Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations : An overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO).

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included.

Salvage radiotherapy in patients with recurrent esophageal carcinoma.

PURPOSE: The feasibility and effectiveness of radiotherapy in the management of recurrent esophageal carcinoma (REC) is reported. PATIENTS AND METHODS: A consecutive cohort of 54 patients with rcT1-4, rcN0-1, or cM0 recurrent esophageal carcinoma (69% squamous cell carcinoma, 31% adenocarcinoma) was treated between 1988 and 2010. The initial treatment for these patients was definitive radiochemotherapy, surgery alone, or neoadjuvant radiochemotherapy + surgical resection in 8 (15%), 33 (61%), and 13 (24%) patients, respectively. The median time to recurrence from initial treatment was 19 months (range 4-79 months). The site of the recurrence was anastomotic or local, nodal, or both in 63%, 30%, and 7% of patients, respectively. Salvage radio(chemo)therapy was carried out with a median dose of 45 Gy (range 30-68 Gy). RESULTS: Median follow-up time for surviving patients from the start of R(C)T was 38 months (range 10-105 months). Relief of symptoms was achieved in 19 of 28 symptomatic patients (68%). The median survival time was 12 months (95% confidence interval (CI) 7-17 months) and the median recurrence-free interval was 8 months (95% CI 4-12 months). The survival rates at 1, 2, and 3 years were 55 ± 7%, 29 ± 6%, and 19 ± 5%, respectively. The recurrence-free survival rates at 1, 2, and 3 years were 44 ± 7%, 22 ± 6%, and 15 ± 5%, respectively. A radiation dose ≥ 45 Gy and conformal RT were associated with a better prognosis. CONCLUSION: RT is feasible and effective in the management of recurrent esophageal carcinoma, especially for relief of symptoms. Toxicity is in an acceptable range. The outcome of REC is poor; however, long-term survival of patients with recurrent esophageal carcinoma after radiochemotherapy might be possible, even with a previous history of radiotherapy in the initial treatment. If re-irradiation of esophageal carcinoma is contemplated, three-dimensional conformal techniques and a minimum total dose of 45 Gy are recommended.

Primary radiotherapy with or without chemotherapy in non-metastatic esophageal squamous cell carcinoma: a retrospective study.

The purpose of this study was to report the outcome of radio(chemo)therapy in the curative management of esophageal squamous cell carcinoma (ESCC). We retrospectively analyzed 163 patients with T1-T4, N0-1, M0 ESCC who were treated between January 1988 and December 2006 at the Technische Universität München. One hundred sixty patients were inoperable due to a poor performance status, comorbidities or locally advanced unresectable disease. External beam radiation therapy (EBRT) was performed with (n= 146) or without (n= 17) systemic chemotherapy. Fifty-four patients received an additional boost with intraluminal brachytherapy (IBT). Surviving patients were followed for a median of 72 months (range 10-173 months). The estimated overall survival (OS) at 2 and 5 years was 27 ± 4% and 11 ± 3%, respectively. Loco-regional recurrence at the primary site was observed in 29% of patients (n= 47). The recurrence-free survival (RFS) at 2 and 5 years was 24 ± 3% and 9 ± 2%, respectively. In multivariate analyses, the ECOG performance status (P= 0.004), 3D conformal (vs conventional) radiotherapy (P= 0.031) and continuous standard fractionation (vs split-course radiotherapy, P= 0.048) were associated with a better OS. Simultaneous chemotherapy (P= 0.49) or IBT (P= 0.31) had no significant impact on survival. Outcome for patients with ESCC is poor. Despite the very unfavorable patient selection (poor performance status, high rate of comorbidities, and advanced disease), long-term survival with radio(chemo)therapy was achieved in about 10% of patients. The introduction of modern treatment techniques/modalities (3D conformal planning/ continuous standard fractionation) might be associated with better outcomes.

Radio(chemo)therapy in the management of squamous cell carcinoma of cervical lymph nodes from an unknown primary site. A retrospective analysis.

PURPOSE: The goal was to retrospectively review the outcome of patients with cervical lymph node metastases of squamuos cell carcinoma of unknown primary site (CUP) treated with radio(chemo)therapy. PATIENTS AND METHODS: A total of 65 patients with CUP N1-3, M0, treated between 1988 and 2009 were evaluated: 61 patients underwent surgical resection followed by postoperative radio(chemo)therapy, 4 patients received definitive radiochemotherapy. Radiotherapy of bilateral neck nodes + the parapharyngeal region (COMP-RT) was performed in 48 patients (80%) and a unilateral radiotherapy of lymph nodes (UL-RT) in 17 patients (20%). RESULTS: After a median follow-up time of 64 months (range 3-219 months), the estimated 2- and 5-year overall survival (OS) rates were 71 ± 6% and 48 ± 7%, respectively. The recurrent free survival (RFS) rate at 2- and 5-years was 58 ± 6% and 48% ± 7%, respectively. Extracapsular spread, resection status (R0 vs. R1/R2), neck lymph node level (I-III vs. IV-V), and Karnofsky index (60-70 vs. 80-100) were significant prognostic factors for OS and RFS in the univariate analysis. Lower nodal stage (N1/N2a vs. N2b/N2c/N3) was significantly associated with a better OS. Resection status and involvement of lymph node level IV significantly affected the OS and RFS in the multivariate analysis. COMP-RT or concurrent chemotherapy was not associated with a better OS or RFS. CONCLUSION: An advantage of comprehensive radiotherapy or radiochemotherapy compared with unilateral radiotherapy of lymph nodes was not observed.

Prediction of very short survival in patients with brain metastases from breast cancer.

AIMS: Current prognostic models are not accurate enough to identify brain metastases patients with very short survival, i.e. <2 months, who are unlikely to derive major benefit from whole brain radiotherapy. Our aim was to develop a more reliable model. MATERIALS AND METHODS: This was a retrospective analysis of a German database, which was used to develop a score, and an additional database from Norway, which was used for validation purposes. RESULTS: The groups included 67 and 32 patients, respectively. An analysis of prognostic factors resulted in a risk score based on performance status, extra-cranial metastases, the interval from breast cancer to brain metastases and a need for corticosteroid treatment, which classified 63 of 67 test patients correctly. However, the validation failed and unfortunately the risk score that performed best in the Norwegian patients (31 of 32 correctly predicted) was not applicable to the German patients. CONCLUSIONS: The prediction of short survival is associated with several caveats and seems to result in an unacceptable risk of withholding radiotherapy in patients who actually survive for longer than 2 months.

Ten-year data on 138 patients with endometrial carcinoma and postoperative vaginal brachytherapy alone: no need for external-beam radiotherapy in low and intermediate risk patients.

OBJECTIVE: To evaluate long-term outcome, risk factors, and causes of death in stage I-IIIA endometrial carcinoma (EC) patients treated only with adjuvant vaginal brachytherapy (VB) and to clarify for which subgroups of patients it is safe to omit external-beam radiotherapy (EBRT). METHODS: Out of 224 EC patients receiving postoperative radiotherapy between 1990 and 2002, 138 had VB alone in curative intent (FIGO [2002]: 85%I, 12%II, 3%IIIA; 18 low risk [IA G1-2, IB G1], 103 intermediate risk [IB G2-3, IC G1-2, IIA-B G1-2], 17 high risk [IC G3, IIIA]). After surgery+/-lymphadenectomy, HDR-brachytherapy prescription (in 95.7% of patients) was 3x10 Gy to the surface or 3x5 Gy at 5 mm tissue depths. RESULTS: Median follow-up was 107 months (range 3-185). Three intermediate and 7 high risk-patients relapsed. The 10-year vaginal control was 99.2%, locoregional control was 95.2% (low/intermediate/high risk: 100%/98.9%/68.8%), and disease-free survival (DFS) was 91.7% (100%/96.8%/55.2%). Risk factors for poor DFS were lymphovascular space invasion, > or = 50% myometrial invasion (univariate, p<0.05), pathological FIGO-stage, and grade 3 (uni-/multivariate, p<0.05). Leading causes of deaths (n=41) were cardiovascular disease (29%) and other malignancies (24%) ahead of EC (19.5%). The 10-year overall survival was 68.5% and the disease-specific survival was 92.4%. Thirty-five secondary tumors in 31 patients led to a higher actuarial death rate (10-year 9.9%, 15-year 17.7%) than EC (7.6%). CONCLUSIONS: Restricting adjuvant therapy to VB alone seems to be safe in low and intermediate risk EC and can be recommended. As death rarely relates to early-stage EC, value of adjuvant therapy is probably better reflected by DFS rather than by overall survival.

Fatigue, serum cytokine levels, and blood cell counts during radiotherapy of patients with breast cancer.

PURPOSE: To assess the level of fatigue during the course of adjuvant radiotherapy (RT) of breast cancer patients and its relation to anxiety, depression, serum cytokines, and blood count levels. METHODS AND MATERIALS: Forty-one patients who received adjuvant RT after breast-conserving surgery were prospectively studied. All patients underwent RT without concomitant chemotherapy. Patients rated their fatigue with two standardized self-assessment instruments, the Fatigue Assessment Questionnaire and a visual analog scale on fatigue intensity, before RT, during weeks 1-5 of RT, and 2 months after RT completion. In addition, the anxiety and depression levels were assessed with the Hospital Anxiety and Depression Scale. A differential blood cell count and the serum levels of the cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha were determined in parallel to the fatigue assessments. RESULTS: Fatigue intensity as assessed with the visual analog scale increased (p <0.001) until treatment week 4 and remained elevated until week 5. Two months after RT, the values had fallen to the pretreatment levels. Fatigue measured with the Fatigue Assessment Questionnaire did not increase significantly during treatment, but the subscores on physical (p = 0.035) and cognitive (p = 0.015) fatigue were elevated during treatment weeks 4 and 5. Affective fatigue did not change significantly. Anxiety, as rated with the Hospital Anxiety and Depression Scale, declined during RT (p = 0.002), but the Hospital Anxiety and Depression Scale depression score did not change significantly. IL-1beta, IL-6, and tumor necrosis factor-alpha levels did not change during therapy and did not correlate with fatigue. Peripheral blood cell levels declined significantly during therapy and were still low 2 months after treatment. Until treatment week 5, lymphocytes were reduced to almost 50% of their initial values. Hemoglobin levels did not correlate with fatigue. CONCLUSIONS: We observed an increase in fatigue during adjuvant RT of patients with breast cancer. Fatigue returned to pretreatment levels 2 months after treatment. No evidence was found that anxiety, depression, serum levels of IL-1beta, IL-6, tumor necrosis factor-alpha, or declining hemoglobin levels were responsible for the treatment-induced fatigue.

Regulation of the energy metabolism of Plasmodium berghei.

Energy metabolism of malaria parasites was investigated in P. berghei infected red blood cells of rat. Although Plasmodia contain mitochondria most of their ATP is formed by glycolysis. Lactate formation is two orders of magnitude higher than in noninfected erythrocytes. The coupling of respiration and glycolysis is very loose, a Pasteur-effect was not found. The key enzymes of glycolysis hexokinase and phosphofructokinase have been partially purified and kinetically characterized. The kinetic properties of both enzymes significantly differ from those of erythrocytes. They are less efficiently inhibited and PFK is activated only by PEP, Fru6P and Pi. The high rate of glycolytic proton formation in Plasmodia inhibits the PFK and thus the anaerobic energy metabolism of the host cell but not that of the parasite. Nevertheless the ATP concentrations in the host and the parasite compartment were found to be nearly identical. This supports the assumption that the parasites make ATP available to their host cell, probably by an adenine nucleotide translocator.

A kinetic model of phosphofructokinase from Plasmodium berghei. Influence of ATP and fructose-6-phosphate.

Phosphofructokinase (PFK) from the malarial parasite Plasmodium berghei shows the following kinetic features: the more the pH is decreased, the more the enzyme is inhibited by ATP; in contrast to PFK from erythrocytes, this inhibition is less potent by two orders of magnitude; as in the red cell, fructose-6-phosphate (F6P) is a positive effector. Kinetic modelling of PFK from P. berghei has been performed by taking the pH-dependence of activity into regard, implicitly by the estimation of pH-dependent kinetic parameters for the inhibition by ATP and the activation by F6P and explicitly by the assumption of protonation-steps involved in allosteric regulation. By means of a novel procedure of model discrimination [D. Buckwitz and H.-G. Holzhütter: A new method to discriminate between enzyme-kinetic models. In: Application of Computational Methods in Medicine (Györi, I., ed.), Akademai, Budapest, in press] we have selected among several kinetic models the best rate equation which provides an adequate quantitative description of the kinetic behaviour of the enzyme in the relevant ranges of substrate concentrations and pH (5.8-7.6). It thus becomes clear how the highly increased glycolytic flux in malaria-infected cells could be affected through PFK.

[Chacterization of human reticulocytes: respiration, Pasteur effect, and electron microscopic findings on mitochondria]. / Charakterisierung von Retikulozyten des Menschen: Atmung, Pasteur-Effekt und elektronenmikroskopische Befunde an Mitochondrien

On 5 blood samples of newborns, whose reticulocytes had been enriched by density gradient centrifugation, and on 25 blood samples of different reticulocytoses of man were determined: the extent of intra- and extramitochondrial respiration, coupling of the electron transfer with the oxidative phosphorylation and the electronmicroscopic appearance, and the number of mitochondria. The reticulocytes occurring in the flowing human blood are in general relatively stiff and are characterized by the following properties:--low respiration--low capacity of the respiratory chain enzymes--weakened Pasteur effect --varying proportion of intramitochondrial respiration and total respiration--decoupling of a major part of the intramitochondrial respiration--low number of mitochondria--qualitative changes of mitochondria. However, there are situations of erythropoiesis where immature reticulocytes are discharged in man (similar to the socalled "stress reticulocytes" of rabbits). On the other hand, it could be shown that the reticulocytes of rabbits are mature in the normal state.