Knowledge and competences in hematological malignancies amongst radiation oncology residents in Germany-results from a national survey.

INTRODUCTION: Radiation oncology is a pivotal modality in the treatment of hematologic malignancies. To enable state-of-the-art patient care, structured education during residency is essential. However, given the lack of detailed data, the scope of educational opportunities available to trainees remains elusive. This prompted our group to perform a national survey amongst radiation oncology residents in Germany assessing the status quo of competences in the treatment of lymphoma and leukemia patients. Furthermore, areas of potential improvement were identified to further the goal of competence-based education for residents. METHODS: A survey-based analysis was conducted to assess the knowledge and competence of radiation oncology residents in Germany regarding hematological malignancies. A decisive questionnaire covering demographics, self-assessment of competences, and areas for improvement was developed in adaption of a survey by the Association of Residents in Radiation Oncology and distributed amongst 1439 members of the German Society of Radiation Oncology. Responses were collected anonymously via an online survey tool and analyzed using descriptive statistics and chi-square tests. RESULTS: A total of 59 complete and 22 partial responses were collected, yielding a 5.6% response rate. Participants' competence varied, with notable experience gaps in pediatric cases, proton therapy, and large-field techniques like total-skin irradiation or pediatric total body irradiation. While participants felt confident in treatment planning and patient counseling, they showed deficiencies in the definition of the planning target volume for modern involved site radiotherapy. Resources for education included national and international guidelines, scientific reviews, and textbooks. Board-certified radiation oncologists and physicians from specialized lymphoma centers demonstrated higher overall competence levels. CONCLUSION: This survey highlights the diversity of resident education regarding hematological malignancies in German radiation oncology programs. Knowledge gaps exist in key areas, including pediatric cases and specialized techniques. Competence-based education, interactive teaching formats, and rotations to specialized centers are potential strategies to address these gaps. The study contributes to the understanding of the federal educational landscape, underscoring the need for standardized and comprehensive training to ensure optimal patient care in hematological malignancies within the context of radiation oncology. Further research and collaborations are warranted to enhance training and expertise in this critical domain.

NOTCH-YAP1/TEAD-DNMT1 Axis Drives Hepatocyte Reprogramming Into Intrahepatic Cholangiocarcinoma.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is a devastating liver cancer with extremely high intra- and inter-tumoral molecular heterogeneity, partly due to its diverse cellular origins. We investigated clinical relevance and the molecular mechanisms underlying hepatocyte (HC)-driven ICC development. METHODS: Expression of ICC driver genes in human diseased livers at risk for ICC development were examined. The sleeping beauty and hydrodynamic tail vein injection based Akt-NICD/YAP1 ICC model was used to investigate pathogenetic roles of SRY-box transcription factor 9 (SOX9) and yes-associated protein 1 (YAP1) in HC-driven ICC. We identified DNA methyltransferase 1 (DNMT1) as a YAP1 target, which was validated by loss- and gain-of-function studies, and its mechanism addressed by chromatin immunoprecipitation sequencing. RESULTS: Co-expression of AKT and Notch intracellular domain (NICD)/YAP1 in HC yielded ICC that represents 13% to 29% of clinical ICC. NICD independently regulates SOX9 and YAP1 and deletion of either, significantly delays ICC development. Yap1 or TEAD inhibition, but not Sox9 deletion, impairs HC-to-biliary epithelial cell (BEC) reprogramming. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directs HC-to-BEC/ICC fate switch through the repression of HC-specific genes regulated by master regulators for HC differentiation, including hepatocyte nuclear factor 4 alpha, hepatocyte nuclear factor 1 alpha, and CCAAT/enhancer-binding protein alpha/beta. DNMT1 loss prevented NOTCH/YAP1-dependent HC-driven cholangiocarcinogenesis, and DNMT1 re-expression restored ICC development following TEAD repression. Co-expression of DNMT1 with AKT was sufficient to induce tumor development including ICC. DNMT1 was detected in a subset of HCs and dysplastic BECs in cholestatic human livers prone to ICC development. CONCLUSION: We identified a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for HC-to-BEC/ICC conversion, which may be relevant in cholestasis-to-ICC pathogenesis in the clinic.

Palliative care on the radiation oncology ward-improvements in clinical care through interdisciplinary ward rounds.

INTRODUCTION: Palliative care is essential for patients with terminal diseases and aims at effective symptom control. This may stand in opposition to radiation treatment as an oncological treatment modality. The hereby presented work demonstrates the successful integration of a palliative care service in the radiation oncology ward. METHODS: Since 2015, 1018 patients were seen by the palliative care service on the radiation oncology ward and have been analyzed in this single center study. To assess teaching efficacy of the consultation service, a survey was conducted among 15 radiation oncology residents. RESULTS: Cooperation between the two departments proved to be efficient with rising patient numbers. Palliative care was able to guide appropriate postdischarge care with the number of patients dying on the radiation oncology ward decreasing significantly (p = 0.009). The main topics for consultation were pain medication (92.3%), organization of postdischarge care (92.3%), and psycho-oncological support (84.6%). Most residents had a positive image of the palliative care service and consented on adjectives like "enriching", "empathic", "collegial", "professionally founded", and a "low threshold for consultation". All participants agreed that cooperation deepened their knowledge on palliative care. CONCLUSION: A synergistic cooperation between a palliative care consultation service and a radiation oncology department addresses patient symptoms on an individual level. It confers advanced knowledge on palliative care which is essential for resident education and patient treatment.

DNA as the main target in radiotherapy-a historical overview from first isolation to anti-tumour immune response.

DNA damage is one of the foremost mechanisms of irradiation at the biological level. After the first isolation of DNA by Friedrich Miescher in the 19th century, the structure of DNA was described by Watson and Crick. Several Nobel Prizes have been awarded for DNA-related discoveries. This review aims to describe the historical perspective of DNA in radiation biology. Over the decades, DNA damage has been identified and quantified after irradiation. Depending on the type of sensing, different proteins are involved in sensing DNA damage and repairing the damage, if possible. For double-strand breaks, the main repair mechanisms are non-homologous end joining and homologous recombination. Additional mechanisms are the Fanconi anaemia pathway and base excision repair. Different methods have been developed for the detection of DNA double-strand breaks. Several drugs have been developed that interfere with different DNA repair mechanisms, e.g., PARP inhibitors. These drugs have been established in the standard treatment of different tumour entities and are being applied in several clinical trials in combination with radiotherapy. Over the past decades, it has become apparent that DNA damage mechanisms are also directly linked to the immune response in tumours. For example, cytosolic DNA fragments activate the innate immune system via the cGAS STING pathway.

Risk management patterns in radiation oncology-results of a national survey within the framework of the Patient Safety in German Radiation Oncology (PaSaGeRO) project.

PURPOSE: Risk management (RM) is a key component of patient safety in radiation oncology (RO). We investigated current approaches on RM in German RO within the framework of the Patient Safety in German Radiation Oncology (PaSaGeRO) project. Aim was not only to evaluate a status quo of RM purposes but furthermore to discover challenges for sustainable RM that should be addressed in future research and recommendations. METHODS: An online survey was conducted from June to August 2021, consisting of 18 items on prospective and reactive RM, protagonists of RM, and self-assessment concerning RM. The survey was designed using LimeSurvey and invitations were sent by e­mail. Answers were requested once per institution. RESULTS: In all, 48 completed questionnaires from university hospitals, general and non-academic hospitals, and private practices were received and considered for evaluation. Prospective and reactive RM was commonly conducted within interprofessional teams; 88% of all institutions performed prospective risk analyses. Most institutions (71%) reported incidents or near-events using multiple reporting systems. Results were presented to the team in 71% for prospective analyses and 85% for analyses of incidents. Risk conferences take place in 46% of institutions. 42% nominated a manager/committee for RM. Knowledge concerning RM was mostly rated "satisfying" (44%). However, 65% of all institutions require more information about RM by professional societies. CONCLUSION: Our results revealed heterogeneous patterns of RM in RO departments, although most departments adhered to common recommendations. Identified mismatches between recommendations and implementation of RM provide baseline data for future research and support definition of teaching content.

Current situation in radiation oncology residency-Results of a national survey performed by the working group Young DEGRO of the German Society of Radiation Oncology.

BACKGROUND: The aim of this study was to assess the current status of the radiation oncology (RO) residency programs in Germany. For this, RO residents and RO specialists were surveyed regarding the current situation of the RO residency training and the working conditions in Germany. METHODS: The Continuing Education Section of the Young DEGRO (yDEGRO) Working Group of the German Society of Radiation Oncology (DEGRO) developed a survey to assess (1) the overall satisfaction, learning objectives, and teaching methods used during training; and (2) the perception of the importance of specific disease patterns in RO training. Open-ended questions were also asked to elicit opinions on areas for improvement. From 21 November to 27 December 2022, RO residents registered with DEGRO and/or in the working group yDEGRO were invited to participate anonymously in an online questionnaire. RESULTS: Overall, 97 participants completed the survey, including 65 RO residents (67%) and 32 RO specialists (33%); 66 (68%) of the respondents reported being employed in the university setting, 23 (23.7%) in the non-university setting, and 8 (8.3%) in private practice. Within the training, heterogeneity was found in the teaching methods used. In terms of knowledge transfer, the greatest importance was accorded to annual continuing education discussions with the head of the residency training (92.8%), participation in tumor boards (85.6%), written training concepts (81.4%), and evaluations at the beginning (76.3%) and end of a rotation (80.4%). The arithmetic mean of satisfaction with specialist training was 6/10 points (SD: 1.99); 88.7% of respondents would like to see a nationally uniform and mandatory curriculum in RO residency training. CONCLUSION: The study provides suggestions for improving RO medical training in Germany: further development of accompanying education and training programs in cooperation with professional associations, e.g., the DEGRO, structured feedback, and supervision.

The new German evidence-based guideline on diffuse large B-cell lymphoma-key aspects for radiation oncologists.

PURPOSE: Diffuse large B­cell lymphoma (DLBCL) is an aggressive lymphoma subtype treated successfully with immunochemotherapy. However, there are conflicting data on the role and impact of consolidative radiation therapy (RT). The publication of the national evidence-based guideline on DLBCL prompted us to review relevant passages on radiation oncology. METHODS: The following article reviews the evidence and recommendations given in the current German evidence-based guideline on DLBCL regarding RT and summarizes pivotal aspects. Additional literature is presented to provide a comprehensive background for the published recommendations. RESULTS: RT shall be administered to all patients with localized positron emission tomography(PET)-positive residues after completion of immunochemotherapy and should use a dose of 30-40 Gray in normofractionation. For RT planning, PET information before and after immunochemotherapy shall be used, with either a PET-CT in the RT treatment position or an image fusion to the planning CT. Conformal techniques shall be used for target volume coverage, with a risk-benefit evaluation for the individual patient. Additionally, RT may be used in the treatment context of various subtypes of DLBCL as well as in the recurrent or refractory treatment situation. CONCLUSION: RT remains an integral part of the treatment repertoire of DLBCL. With the use of PET-guided treatment, RT is indicated for patients with metabolically active tumors. In the context of the ongoing development of targeted therapies, new RT indications may evolve.

Impact of dose escalation on colostomy-free survival and treatment outcome in squamous cell anal carcinoma.

PURPOSE: Primary radiochemotherapy (RCT) constitutes the standard of care for early- and advanced-stage anal carcinoma. This retrospective study investigates the impact of dose escalation on colostomy-free survival (CFS), overall survival (OS), locoregional control (LRC), progression-free survival (PFS), and acute and late toxicities in patients with squamous cell anal cancer. METHODS: Considered were the outcomes of 87 patients with anal cancer treated with radiation/RCT between May 2004 and January 2020 at our institution. Toxicities were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE version 5.0). RESULTS: The 87 patients received treatment with a median boost of 63 Gy to the primary tumor. With a median follow-up of 32 months, the 3­year CFS, OS, LRC, and PFS were 79.5%, 71.4%, 83.9%, and 78.5%, respectively. Tumor relapse occurred in 13 patients (14.9%). Dose escalation to > 63 Gy (maximum 66.6 Gy) to the primary tumor in 38/87 patients revealed a nonsignificant trend for improved 3­year CFS (82.4% vs. 97%, P = 0.092), a significantly improved CFS for T2/T3 tumors (72.6% vs. 100%, P = 0.008), and a significantly improved 3­year PFS for T1/T2 tumors (76.7% vs. 100%, P = 0.035). While acute toxicities did not differ, dose escalation > 63 Gy led to a higher rate of chronic skin toxicities (43.8% vs. 69%, P = 0.042). Treatment with intensity-modulated radiotherapy (IMRT) showed a significant improvement in 3­year OS (75.4% vs. 53.8%, P = 0.048). In multivariate analysis, significant improvements for T1/T2 tumors (CFS, OS, LRC, PFS), G1/2 tumors (PFS), and IMRT (OS) were shown. The nonsignificant trend for CFS improvement with dose escalation > 63 Gy was also apparent in multivariate analysis (P = 0.067). CONCLUSION: Dose escalation > 63 Gy (maximum 66.6 Gy) may improve CFS and PFS for certain subgroups, with a concomitant increase in chronic skin toxicities. Modern IMRT seems to be associated with an improvement in OS.

Confounders of intraoperative frozen section pathology during glioma surgery.

Although frozen section pathology (FSP) is commonly performed during surgery for glioma-suspicious lesions, confounders of accuracy are largely unknown. FSP and final diagnosis were compared in 398 surgeries for glioma-suspicious lesions. Diagnostic accuracy, risk factors for diagnostic shift from neoplastic to non-neoplastic tissue and vice versa according to the final diagnosis, and the impact on intraoperative and postoperative decision-making were analyzed. Diagnostic shift occurred in 70 cases (18%), and sensitivity, specificity, and the positive (PPV) and negative (NPV) predictive value of FSP were 82.5%, 77.8%, 99.4%, and 9.3%, respectively. No correlations between shift and patients' age and sex, sample fluorescence or volume, tumor location, correct information on the pathology form, final high- or low-grade histology, or molecular alterations were found (p > .05, each). Shift was more common after irradiation (25% vs 15%; p = .025) or chemotherapy (26% vs 15%; p = .022) than in treatment naïve cases and correlated with the type of surgery (p = .002). FSP altered intraoperative decision-making in 25 cases (6%). Postoperative shift led to repeated surgery in 12 patients (3%). In 45 cases, in which FSP and final diagnosis based on the same tissue, shift occurred in only 5 patients (11%), and sensitivity, specificity, PPV, and NPV for FSP were 77.4%, 78.6%, 88.9%, and 61.1%, respectively. No correlations between diagnostic shift and any of the analyzed variables were found (p > .05, each). Although accuracy of FSP during glioma surgery is sufficient, moderate NPV should be considered during intraoperative decision-making. While confounders are sparse, accuracy might be increased by repeated sampling. Diagnostic shift rarely alters postoperative treatment strategy.

Intestinal Barrier Dysfunction in Fatty Liver Disease: Roles of Microbiota, Mucosal Immune System, and Bile Acids.

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of progressive liver diseases ranging from simple steatosis to steatohepatitis and fibrosis. Globally, NAFLD is the leading cause of morbidity and mortality associated with chronic liver disease, and NAFLD patients are at a higher risk of developing cirrhosis and hepatocellular carcinoma. While there is a consensus that inflammation plays a key role in promoting NAFLD progression, the underlying mechanisms are not well understood. Recent clinical and experimental evidence suggest that increased hepatic translocation of gut microbial antigens, secondary to diet-induced impairment of the intestinal barrier may be important in driving hepatic inflammation in NAFLD. Here, we briefly review various endogenous and exogenous factors influencing the intestinal barrier and present recent advances in our understanding of cellular and molecular mechanisms underlying intestinal barrier dysfunction in NAFLD.

Nuclear factor erythroid 2-related factor 2 and ß-Catenin Coactivation in Hepatocellular Cancer: Biological and Therapeutic Implications.

BACKGROUND AND AIMS: HCC remains a major unmet clinical need. Although activating catenin beta-1 (CTNNB1) mutations are observed in prominent subsets of HCC cases, these by themselves are insufficient for hepatocarcinogenesis. Coexpression of mutant CTNNB1 with clinically relevant co-occurrence has yielded HCCs. Here, we identify cooperation between ß-catenin and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in HCC. APPROACH AND RESULTS: Public HCC data sets were assessed for concomitant presence of CTNNB1 mutations and either mutations in nuclear factor erythroid-2-related factor-2 (NFE2L2) or Kelch like-ECH-associated protein 1 (KEAP1), or Nrf2 activation by gene signature. HCC development in mice and similarity to human HCC subsets was assessed following coexpression of T41A-CTNNB1 with either wild-type (WT)-, G31A-, or T80K-NFE2L2. Based on mammalian target of rapamycin complex 1 activation in CTNNB1-mutated HCCs, response of preclinical HCC to mammalian target of rapamycin (mTOR) inhibitor was investigated. Overall, 9% of HCC cases showed concomitant CTNNB1 mutations and Nrf2 activation, subsets of which were attributable to mutations in NFE2L2/KEAP1. Coexpression of mutated CTNNB1 with mutant NFE2L2, but not WT-NFE2L2, led to HCC development and mortality by 12-14 weeks. These HCCs were positive for ß-catenin targets, like glutamine synthetase and cyclin-D1, and Nrf2 targets, like NAD(P)H quinone dehydrogenase 1 and peroxiredoxin 1. RNA-sequencing and pathway analysis showed high concordance of preclinical HCC to human HCC subset showing activation of unique (iron homeostasis and glioblastoma multiforme signaling) and expected (glutamine metabolism) pathways. NFE2L2-CTNNB1 HCC mice were treated with mTOR inhibitor everolimus (5-mg/kg diet ad libitum), which led to >50% decrease in tumor burden. CONCLUSIONS: Coactivation of ß-catenin and Nrf2 is evident in 9% of all human HCCs. Coexpression of mutant NFE2L2 and mutant CTNNB1 led to clinically relevant HCC development in mice, which responded to mTOR inhibitors. Thus, this model has both biological and therapeutic implications.

Digital transfer in radiation oncology education for medical students-single-center data and systemic review of the literature.

PURPOSE: Modern medical education demands innovative, competence-orientated concepts. The forced digital transfer of teaching due to the coronavirus pandemic also affected radiation oncology (RO). The following analysis investigates whether the attractivity of RO teaching at our faculty could be maintained during the pandemic and which possibilities exist to involve students (in active learning). The latter aspect is further elaborated on a broader scale by a systemic review of the literature on competence-orientated digital education. METHODS: Evaluation results and participation rates of clinical lectures in radiation oncology (RO) were analyzed between the winter semester 2018/2019 and the summer semester 2021. A systemic review of the literature on digital education in RO for medical students was conducted. RESULTS: Concerning evaluation results, a significant improvement for the 7th and 9th semesters was observed in comparison between the pre-pandemic and pandemic semesters (p = 0.046 and p = 0.05, respectively). Overall participation rates did not differ. However, the number of students attending > 75% of classes in the respective semester increased significantly between the pre-pandemic and pandemic period (median values: 38 vs. 79%, p = 0.046; 44 vs. 73%, p = 0.05; 45 vs. 64%, p = 0.05; 41 vs. 77%, p = 0.05; 41 vs. 71%, p = 0.05, for the 6th to 10th semester, respectively). CONCLUSION: The analysis demonstrates the possibility of efficient digital transfer of a core curriculum in RO to the digital era, with a more continuous participation of students. This transfer may enable amelioration of teaching quality and the introduction of innovative and interactive concepts in accordance with the literature.

[Radiotherapy for the treatment of leukemia]. / Strahlentherapeutische Behandlung von Leukämien.

Background: Lymphoma cells are highly radiosensitive and consequently, radiation therapy is a rational addition to systemic therapy in the treatment of leukemia. Especially as a conditioning regimen before allogeneic stem cell transplantation, radiation therapy, in the form of total body irradiation, is an established concept. Objectives: The present work provides an overview on the execution and side effects of radiation treatment in leukemia. Especially (long-term) side effects after total body irradiation are presented. Materials and methods: A selective search in the database PubMed on radiation treatment of leukemia and on total body irradiation has been carried out, focusing on toxicities as well as technical and conceptional innovations. Results: Total body irradiation is a successful conditioning therapy before allogeneic stem cell transplantation and is accompanied by a diverse, but manageable, toxicity spectrum with endocrinological, cardiopulmonary, ophthalmological, nephrological and neurological long-term side effects as well as secondary neoplasia. In addition, low-dose radiotherapy may be utilized to treat myeloid sarcoma (chloroma). Conclusions: The variety of side effects after total body irradiation requires an interdisciplinary and long-term aftercare provided by radiation oncologists and medical oncologists/the transplantation team. Technical evolutions may result in a more selective targeting of the bone marrow and lymphatic organs. At the moment, these techniques are not established in clinical routine but are being evaluated in clinical trials.

Hybrid volumetric modulated arc therapy for hypofractionated radiotherapy of breast cancer: a treatment planning study.

PURPOSE: This study aims to evaluate the best possible practice using hybrid volumetric modulated arc therapy (H-VMAT) for hypofractionated radiation therapy of breast cancer. Different combinations of H­VMAT-a combination of three-dimensional radiotherapy (3D-CRT) and VMAT-were analyzed regarding planning target volume (PTV), dose coverage, and exposure to organs at risk (OAR). METHODS: Planning computed tomography scans were acquired in deep-inspiration breath-hold. A total of 520 treatment plans were calculated and evaluated for 40 patients, comprising six different H­VMAT plans and a 3D-CRT plan as reference. H­VMAT plans consisted of two treatment plans including 3D-CRT and VMAT. During H­VMAT planning, the use of hard wedge filters (HWF) and beam energies were varied. The reference plans were planned with mixed beam energies and the inclusion/omission of HWF. RESULTS: Compared to the reference treatment plans, all H­VMAT plans showed consistently better PTV dose coverage, conformity, and homogeneity. Additionally, OAR protection was significantly improved with several H­VMAT combinations (p < 0.05). The comparison of different H­VMAT combinations showed that inclusion of HWF in the base plan had a negative impact on PTV dose coverage, conformity, and OAR exposure. It also increased the planned monitor units and beam-on time. Advantages of using lower beam energies (6-MV photons) in both the base plan and in the VMAT supplementary dose were observed. CONCLUSION: The H­VMAT technique is an effective possibility for generating homogenous and conformal dose distributions. With the right choice of H­VMAT combination, superior OAR protection is achieved compared to 3D-CRT.

Impact of radiation techniques on lung toxicity in patients with mediastinal Hodgkin's lymphoma.

PURPOSE: Mediastinal radiotherapy (RT), especially when combined with bleomycin, may result in substantial pulmonary morbidity and mortality. The use of modern RT techniques like intensity-modulated radiotherapy (IMRT) is gaining interest to spare organs at risk. METHODS: We evaluated 27 patients who underwent RT for Hodgkin's lymphoma between 2009 and 2013 at our institution. For each patient, three different treatment plans for a 30-Gy involved-field RT (IFRT) were created (anterior-posterior-posterior-anterior setup [APPA], 5­field IMRT, and 7­field IMRT) and analyzed concerning their inherent "normal tissue complication probability" (NTCP) for pneumonitis and secondary pulmonary malignancy. RESULTS: The comparison of different radiation techniques showed a significant difference in favor of standard APPA (p < 0.01). The risk of lung toxicity was significantly higher in plans using 7­field IMRT than in plans using 5­field IMRT. The absolute juxtaposition showed an increase in risk for radiation pneumonitis of 1% for plans using 5­field IMRT over APPA according to QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) parameters (Burman: 0.15%) and 2.6% when using 7­field IMRT over APPA (Burman: 0.7%) as well as 1.6% when using 7­field IMRT over 5­field IMRT (Burman: 0.6%). Further analysis showed an increase in risk for secondary pulmonary malignancies to be statistically significant (p < 0.01); mean induction probability for pulmonary malignoma was 0.1% higher in plans using 5­field IMRT than APPA and 0.19% higher in plans using 7­field IMRT than APPA as well as 0.09% higher in plans using 7­field IMRT than 5­field IMRT. During a median follow-up period of 65 months (95% confidence interval: 53.8-76.2 months), only one patient developed radiation-induced pneumonitis. No secondary pulmonary malignancies have been detected to date. CONCLUSION: Radiation-induced lung toxicity is rare after treatment for Hodgkin lymphoma but may be influenced significantly by the RT technique used. In this study, APPA RT plans demonstrated a decrease in potential radiation pneumonitis and pulmonary malignancies. Biological planning using NTCP may have the potential to define personalized RT strategies.

Polyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic Liver Injury.

The liver contains diploid and polyploid hepatocytes (tetraploid, octaploid, etc.), with polyploids comprising ≥90% of the hepatocyte population in adult mice. Polyploid hepatocytes form multipolar spindles in mitosis, which lead to chromosome gains/losses and random aneuploidy. The effect of aneuploidy on liver function is unclear, and the degree of liver aneuploidy is debated, with reports showing aneuploidy affects 5% to 60% of hepatocytes. To study relationships among liver polyploidy, aneuploidy, and adaptation, mice lacking E2f7 and E2f8 in the liver (LKO), which have a polyploidization defect, were used. Polyploids were reduced fourfold in LKO livers, and LKO hepatocytes remained predominantly diploid after extensive proliferation. Moreover, nearly all LKO hepatocytes were euploid compared with control hepatocytes, suggesting polyploid hepatocytes are required for production of aneuploid progeny. To determine whether reduced polyploidy impairs adaptation, LKO mice were bred onto a tyrosinemia background, a disease model whereby the liver can develop disease-resistant, regenerative nodules. Although tyrosinemic LKO mice were more susceptible to morbidities and death associated with tyrosinemia-induced liver failure, they developed regenerating nodules similar to control mice. Analyses revealed that nodules in the tyrosinemic livers were generated by aneuploidy and inactivating mutations. In summary, we identified new roles for polyploid hepatocytes and demonstrated that they are required for the formation of aneuploid progeny and can facilitate adaptation to chronic liver disease.

Hepatocyte-Specific ß-Catenin Deletion During Severe Liver Injury Provokes Cholangiocytes to Differentiate Into Hepatocytes.

Liver regeneration after injury is normally mediated by proliferation of hepatocytes, although recent studies have suggested biliary epithelial cells (BECs) can differentiate into hepatocytes during severe liver injury when hepatocyte proliferation is impaired. We investigated the effect of hepatocyte-specific ß-catenin deletion in recovery from severe liver injury and BEC-to-hepatocyte differentiation. To induce liver injury, we administered choline-deficient, ethionine-supplemented (CDE) diet to three different mouse models, the first being mice with deletion of ß-catenin in both BECs and hepatocytes (Albumin-Cre; Ctnnb1flox/flox mice). In our second model, we performed hepatocyte lineage tracing by injecting Ctnnb1flox/flox ; Rosa-stopflox/flox -EYFP mice with the adeno-associated virus serotype 8 encoding Cre recombinase under the control of the thyroid binding globulin promoter, a virus that infects only hepatocytes. Finally, we performed BEC lineage tracing via Krt19-CreERT ; Rosa-stopflox/flox -tdTomato mice. To observe BEC-to-hepatocyte differentiation, mice were allowed to recover on normal diet following CDE diet-induced liver injury. Livers were collected from all mice and analyzed by quantitative real-time polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence. We show that mice with lack of ß-catenin in hepatocytes placed on the CDE diet develop severe liver injury with impaired hepatocyte proliferation, creating a stimulus for BECs to differentiate into hepatocytes. In particular, we use both hepatocyte and BEC lineage tracing to show that BECs differentiate into hepatocytes, which go on to repopulate the liver during long-term recovery. Conclusion: ß-catenin is important for liver regeneration after CDE diet-induced liver injury, and BEC-derived hepatocytes can permanently incorporate into the liver parenchyma to mediate liver regeneration.

Implementing a new scale for failure mode and effects analysis (FMEA) for risk analysis in a radiation oncology department.

PURPOSE: Patients and staffs are endangered by different failure modes during clinical routine in radiation oncology and risks are difficult to stratify. We implemented the method of failure mode and effects analysis (FMEA) via questionnaires in our institution and introduced an adapted scale applicable for radiation oncology. METHODS: Failure modes in physical treatment planning and daily routine were detected and stratified by ranking occurrence, severity, and detectability in a questionnaire. Multiplication of these values offers the risk priority number (RPN). We implemented an ordinal rating scale (ORS) as a combination of earlier published scales from the literature. This scale was optimized for German radiation oncology. We compared RPN using this ORS versus use of a rather subjective visual analogue rating scale (VRS). RESULTS: Mean RPN using ORS was 62.3 vs. 67.5 using VRS (p = 0.7). Use of ORS led to improved completeness of questionnaires (91 vs. 79%) and stronger agreement among the experts, especially concerning failure modes during radiation routine. The majority of interviewed experts found the analysis by using the ORS easier and expected a saving of time as well as higher intra- and interobserver reliability. CONCLUSION: The introduced rating scale together with a questionnaire survey provides merit for conducting FMEA in radiation oncology as results are comparable to the use of VRS and the process is facilitated.

De-escalated radiotherapy for indolent primary cutaneous B-cell lymphoma.

OBJECTIVE: Radiotherapy (RT) has an established role in the curative treatment of indolent primary cutaneous B­cell lymphoma (PCBCL). With the role of low-dose regimens such as 2 × 2 Gy being uncertain, we compared conventional-dose RT to a low-dose approach and investigated outcome and toxicities. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 26 patients with 44 cutaneous lesions treated at our institution between 2007 and 2017, comprising 22 marginal zone lymphoma (PCMZL) lesions and 22 follicle center lymphoma (PCFCL) lesions. Seven lesions (16%) were treated with low-dose RT (LDRT) (4 Gy) and 37 (84%) with conventional-dose RT (≥24 Gy, median 40 Gy). Median follow-up duration was 76 months. RESULTS: The overall response rate (ORR) was 91% (complete response rate [CRR]: 75%). The 5­year local control rate (LCR) was 88% and the 10-year LCR was 84%. The response rates were significantly higher following conventional-dose RT (ORR: 92% vs. 86%; CRR: 84% vs. 29%; P = 0.007). In terms of radiation dose, the rate of infield relapses (14% vs. 11%, P = 0.4) and the 5­year LCR (86% vs. 90%, P = 0.4) were comparable in the LDRT and conventional-dose RT groups. During RT courses, about two-thirds of patients experienced mild toxicities, with grade I and II acute toxicity rates of 61% and 9%, respectively, with lower incidences of grade I (14% vs. 70%) and grade II (0% vs. 8%, P = 0.004) toxicities following LDRT. CONCLUSION: This long-term analysis confirms the excellent outcome of RT in the management of PCBCL. The LDRT concept with 4 Gy was associated with a comparable LCR and reduced rates of acute toxicity. However, the response rates were significantly lower for this group and LDRT may therefore not be recommended as standard treatment.

Radiotherapy of extranodal low-grade follicular and marginal zone lymphomas: long-term follow-up of 159 patients.

OBJECTIVE: To evaluate clinical, histopathologic, and radiation (RT) dose parameters in patients with extranodal low-grade (ENLG) non-Hodgkin lymphoma (NHL) and their possible impact on local control (LC) and survival. MATERIALS AND METHODS: The medical records of 159 patients with 181 histologically confirmed ENLG-NHL lesions treated at our institution were reviewed retrospectively. RESULTS: The predominant histological subtype (73%) was marginal zone lymphoma (MZL). Common lesion sites were the gastrointestinal tract (GIT; 33%), skin (26%), and orbit (21%). The majority of patients (88%) presented with stage I/II disease. Thirty-three (20%) lesions were treated with reduced-dose RT (≤30.6 Gy) and 148 lesions (80%) with conventional-dose RT (>30.6 Gy), with an overall median dose of 39.6 Gy (range 4-63). The median follow-up period was 72 months. The 10-year local control (LC), Progression-free survival (PFS), and overall survival (OS) rates were 96, 65, and 82%, respectively. Higher overall response rate (ORR; 98% vs. 94%, p = 0.001) and complete response rate (CRR; 95% vs. 73%, p = 0.001) were observed in patients treated with conventional-dose regimens than in those treated with reduced-dose regimens. Ten-year PFS (p = 0.90) and OS (p = 0.40) was similar between the two dose groups. RT was well tolerated in both dose groups, with no grade 4/5 toxicities. In the multivariate analysis, RT dose and timing (upfront or salvage) were related to LC, whereas age, histology, and complete response (CR) to RT were associated with PFS. Patient age and radiation field size impacted OS. CONCLUSION: RT is an effective and curative local treatment for early-stage FL and MZL at conventional and reduced radiation doses. Conventional-doses seems to be associated with local response improvement, without significant differences in PFS rates. Age, histology, and response to RT may influence the PFS.