at risk using different contouring guidelines for definition of the clinical target volume in anal cancer.

BACKGROUND: There are different contouring guidelines for definition of the clinical target volume (CTV) for intensity-modulated radiation therapy (IMRT) of anal cancer (AC). We conducted a planning comparison study to evaluate and compare the dose to relevant organs at risk (OARs) while using different CTV definitions. METHODS: Twelve patients with a primary diagnosis of anal cancer, who were treated with primary chemoradiation (CRT), were selected. We generated four guideline-specific CTVs and subsequently planned target volumes (PTVs) on the planning CT scan of each patient. An IMRT plan for volumetric arc therapy (VMAT) was set up for each PTV. Dose parameters of the planned target volume (PTV) and OARs were evaluated and compared, too. RESULTS: The mean volume of the four PTVs ranged from 2138 cc to 2433 cc. The target volumes contoured by the authors based on the recommendations of each group were similar in the pelvis, while they differed significantly in the inguinal region. There were no significant differences between the four target volumes with regard to the dose parameters of the cranially located OARs. Conversely, some dose parameters concerning the genitals and the skin varied significantly among the different guidelines. CONCLUSION: The four contouring guidelines differ significantly concerning the inguinal region. In order to avoid inguinal recurrence and to protect relevant OARs, further investigations are needed to generate uniform standards for definition of the elective clinical target volume in the inguinal region.

Pre-operative cellular dissociation grading in biopsies is highly predictive of post-operative tumour stage and patient outcome in head and neck squamous cell carcinoma.

BACKGROUND: Pre-operative treatment planning in head and neck squamous cell carcinoma (HNSCC) is mainly dictated by clinical staging, which has major shortcomings. Histologic grading is irrelevant due to its lack of prognostic impact. Recently, a novel grading termed Cellular Dissociation Grade (CDG) based on Tumour Budding and Cell Nest Size was shown to be highly prognostic for resected HNSCC. We aimed to probe the predictive and prognostic impact of CDG in the pre-operative biopsies of HNSCC. METHODS: We evaluated CDG in n = 160 pre-therapeutic biopsies from patients who received standardised treatment following German guidelines, and correlated the results with pre- and post-therapeutic staging data and clinical outcome. RESULTS: Pre-operative CDG was highly predictive of post-operative tumour stage, including the prediction of occult lymph node metastasis. Uni- and multivariate analysis revealed CDG to be an independent prognosticator of overall, disease-specific and disease-free survival (p < 0.001). Hazard ratio for disease-specific survival was 6.1 (11.1) for nG2 (nG3) compared with nG1 tumours. CONCLUSIONS: CDG is a strong outcome predictor in the pre-treatment scenario of HNSCC and identifies patients with nodal-negative disease. CDG is a purely histology-based prognosticator in the pre-therapeutic setting that supplements clinical staging and may aide therapeutic stratification of HNSCC patients.

Post-neoadjuvant cellular dissociation grading based on tumour budding and cell nest size is associated with therapy response and survival in oesophageal squamous cell carcinoma.

BACKGROUND: Cellular Dissociation Grade (CDG) composed of tumour budding and cell nest size has been shown to independently predict prognosis in pre-therapeutic biopsies and primary resections of oesophageal squamous cell carcinoma (ESCC). Here, we aimed to evaluate the prognostic impact of CDG in ESCC after neoadjuvant therapy. METHODS: We evaluated cell nest size and tumour budding activity in 122 post-neoadjuvant ESCC resections, correlated the results with tumour regression groups and patient survival and compared the results with data from primary resected cases as well as pre-therapeutic biopsies. RESULTS: CDG remained stable when results from pre-therapeutic biopsies and post-therapeutic resections from the same patient were compared. CDG was associated with therapy response and a strong predictor of overall, disease-specific (DSS) and disease-free (DFS) survival in univariate analysis and-besides metastasis-remained the only significant survival predictor for DSS and DFS in multivariate analysis. Multivariate DFS hazard ratios reached 3.3 for CDG-G2 and 4.9 for CDG-G3 neoplasms compared with CDG-G1 carcinomas (p = 0.016). CONCLUSIONS: CDG is the only morphology-based grading algorithm published to date, which in concert with regression grading, is able to contribute relevant prognostic information in the post-neoadjuvant setting of ESCC.

Tumor grading of soft tissue sarcomas using MRI-based radiomics.

BACKGROUND: Treatment decisions for multimodal therapy in soft tissue sarcoma (STS) patients greatly depend on the differentiation between low-grade and high-grade tumors. We developed MRI-based radiomics grading models for the differentiation between low-grade (G1) and high-grade (G2/G3) STS. METHODS: The study was registered at ClinicalTrials.gov (number NCT03798795). Contrast-enhanced T1-weighted fat saturated (T1FSGd), fat-saturated T2-weighted (T2FS) MRI sequences, and tumor grading following the French Federation of Cancer Centers Sarcoma Group obtained from pre-therapeutic biopsies were gathered from two independent retrospective patient cohorts. Volumes of interest were manually segmented. After preprocessing, 1394 radiomics features were extracted from each sequence. Features unstable in 21 independent multiple-segmentations were excluded. Least absolute shrinkage and selection operator models were developed using nested cross-validation on a training patient cohort (122 patients). The influence of ComBatHarmonization was assessed for correction of batch effects. FINDINGS: Three radiomic models based on T2FS, T1FSGd and a combined model achieved predictive performances with an area under the receiver operator characteristic curve (AUC) of 0.78, 0.69, and 0.76 on the independent validation set (103 patients), respectively. The T2FS-based model showed the best reproducibility. The radiomics model involving T1FSGd-based features achieved significant patient stratification. Combining the T2FS radiomic model into a nomogram with clinical staging improved prognostic performance and the clinical net benefit above clinical staging alone. INTERPRETATION: MRI-based radiomics tumor grading models effectively classify low-grade and high-grade soft tissue sarcomas. FUND: The authors received support by the medical faculty of the Technical University of Munich and the German Cancer Consortium.

Incidental dose distribution to locoregional lymph nodes of breast cancer patients undergoing adjuvant radiotherapy with tomotherapy - is it time to adjust current contouring guidelines to the radiation technique?

PURPOSE/OBJECTIVE(S): Along with breast-conserving surgery (BCS), adjuvant radiotherapy (RT) of patients with early breast cancer plays a crucial role in the oncologic treatment concept. Conventionally, irradiation is carried out with the aid of tangentially arranged fields. However, more modern and more complex radiation techniques such as IMRT (intensity-modulated radio therapy) are used more frequently, as they improve dose conformity and homogeneity and, in some cases, achieve better protection of adjacent risk factors. The use of this technique has implications for the incidental- and thus unintended- irradiation of adjacent loco regional lymph drainage in axillary lymph node levels I-III and internal mammary lymph nodes (IMLNs). A comparison of a homogeneous "real-life" patient collective, treated with helical tomotherapy (TT), patients treated with 3D conformal RT conventional tangentially arranged fields (3DCRT) and deep inspiration breath hold (3DCRT-DIBH), was conducted. MATERIALS/METHODS: This study included 90 treatment plans after BCS, irradiated in our clinic from January 2012 to August 2016 with TT (n = 30) and 3D-CRT (n = 30), 3DCRT DIBH (n = 30). PTVs were contoured at different time points by different radiation oncologists (> 7). TT was performed with a total dose of 50.4 Gy and a single dose of 1.8 Gy with a simultaneous integrated boost (SIB) to the tumor cavity (TT group). Patients irradiated with 3DCRT/3DCRT DIBH received 50 Gy à 2 Gy and a sequential boost. Contouring of lymph drainage routes was performed retrospectively according to RTOG guidelines. RESULTS: Average doses (DMean) in axillary lymph node Level I/Level II/Level III were 31.6 Gy/8.43 Gy/2.38 Gy for TT, 24.0 Gy/11.2 Gy/3.97 Gy for 3DCRT and 24.7 Gy/13.3 Gy/5.59 Gy for 3DCRT-DIBH patients. Internal mammary lymph nodes (IMLNs) Dmean were 27.8 Gy (TT), 13.5 Gy (3DCRT), and 18.7 Gy (3DCRT-DIBH). Comparing TT to 3DCRT-DIBH dose varied significantly in all axillary lymph node levels and the IMLNs. Comparing TT to 3DCRT significant dose difference in Level I and IMLNs was observed. CONCLUSION: Dose applied to locoregional lymph drainage pathways varies comparing tomotherapy plans to conventional tangentially arranged fields. Studies are warranted whether dose variations influence loco-regional spread and must have implications for target volume definition guidelines.

Have we achieved adequate recommendations for target volume definitions in anal cancer? A PET imaging based patterns of failure analysis in the context of established contouring guidelines.

BACKGROUND: There are different contouring guidelines for the clinical target volume (CTV) in anal cancer (AC) which vary concerning recommendations for radiation margins in different anatomical regions, especially on inguinal site. PET imaging has become more important in primary staging of AC as a very sensitive method to detect lymph node (LN) metastases. Using PET imaging, we evaluated patterns of LN spread, and examined the differences of the respective contouring guidelines on the basis of our results. METHODS: We carried out a retrospective study of thirty-seven AC patients treated with chemoradiation (CRT) who underwent FDG-PET imaging for primary staging in our department between 2011 and 2018. Patients showing PET positive LN were included in this analysis. Using a color code, LN metastases of all patients were delineated on a template with "standard anatomy" and were divided indicating whether their location was in- or out-field of the standard CTV as recommended by the Radiation Therapy Oncology Group (RTOG), the Australasian Gastrointestinal Trials Group (AGITG) or the British National Guidance (BNG). Furthermore, a detailed analysis of the location of LN of the inguinal region was performed. RESULTS: Twenty-two out of thirty-seven AC patients with pre-treatment PET imaging had PET positive LN metastases, accumulating to a total of 154 LN. The most commonly affected anatomical region was inguinal (49 LN, 32%). All para-rectal, external/internal iliac, and pre-sacral LN were covered by the recommended CTVs of the three different guidelines. Of forty-nine involved inguinal LN, fourteen (29%), seven (14%) and five (10%) were situated outside of the recommended CTVs by RTOG, AGITG and BNG. Inguinal LN could be located up to 5.7 cm inferiorly to the femoral saphenous junction and 2.8 cm medial or laterally to the big femoral vessels. CONCLUSION: Pelvis-related, various recommendations are largely consistent, and all LN are covered by the recommended CTVs. LN "misses" appear generally cranially (common iliac or para-aortic) or caudally (inguinal) to the recommended CTVs. The established guidelines differ significantly, particular regarding the inguinal region. Based on our results, we presented our suggestions for CTV definition of the inguinal region. LN involvement of a larger number of patients should be investigated to enable final recommendations.