Publications by authors named "Michael Oertel"

69 Publications

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

Semin Liver Dis 2022 May 23;42(2):122-137. Epub 2022 Jun 23.

Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0042-1748037DOI Listing
May 2022

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

Gastroenterology 2022 May 10. Epub 2022 May 10.

Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Electronic address:

Background And Aim: Intrahepatic cholangiocarcinoma (ICC) is a devastating liver cancer with extremely high intra- and intertumoral 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 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: Coexpression of AKT and Notch intracellular domain/YAP1 in HC yielded ICC that represents 16% to 30% of clinical ICC. Notch intracellular domain independently regulates SRY-box transcription factor 9 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. Coexpression 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 of HC-to-BEC/ICC conversion, which may be relevant in cholestasis-to-ICC pathogenesis in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2022.05.007DOI Listing
May 2022

[Radiotherapy for the treatment of leukemia].

Onkologe (Berl) 2022 Apr 25:1-7. Epub 2022 Apr 25.

Klinik für Strahlentherapie - Radioonkologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Deutschland.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00761-022-01163-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035974PMC
April 2022

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

Strahlenther Onkol 2022 Apr 29. Epub 2022 Apr 29.

Department of Radiation Oncology, University Hospital Muenster, Albert-Schweitzer-Campus 1, building A1, 48149, Muenster, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00066-022-01939-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9053120PMC
April 2022

PET/CT-based adaptive radiotherapy of locally advanced non-small cell lung cancer in multicenter yDEGRO ARO 2017-01 cohort study.

Radiat Oncol 2022 Feb 9;17(1):29. Epub 2022 Feb 9.

Department of Radiation Oncology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.

Background: Stage III non-small cell lung cancer (NSCLC) represents a highly heterogeneous disease and treatment burden. Advances in imaging modality show promising results for radiotherapy planning. In this multicentric study, we evaluated the impact of PET/CT-based radiotherapy planning on the prognosis of patients with stage III NSCLC.

Method And Patients: A retrospective observational cohort study (ARO 2017-01/NCT03055715) was conducted by the young DEGRO trial group of the German Society for Radiation Oncology (DEGRO) with the primary objective to assess the effect of tumour volume change during chemoradiotherapy and the secondary objective to assess the effect of treatment planning on survival. Three hundred forty-seven patients with stage III NSCLC treated at 21 university centers between January 2010 and December 2013 were enrolled in this trial. Patients received primary curative chemoradiotherapy with an intended dose of 50 Gy (hypofractionated) or > 60 Gy (normofractionated). To assess the effect of radiotherapy planning modality on overall survival, we used multivariate frailty models. Models were adjusted for gross tumor volume at the initiation of therapy, age, sex, simultaneous chemotherapy, lung comorbidities, RT dose and tumor grade. By considering the random effect, we can account for heterogeneity in survival and considered covariates within the model in relation to the study side.

Results: Patients were predominantly male (n = 269, 78.4%) with mainly adenocarcinoma (56.4%) and an average of 67.2 years. Adaptation of radiotherapy with consecutive reduction of irradiation volume showed no significant disadvantage for patient survival (HR = 1.21, 95% CI 0.89-1.64). The use of PET/CT co-registration in radiation planning tended to result in better oncologic outcomes, although no significant association could be shown (HR = 0.8, 95% CI 0.56-1.16). Centers with a consistent planning strategy performed better than those without a preferred planning method (0.62, 95% CI 0.41-0.94).

Conclusion: A consistent planning strategy has positive effects on overall survival. The use of PET/CT-based adaptive radiotherapy planning shows a similar survival prospect with the prospective of lower treatment volumes. In future research, toxicities need to be analysed in order to assess such reasoning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13014-022-01997-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8827193PMC
February 2022

Homage to the Square? Lessons Learned From Bauhaus Master Josef Albers.

Authors:
Michael Oertel

Pract Radiat Oncol 2022 Mar-Apr;12(2):88-89. Epub 2021 Dec 11.

Department of Radiation Oncology, University Hospital Muenster, Muenster, Germany. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prro.2021.11.007DOI Listing
March 2022

In Reply.

Dtsch Arztebl Int 2021 09;118(37):616-617

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3238/arztebl.m2021.0280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704826PMC
September 2021

The Burden of Survivorship on Hematological Patients-Long-Term Analysis of Toxicities after Total Body Irradiation and Allogeneic Stem Cell Transplantation.

Cancers (Basel) 2021 Nov 11;13(22). Epub 2021 Nov 11.

Department of Radiation Oncology, University Hospital Muenster, 48149 Munster, Germany.

Total body irradiation is an effective conditioning modality before autologous or allogeneic stem cell transplantation. With the whole body being the radiation target volume, a diverse spectrum of toxicities has been reported. This fact prompted us to investigate the long-term sequelae of this treatment concept in a large patient cohort. Overall, 322 patients with acute leukemia or myelodysplastic syndrome with a minimum follow-up of one year were included (the median follow-up in this study was 68 months). Pulmonary, cardiac, ocular, neurological and renal toxicities were observed in 23.9%, 14.0%, 23.6%, 23.9% and 20.2% of all patients, respectively. The majority of these side effects were grades 1 and 2 (64.9-89.2% of all toxicities in the respective categories). The use of 12 Gray total body irradiation resulted in a significant increase in ocular toxicities ( = 0.013) and severe mucositis ( < 0.001). Renal toxicities were influenced by the age at transplantation (relative risk: 1.06, < 0.001) and disease entity. In summary, total body irradiation triggers a multifaceted, but manageable, toxicity profile. Except for ocular toxicities and mucositis, a 12 Gray regimen did not lead to an increase in long-term side effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13225640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616356PMC
November 2021

[Bridging before CAR T-cell therapy-a new opportunity for radiotherapy?]

Strahlenther Onkol 2021 12 26;197(12):1154-1156. Epub 2021 Oct 26.

Klinik für Strahlentherapie - Radioonkologie, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149, Münster, Deutschland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00066-021-01863-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604826PMC
December 2021

Examining the Use of Radiation Therapy for Cholangiocarcinoma: Benefits through Modern Techniques.

Oncol Res Treat 2021 21;44(7-8):408-413. Epub 2021 Jul 21.

Department of Radiation Oncology, University Hospital of Münster, Münster, Germany.

Background: Cholangiocarcinoma (CCA) is a rare malignant tumor of the bile duct epithelium. At first diagnosis, only a minority of patients are eligible for surgery, which is regarded as the only curative treatment. This study examines the role of radiation therapy (RT) and chemoradiotherapy (CRT) in the definitive and adjuvant treatment situation.

Methods: The monocentric, retrospective analysis included 39 patients with CCA undergoing 53 RT courses. Data were collected from January 2005 to September 2018. There were 11 cases of CRT, 6 of which were definitive. Surgery was either palliative (n = 6) or radical (n = 15).

Results: After RT, the median overall survival (OS) was 10.4 months (m), median progression-free survival was 5.6 m, and median duration of local control (DOLC) was 8.9 m. There was a significant difference in survival between patients with and without locoregional lymph node metastasis (OS: 4.3 vs. 15.4 m, p = 0.031). After treatment of a primary tumor, DOLC was about twice as long as in the recurrent situation (10.4 vs. 5.4 m, p = 0.032). Conservative therapy significantly elevated the risk of local recurrence compared to radical surgery in univariate and multivariate analyses. Side effects were mostly classified as mild to moderate. Termination of RT and increased alanine aminotransferase were significantly less frequent after stereotactic body radiation therapy and hypofractionation.

Conclusion: RT can achieve local control in patients with CCA. Toxicities of RT are manageable but require close clinical and laboratory follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000517533DOI Listing
September 2021

Pulmonary Toxicity after Total Body Irradiation-An Underrated Complication? Estimation of Risk via Normal Tissue Complication Probability Calculations and Correlation with Clinical Data.

Cancers (Basel) 2021 Jun 12;13(12). Epub 2021 Jun 12.

Department of Radiation Oncology, University Hospital Muenster, 48149 Muenster, Germany.

Total body irradiation (TBI) is an essential part of various conditioning regimens prior to allogeneic stem cell transplantation, but is accompanied by relevant (long-term) toxicities. In the lungs, a complex mechanism induces initial inflammation (pneumonitis) followed by chronic fibrosis. The hereby presented analysis investigates the occurrence of pulmonary toxicity in a large patient collective and correlates it with data derived from normal tissue complication probability (NTCP) calculations. The clinical data of 335 hemato-oncological patients undergoing TBI were analyzed with a follow-up of 85 months. Overall, 24.8% of all patients displayed lung toxicities, predominantly pneumonia and pulmonary obstructions (13.4% and 6.0%, respectively). NTCP calculations estimated median risks to be 20.3%, 0.6% and 20.4% for overall pneumonitis (both radiological and clinical), symptomatic pneumonitis and lung fibrosis, respectively. These numbers are consistent with real-world data from the literature and further specify radiological and clinical apparent toxicity rates. Overall, the estimated risk for clinical apparent pneumonitis is very low, corresponding to the probability of non-infectious acute respiratory distress syndrome, although the underlying pathophysiology is not identical. Radiological pneumonitis and lung fibrosis are expected to be more common but require a more precise documentation by the transplantation team, radiologists and radiation oncologists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13122946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231208PMC
June 2021

Radiotherapy in Follicular Lymphoma Staged by F-FDG-PET/CT: A German Monocenter Study.

Biomedicines 2021 May 17;9(5). Epub 2021 May 17.

Department of Radiation Oncology, University Hospital of Muenster, 48149 Muenster, Germany.

This retrospective study examined the role of F-fluorodeoxyglucose-positron emission tomography/computed tomography (F-FDG-PET/CT) in stage-related therapy of follicular lymphomas (FL). Twelve patients each in stages I and II, 13 in stage III and 11 in stage IV were treated in the Department of Radiation Oncology, University Hospital of Muenster, Germany from 2004 to 2016. Radiotherapy (RT), as well as additional chemoimmunotherapy were analyzed with a median follow-up of 87.6 months. Ultrasound (US), CT and F-FDG-PET/CT were used to determine progression-free survival (PFS), overall survival (OS) and lymphoma-specific survival (LSS) over 5- and 10- years. 23 of 24 patients with stage I/II (95.8%) had complete remissions (CR) and 17 of 24 patients with stages III/IV FL showed CR (70.8%). 5- and 10-year PFS in stages I/II was 90.0%/78.1% vs. 44.3%/28.5% in stages III/IV. 5- and 10-year OS rates in stages I/II was 100%/93.3% vs. 53.7%/48.4% in stages III/IV. 5- and 10-year LSS of stages I/II was 100%/93.8% vs. 69.2%/62.3% in stages III/IV. FL of stages I/II, staged by F-FDG-PET/CT, revealed better survival rates and lower risk of recurrence compared to studies without PET/CT-staging. Especially, patients with PET/CT proven stage I disease showed significantly better survival and lower relapses rates after RT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9050561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156324PMC
May 2021

Late Sequelae of Radiotherapy—The Effect of Technical and Conceptual Innovations in Radiation Oncology.

Dtsch Arztebl Int 2021 03;118(12):205-211

Background: Approximately half of all patients with tumors need radiotherapy. Long-term survivors may suffer from late sequelae of the treatment. The existing radiotherapeutic techniques are being refined so that radiation can be applied more precisely, with the goal of limiting the radiation exposure of normal tissue and reducing late sequelae.

Methods: This review is based on the findings of a selective search in PubMed for publications on late sequelae of conventional percutaneous radiotherapy, January 2000 to May 2020. Late sequelae affecting the central nervous system, lungs, and heart and the development of second tumors are presented, and radiobiological mechanisms and the relevant technical and conceptual considerations are discussed.

Results: The current standard of treatment involves the use of linear accelerators, intensity-modulated radiotherapy (IMRT), image-guided and respiratory-gated radiotherapy, and the integration of positron emission tomography combined with computed tomography (PET-CT) in radiation treatment planning. Cardiotoxicity has been reduced with regard to the risk of coronary heart disease after radiotherapy for Hodgkin's lymphoma (hazard ratio [HR] 0.44 [0.23; 0.85]). It was also found that the rate of radiation- induced pneumonitis dropped from 7.9% with conformal treatment to 3.5% with IMRT in a phase III lung cancer trial. It is hoped that neurocognitive functional impairment will be reduced by hippocampal avoidance in modern treatment planning: an initial phase III trial yielded a hazard ratio of 0.74 [0.58; 0.94]. It is estimated that 8% of second solid tumors in adults are induced by radiotherapy (3 additional tumors per 1000 patients at 10 years).

Conclusion: Special challenges for research in this field arise from the long latency of radiation sequelae and the need for largescale, well-documented patient collectives in order to discern dose-effect relationships, and take account of cofactors, when the overall number of events is small. It is hoped that further technical and conceptual advances will be made in the areas of adaptive radiotherapy, proton and heavy-ion therapy, and personalized therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3238/arztebl.m2021.0024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278127PMC
March 2021

Biophysical Analysis of Acute and Late Toxicity of Radiotherapy in Gastric Marginal Zone Lymphoma-Impact of Radiation Dose and Planning Target Volume.

Cancers (Basel) 2021 Mar 19;13(6). Epub 2021 Mar 19.

Department of Radiation Oncology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.

Successful studies on radiation therapy for gastric lymphoma led to a decrease in planning target volume (PTV) and radiation dose with low toxicities, maintaining excellent survival rates. It remains unclear as to which effects are to be expected concerning dose burden on organs at risk (OAR) by decrease in PTV vs. dose and whether a direct impact on toxicity might be expected. We evaluated 72 radiation plans, generated prospectively for a cohort of 18 patients who were treated for indolent gastric lymphoma in our department. As a prospective work, four radiation plans with different radiation doses and target volumes (40 Gy-involved field, 40 Gy-involved site, 30 Gy-involved field, 30 Gy-involved site) were generated for each patient. Mean dose burden on adjacent organs was compared between the planning groups. Cohort toxicity data served to estimate parameters for the Lyman-Kutcher-Burman (LKB) model for normal tissue complication probability (NTCP). These were used to anticipate adverse events for OAR. Literature parameters were used to estimate high-grade toxicities of OAR. Decrease of dose and/or PTV led to median dose reductions between 0.13 and 5.2 Gy, with a significant dose reduction on neighboring organs. Estimated model parameters for liver, spleen, and bowel toxicity were feasible to predict cohort toxicities. NTCP for the endpoints elevated liver enzymes, low platelet count, and diarrhea ranged between 15.9 and 22.8%, 27.6 and 32.4%, and 21.8 and 26.4% for the respective four plan variations. Field and dose reduction highly impact dose burden and NTCP for OAR during stomach radiation. Our estimated LKB model parameters offer a good approximation for low-grade toxicities in abdominal organs with modern radiation techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13061390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003236PMC
March 2021

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

Hepatology 2021 08 21;74(2):741-759. Epub 2021 Jun 21.

Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA.

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 β-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 β-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 β-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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326305PMC
August 2021

Impact of different radiation techniques and doses on cardiac implantable electronic devices.

Z Med Phys 2021 Aug 29;31(3):327-335. Epub 2021 Jan 29.

Universitaetsklinikum Muenster, Department of Radiation Oncology, Albert-Schweitzer Campus 1 A, 48149, Muenster, Germany.

Background And Objective: Purpose of this investigation was to get deeper insight into the impact of different radiation techniques and doses on cardiac implantable electric devices (CIEDs). We aimed to mimic a worst-case scenario with very high doses and external radiation being applied directly on the devices.

Methods: Radiation was applied on 21 CIEDs as photon or electron therapy with maximum dose of 150Gy in fractions of 2 -20Gy. CIEDS were put directly into the beam. Brachytherapy was applied with doses of 6Gy to a maximum of 42Gy. Check-ups took place after every fraction and one week after radiation. We calculated the estimated potential risk for the health and survival of patients as well as the risk for CIEDs' loss of function.

Results: 28 life- or health-threatening errors occurred during photon therapy, 3/7 devices showed complete loss of function. During electron therapy, 31 potentially patient-threatening errors and 2 losses of function were detected. During brachytherapy, none of the devices showed loss of function but 8 patient-threatening errors occurred. Inadequate shock releases were mostly seen after photon and brachytherapy, random noises occurred more often during electron therapy. The earliest potentially serious error occurred during after 2Gy photon radiation and 6Gy brachytherapy. Losses of function occurred earliest at 80Gy.

Conclusion: The results underline the warning for precaution concerning CIED patients derived from recommendations in the literature. Our study offers new information especially about the impact of electron radiation and brachytherapy on CIEDs. Risk for the devices to for loss of telemetry or battery capacity might be negligible with normafractionated therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.zemedi.2020.12.003DOI Listing
August 2021

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

Strahlenther Onkol 2021 Apr 17;197(4):296-307. Epub 2020 Oct 17.

Department of Radiation Oncology, University Hospital Muenster, Building A1, 1 Albert-Schweitzer-Campus, 48149, Muenster, Germany.

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 H‑VMAT-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 H‑VMAT plans and a 3D-CRT plan as reference. H‑VMAT plans consisted of two treatment plans including 3D-CRT and VMAT. During H‑VMAT 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 H‑VMAT plans showed consistently better PTV dose coverage, conformity, and homogeneity. Additionally, OAR protection was significantly improved with several H‑VMAT combinations (p < 0.05). The comparison of different H‑VMAT 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 H‑VMAT technique is an effective possibility for generating homogenous and conformal dose distributions. With the right choice of H‑VMAT combination, superior OAR protection is achieved compared to 3D-CRT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00066-020-01696-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987622PMC
April 2021

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

Strahlenther Onkol 2020 Dec 19;196(12):1128-1134. Epub 2020 Sep 19.

Department of Radiation Oncology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00066-020-01686-wDOI Listing
December 2020

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

Strahlenther Onkol 2021 Jan 18;197(1):56-62. Epub 2020 Sep 18.

Department of Radiation Oncology, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany.

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], 5‑field IMRT, and 7‑field 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 7‑field IMRT than in plans using 5‑field IMRT. The absolute juxtaposition showed an increase in risk for radiation pneumonitis of 1% for plans using 5‑field IMRT over APPA according to QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) parameters (Burman: 0.15%) and 2.6% when using 7‑field IMRT over APPA (Burman: 0.7%) as well as 1.6% when using 7‑field IMRT over 5‑field 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 5‑field IMRT than APPA and 0.19% higher in plans using 7‑field IMRT than APPA as well as 0.09% higher in plans using 7‑field IMRT than 5‑field 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00066-020-01682-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499413PMC
January 2021

Radiotherapy Dose and Volume De-escalation in Ocular Adnexal Lymphoma.

Anticancer Res 2020 Jul;40(7):4041-4046

Department of Radiation Oncology, University Hospital Muenster, Muenster, Germany.

Aim: Modern radiotherapy (RT) technique and therapy de-escalation have led to encouraging results in lymphoma management. In this study, we aimed to describe the oncological and toxicity outcome in patients with ocular adnexal lymphoma.

Patients And Methods: A total of 45 patients with 52 orbital lesions who were treated at our Institution between 2003 and 2019 were considered. Clinical characteristics, treatment outcomes, and toxicity were assessed. Patients receiving 4-6 Gy were categorized as receiving ultra-low-dose RT, 24-30.6 Gy as standard-dose RT, and >30.6 Gy as high-dose RT.

Results: The predominant histological subtype was marginal zone lymphoma in 39 lesions (75%). Radiation dose ranged from 4-50.4 Gy. In the whole cohort, 11% of the lesions were treated with ultra-low-dose RT, 33% with standard-dose RT, and 56% with high-dose RT; 60% of lesions were treated using intensity-modulated RT (IMRT), while 44% of lesions were treated with partial orbital RT. The median duration of follow-up was 33 months. The overall response rate was 94% (complete response rate=83%). The 5-year local control rate, progression-free survival, and overall survival were 100%, 76%, and 92%, respectively. We did not detect any significant difference in progression-free or overall survival regarding different radiation doses and volumes. Ultra-low-dose RT was associated with a significantly lower rate of grade 2 late toxicities (0% vs. 6% and 31%, p=0.05) in comparison with standard-dose and high-dose RT, respectively. Patients who received IMRT had a significant fewer acute grade 2 (16% vs. 43%, p=0.05) and a trend towards lower late grade 2 toxicities (9% vs. 33%, p=0.06).

Conclusion: Radiation dose and volume de-escalation seem to be safe and effective, with excellent local control and survival in the management of ocular adnexal lymphoma. IMRT seems to be associated with less toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.14400DOI Listing
July 2020

Maximizing the Clinical Benefit of Radiotherapy in Solitary Plasmacytoma: An International Multicenter Analysis.

Cancers (Basel) 2020 Mar 13;12(3). Epub 2020 Mar 13.

Department of Radiation Oncology, University Hospital of Munster, Albert-Schweitzer-Campus 1, Building A1, 48149 Munster, Germany.

: Although local definitive radiotherapy (RT) is considered the standard of care for solitary plasmacytoma (SP), the optimal RT parameters for SP patients have not been defined. The aim of this retrospective study is to analyze the effectiveness of various RT doses, volumes, and techniques, as well as to define the relevant prognostic factors in SP. : Between 2000 and 2019, 84 patients, including 54 with solitary bone plasmacytoma (SBP) and 30 with extramedullary plasmacytoma (EMP), underwent RT at six institutions. : The overall RT median dose was 42 Gy (range, 36.0-59.4). The median follow-up period was 46 months. Overall, the local control (LC) rate was 96%, while the complete remission (CR) rate was 46%. The 5-year local relapse-free survival (LRFS), multiple myeloma-free survival (MMFS), progression-free survival (PFS), and overall survival (OS) rates were 89%, 71%, 55%, and 93%, respectively. Using an RT dose above 40 Gy was associated with a higher complete remission (CR) rate and a lower rate of local relapse. Modern irradiation techniques were associated with a trend toward a higher LC rate (98% vs. 87% for conventional, = 0.09) and a significantly lower local relapse rate (6% vs. 25% for conventional, = 0.04). However, RT dose escalation and technique did not lead to a significant effect on MMFS, PFS, and OS. Univariate analyses identified several patient characteristics as potentially relevant prognostic factors. In SBP patients, systemic therapy administration was associated significantly with MMFS and PFS rates. : Using an RT dose >40 Gy and modern RT techniques may improve the local control and reduce the rate of relapse, without a significant impact on survival rates. The addition of systemic therapies may improve the MMFS and PFS rates of SBP patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12030676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139814PMC
March 2020

Activation of WNT/Beta-Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta-Catenin Complex After Murine Bile Duct Ligation.

Hepatol Commun 2019 Dec 14;3(12):1642-1655. Epub 2019 Oct 14.

Department of Pathology University of Pittsburgh Pittsburgh PA.

We have recently shown that loss of β-catenin prevents the development of cholestatic liver injury and fibrosis after bile duct ligation (BDL) due to loss of the inhibitory farnesoid X receptor (FXR)/β-catenin complex, which results in decreased hepatic bile acids (BAs) through activation of FXR. To further understand the role of Wnt/β-catenin signaling in regulating BA metabolism and cholestasis, we performed BDL on mice in which hepatocyte Wnt signaling is deficient but β-catenin is intact (low-density lipoprotein receptor-related protein [LRP]5/6 knockout [DKO]) as well as mice that have enhanced hepatocyte β-catenin expression (serine 45 mutated to aspartic acid [S45D] transgenic [TG] mice). Despite decreased biliary injury after BDL, hepatic injury, fibrosis, and inflammation were comparable in DKO and wild-type (WT) mice. Notably, the FXR/β-catenin complex was maintained in DKO livers after BDL, coincident with significantly elevated hepatic BA levels. Similarly, TG mice did not display accelerated injury or increased mortality despite overexpression of β-catenin. There was no augmentation of FXR/β-catenin association in TG livers; this resulted in equivalent hepatic BAs in WT and TG mice after BDL. Finally, we analyzed the effect of BDL on β-catenin activity and identified an increase in periportal cytoplasmic stabilization and association with T-cell factor 4 that correlated with increased expression of distinct downstream target genes. Localization of β-catenin and expression of Wnt-regulated genes were altered in liver after BDL; however, neither elimination of Wnt/β-catenin signaling nor overexpression of β-catenin in hepatocytes significantly impacted the phenotype or progression of BA-driven cholestatic injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep4.1430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887668PMC
December 2019

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

Strahlenther Onkol 2020 Feb 22;196(2):126-131. Epub 2019 Nov 22.

Department of Radiation Oncology, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.

Objective: Radiotherapy (RT) has an established role in the curative treatment of indolent primary cutaneous B‑cell 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 5‑year 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 5‑year 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00066-019-01541-7DOI Listing
February 2020

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

Strahlenther Onkol 2020 Feb 15;196(2):117-125. Epub 2019 Nov 15.

Radiation Oncology Department, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00066-019-01538-2DOI Listing
February 2020

Correction: mTOR inhibition affects Yap1-β-catenin-induced hepatoblastoma growth and development.

Oncotarget 2019 Sep 24;10(54):5670. Epub 2019 Sep 24.

Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

[This corrects the article DOI: 10.18632/oncotarget.26668.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771459PMC
September 2019

A treatment planning study comparing IMRT techniques and cyber knife for stereotactic body radiotherapy of low-risk prostate carcinoma.

Radiat Oncol 2019 Aug 9;14(1):143. Epub 2019 Aug 9.

Department of Radiation Oncology of the University Hospital Muenster, Albert-Schweitzer-Campus 1, Gebäude 1, 48149, Muenster, Germany.

Purpose: Comparing radiation treatment plans by using the same safety margins and dose objectives for all techniques, to ascertain the optimal radiation technique for the stereotactic body radiotherapy (SBRT) of low-risk prostate cancer.

Material And Methods: Treatment plans for 27 randomly selected patients were compared using intensity-modulated (IMRT) techniques as Sliding Window (SW), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT), as well as Cyber Knife (CK) system. The target dose was calculated to 36.25 Gy delivered in five fractions over 1 week. Dosimetric indices for target volume and organs at risk (OAR) as well as normal tissue complication probability (NTCP) of late rectal and urinary bladder toxicities were analyzed.

Results: The CK provided lower homogeneity in the target volume, but higher values for most of the conformity indices compared to the IMRT approaches. The SW demonstrated superior rectum sparing at medium-to-high dose range (V18 Gy - V32.6 Gy) compared to other techniques (p < 0.05). The whole urinary bladder experienced the best shielding by SW and VMAT at the medium dose (V18 Gy, p < 0.05 versus CK), however we obtained no relevant differences between techniques at the high dose. Generally, the CK demonstrated significantly superior rectum and bladder exposure at V18 Gy as compared to HT, SW, and VMAT. For the rectum, mean NTCP values were significantly superior for HT (NTCP = 2.3%, p < 0.05), and for urinary bladder, the NTCP showed no significant advantages for any technique.

Conclusion: No absolute dosimetric advantage was revealed to choose between CK or IMRT techniques for the SBRT of low-grade prostate cancer. Using the same safety margins and dose objectives, IMRT techniques demonstrated superior sparing of the rectum and bladder at a medium dose compared to CK. Comparing different IMRT approaches SW displayed superior rectum sparing at a medium-to-high dose range, whereas both SW and RA revealed superior bladder sparing compared to HT. HT demonstrated a significantly lower NTCP outcome compared to CK or IMRT techniques regarding the rectum. Radiation plans can be optimized further by an individual modification of dose objectives independent of the treatment plan strategy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13014-019-1353-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689170PMC
August 2019

Biliary Obstruction Promotes Multilineage Differentiation of Hepatic Stem Cells.

Hepatol Commun 2019 Aug 23;3(8):1137-1150. Epub 2019 May 23.

Department of Pathology, Division of Experimental Pathology University of Pittsburgh Pittsburgh PA.

Because of their high regenerative potential, stem cells are an ideal resource for development of therapies that replace injured tissue mass and restore function in patients with end-stage liver diseases. Using a rat model of bile duct ligation (BDL) and biliary fibrosis, we investigated cell engraftment, liver repopulation, and ectopic tissue formation after intrasplenic transplantation of epithelial stem/progenitor cells. Fetal liver cells were infused into the spleens of Fisher 344 rats with progressing biliary fibrosis induced by common BDL or rats without BDL. Cell delivery was well tolerated. After migration to the liver, donor-derived stem/progenitor cells engrafted, differentiated into hepatocytes and cholangiocytes, and formed large cell clusters at 2 months in BDL rats but not controls. Substantial numbers of donor cells were also detected at the splenic injection site where they generated hepatic and nonhepatic tissue. Transplanted cells differentiated into phenotypes other than hepato/cholangiocytic cells only in rats that underwent BDL. Quantitative reverse-transcription polymerase chain reaction analyses demonstrated marked up-regulation of tissue-specific genes of nonhepatic endodermal lineages (e.g., caudal type homeobox 2 [], pancreatic and duodenal homeobox 1 [], keratin 13 []), confirmed by immunohistochemistry. : BDL and its induced fibrosis promote liver repopulation by ectopically transplanted fetal liver-derived cells. These cell fractions contain multipotent stem cells that colonize the spleen of BDL rats and differentiate into multiple gastrointestinal tissues, including liver, pancreas, intestine, and esophagus. The splenic microenvironment, therefore, represents an ideal niche to assess the differentiation of these stem cells, while BDL provides a stimulus that induces their differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep4.1367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672331PMC
August 2019

Successful integration of radiation oncology in preclinical medical education : Experiences with an interdisciplinary training project.

Strahlenther Onkol 2019 Dec 15;195(12):1104-1109. Epub 2019 Jul 15.

Institute of Anatomy and Molecular Neurobiology, University of Muenster, Vesaliusweg 2-4, 48149, Muenster, Germany.

Purpose: Modern impartation of both anatomic and radiation oncology (RO) knowledge in medical education enables a transfer of preclinical knowledge to clinical practice, which may be addressed by multidisciplinary concepts. The faculty's "Anatomy and imaging" course attempts to integrate RO, radiology and nuclear medicine into the preclinical curriculum. The present analysis focuses on the description of the course concept and discusses the potential didactic impact of the implementation of RO.

Methods: In total 5 semester cohorts have undertaken the course since the introduction of RO in the winter semester of 2015/2016 with 682 students participating. It is designed as a small group circuit training with a teaching content of 8 h daily. Course evaluation was performed on a 100-item Likert scale.

Results: General evaluation showed an average of 9.3-12.7 on a Likert scale (0 being the best, 100 being the worst grade). Use of media, relevance for medical training, gain of interest in medicine in general and overall satisfaction with the course received excellent mean values. For RO, there was a high degree of consent with the following statements: "the course was well organized", "subjects and presentation were well-structured", "topics were well chosen", "the time for exercises was sufficient" and "teaching by student tutors and physicians was adequate".

Conclusion: The present evaluation demonstrates the feasibility of introducing RO in the preclinical part of medical education. The course concept shows excellent results in evaluation and may help in broadening RO knowledge and in recruiting new doctoral candidates and residents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00066-019-01492-zDOI Listing
December 2019

Effect of Postoperative Radiotherapy for Brain Metastases: An Analysis.

Oncol Res Treat 2019 17;42(5):256-262. Epub 2019 Apr 17.

Department of Radiation Oncology, University Hospital Münster, Münster, Germany.

Introduction: Brain metastases (BM) have a very poor prognosis, creating a demand for effective local therapies, such as radiotherapy (RT) and neurosurgery, the combination of which is debatable. The aim of the present study was to investigate prognostic factors and to develop treatment recommendations for patients with BM.

Material And Methods: A total of 84 patients treated between May 2011 and July 2016 were analyzed in a single-institution retrospective study.

Results: Overall survival (OS) was 10.3 months. Poor OS was defined by a Karnofsky performance index of ≤70% (2.9 vs. 15.8 months; p = 0.009), male gender (6.5 vs. 18.3 months; p = 0.044), and incomplete neurosurgical resection (2.5 vs. 15.8 months; p = 0.017). These factors were also shown to be significant in univariate analysis, while only radical resection remained significant in multivariate testing (p = 0.023). A direct comparison between whole-brain RT (with or without boost) and local RT illustrated a superior OS for local therapy (22.7 vs. 9.5 months; p = 0.022), especially in case of up to 3 metastases (p = 0.041). Intracranial control was 81% with a median duration of 31.6 months.

Conclusion: Combined modality treatment of RT and neurosurgery is effective and feasible. A complete removal of all metastases is the cardinal prognostic factor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000499323DOI Listing
September 2019
-->