Stefan Könemann

Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials.

PURPOSE The impact of different local therapy approaches on local control, event-free survival, and secondary malignancies in the CESS 81, CESS 86, and EICESS 92 trials was investigated. METHODS AND MATERIALS The data of 1058 patients with localized Ewing tumors were analyzed. Wherever feasible, a surgical local therapy approach was used. In patients with a poor histologic response or with intralesional and marginal resections, this was to be followed by radiotherapy (RT). In EICESS 92, preoperative RT was introduced for patients with expected close resection margins. Definitive RT was used in cases in which surgical resection seemed impossible. In CESS 81, vincristine, adriamycin, cyclophosphamide, and actinomycin D was used. In CESS 86, vincristine, adriamycin, ifosfamide, and actinomycin D was introduced for patients with central tumors or primaries >100 cm(3). In CESS 92, etoposide, vincristine, adriamycin, ifosfamide, and actinomycin D was randomized against vincristine, adriamycin, ifosfamide, and actinomycin D in patients with primaries >100 cm(3). RESULTS The rate of local failure was 7.5% after surgery with or without postoperative RT, and was 5.3% after preoperative and 26.3% after definitive RT (p = 0.001). Event-free survival was reduced after definitive RT (p = 0.0001). Irradiated patients represented a negatively selected population with unfavorable tumor sites. Definitive RT showed comparable local control to that of postoperative RT after intralesional resections. Patients with postoperative RT had improved local control after intralesional resections and in tumors with wide resection and poor histologic response compared with patients receiving surgery alone. Patients with marginal resections with or without postoperative radiotherapy showed comparable local control, yet the number of patients with good histologic response was higher in the latter treatment group (72.2% vs. 38.5%). CONCLUSION Patients with resectable tumors after initial chemotherapy had a low local failure rate. With preoperative RT, local control was comparable. RT is indicated to avoid intralesional resections. After intralesional or marginal resections and after a poor histologic response and wide resection, postoperative RT may improve local control.

Late effects of thoracic irradiation in children.

Purpose:To summarize the literature regarding the late effects of radiotherapy to the thorax in childhood and adolescence with special emphasis on cardiac and pulmonary impairment.Material and Methods:The literature was critically reviewed using the PubMed® database with the key words “late effects”, “late sequelae”, “child”, “childhood”, “adolescence”, “radiation”, “radiotherapy”, “thorax”, “lung”, “heart”, and “pulmonary”.Results:17 publications dealing with radiation-induced pulmonary and cardiac late sequelae in children could be identified and were analyzed in detail. 29 further publications with additional information were also included in the analysis. Pulmonary function impairment after mediastinal irradiation arose in one third of all pediatric patients, even when treatment was performed with normofractionated lower doses (15–25 Gy). Whole lung irradiation was regularly followed by pulmonary function impairment with differing rates in several reports. However, clinically symptomatic function impairment like dyspnea was less frequent. Irradiation of up to 25 Gy (single doses ≤ 2 Gy) to the heart showed little or no cardiac toxicity in analyses of irradiated children (median follow-up 1.3–14.3 years). Doses of > 25 Gy (single doses ≤ 2–3.3 Gy) led to several cardiac dysfunctions. However, new data from adults with longer follow-up may indicate threshold doses as low as 1 Gy. Impairment of skeletal growth, breast hypoplasia, and secondary malignancy were further potential late sequelae.Conclusion:Several retrospective reports described radiation-associated late sequelae in children. However, there is still a lack of sufficient data regarding the characterization of dose-volume effects.Ziel:Zusammenfassung der Literatur bezüglich Spätfolgen nach Strahlentherapie am Thorax bei Kindern und Jugendlichen mit einem Schwerpunkt auf kardialen und pulmonalen Funktionseinschränkungen.Material und Methodik:Literaturzusammenstellung mittels der PubMed®-Datenbank mit den Suchbegriffen „late effects“, „late sequelae“, „child“, „childhood“, „adolescence“, „radiation“, „radiotherapy“, „thorax“, „lung“, „heart“ und „pulmonary“.Ergebnisse:17 Publikationen mit Daten zu strahlentherapieinduzierten pulmonalen und kardialen Spätfolgen bei Kindern wurden identifiziert und detailliert analysiert. Weitere 29 Publikationen mit zusätzlichen Informationen wurden in die Analyse mit eingeschlossen. Pulmonale Funktionseinschränkungen nach mediastinaler Bestrahlung im Kindesalter traten bei einem Drittel aller Patienten auf, auch wenn die Behandlung normofraktioniert mit Dosen von 15–25 Gy durchgeführt wurde (Tabelle 1a). Eine Ganzlungenbestrahlung ging regelmäßig mit einer gewissen Einschränkung einher (Tabelle 1b). Symptomatische Funktionseinschränkungen wie Dyspnoe waren jedoch seltener. Eine Bestrahlung bis zu 25 Gy am Herzen (Einzeldosen ≤ 2 Gy) zeigte keine oder wenige kardiale Spätfolgen in den Analysen zur Bestrahlung im Kindesalter (mediane Nachbeobachtung 1,3–14,3 Jahre). Höhere Bestrahlungsdosen > 25 Gy (Einzeldosen ≤ 2–3,3 Gy) führten zu einigen kardialen Spätfolgen (Tabelle 2). Allerdings deuten neue Daten bei Erwachsenen auf Dosisschwellenwerte von 1 Gy hin. Wachstumsstörungen, Brusthypoplasien und Sekundärmalignome wurden ebenso beschrieben.Schlussfolgerung:Einige retrospektive Berichte beschreiben strahlentherapieassoziierte Spätfolgen im Kindesalter. Allerdings gibt es keine suffizienten Daten bezüglich der Charakterisierung von Dosis-Volumen-Effekten.

Monitoring radiation-induced changes in bone marrow histopathology with ultra-small superparamagnetic iron oxide (USPIO)-enhanced MRI.

The purpose of this study was to monitor radiation‐induced alterations of the blood‐bone marrow barrier (BMB) and the reticuloendothelial system (RES) with AMI‐227‐enhanced magnetic resonance imaging (MRI). Twenty New Zealand white rabbits (n = 10 following total body irradiation and n = 10 controls) underwent AMI‐227‐enhanced MRI. Pulse sequences included dynamic fast low‐angle shot (FLASH; TR/TE 50/4 msec, flip angle 60°) MRI and static T1‐ and T2‐weighted spin‐echo (SE) and turbo‐SE sequences of the lumbar spine and sacrum. Bone marrow enhancement was quantified as Δ signal intensity (SI) (%) = |[(SIpost ‐ SIpre)/SIpre] × 100%| and compared with histopathology, including iron stains and electron microscopy. Dynamic bone marrow ΔSI (%) data steadily increased up to 10–15 minutes after AMI‐227 administration, while blood ΔSI (%) data stayed nearly constant, histologically corresponding to iron oxide leakage into the bone marrow interstitium. This bone marrow contrast enhancement increased significantly following irradiation, corresponding to alterations of the endothelial lining of the bone marrow sinusoids. Late postcontrast images exhibited a significant positive T1 enhancement and negative T2 enhancement of the normal bone marrow, which further increased with irradiation due to increased RES activity. Irradiation‐induced changes in bone marrow physiology could be reliably assessed with AMI‐227‐enhanced MRI. J. Magn. Reson. Imaging 1999;9:643–652, 1999.

Whole lung irradiation in patients with exclusively pulmonary metastases of Ewing tumors. Toxicity analysis and treatment results of the EICESS-92 trial.

Background:In the European Intergroup Cooperative Ewings Sarcoma Study (EICESS) 92, whole lung irradiation (WLI) was performed in patients with primary lung metastases. This retrospective analysis evaluates the pulmonary function and the outcome of patients with exclusively pulmonary metastases.Patients and Methods:Between 1990 and 1999, 99 patients were registered into the EICESS-92-study trial with exclusively pulmonary metastases of Ewing tumors. The multimodal treatment regimen included polychemotherapy and local therapy to the primary tumor. WLI was performed with a dose between 12–21 Gy. 70 patients were treated with WLI, 13 of them received a further boost to their primary tumor in the thorax up to a cumulative dose of 54 Gy.Results:Pulmonary function tests were available for 37 patients treated with WLI (± boost). None, mild, moderate or severe pulmonary complications were seen in 43%, 29%, 21% and 7% of patients treated with WLI without further boost (median follow-up 25.2 months). Patients with an additional radiation boost or surgery to the thorax showed slightly higher rates of complications. Overall survival (OAS) showed a trend towards better results for patients with WLI (5-year-OAS: 0.61 for WLI vs. 0.49 for no WLI, p = 0.36).Conclusion:These data indicate a benefit and acceptable toxicity for WLI in the presented collective of patients. As long as there is no randomized prospective analysis, the present data confirm the indication for WLI in Ewing tumor patients with primary exclusively lung metastases.Hintergrund:In der European Intergroup Cooperative Ewings Sarcoma Study (EICESS) 92 wurde bei Patienten mit primären Lungenmetastasen eine Ganzlungenbestrahlung durchgeführt. Für diese retrospektive Analyse wurden Lungenfunktion und Behandlungsergebnisse von Patienten mit ausschließlich pulmonaler Metastasierung analysiert.Patienten und Methodik:Von 1990 bis 1999 wurden 99 Patienten mit primären Lungenmetastasen ohne weitere Metastasierung von Ewing-Tumoren in der EICESS-92-Studie registriert. Das multimodale Therapieregime beinhaltete Polychemotherapie und Lokaltherapie für den Primarius. Die Ganzlungenbestrahlung wurde mit Dosen von 12 bis 21 Gy durchgeführt. 70 Patienten erhielten eine Ganzlungenbestrahlung, 13 davon mit einem weiteren Boost auf den Primarius im Thorax bis maximal kumulativ 54 Gy.Ergebnisse:Lungenfunktionsanalysen waren bei 37 Patienten mit Ganzlungenbestrahlung (± Boost) zu erheben. Keine, milde, moderate oder schwere pulmonale Einschränkungen waren in 43%, 29%, 21% und 7% der Patienten mit alleiniger Ganzlungenbestrahlung zu erheben (mediane Nachbeobachtungszeit 25,2 Monate) (Tabellen 2 und 3: Vergleich der Patientencharakteristika von Patienten mit/ohne Funktionseinschränkungen (Tabelle 2) bzw. mit/ohne Lungenfunktionsprüfung im Verlauf (Tabelle 3). Patienten mit einem zusätzlichen Boost oder einer Operation am Thorax (Tabelle 1) zeigten etwas höhere Komplikationsraten. Im Trend zeigte das Gesamtüberleben für die Patienten, die eine Ganzlungenbestrahlung erhalten hatten, bessere Ergebnisse (Abbildung 1: Gesamtüberleben bei Patienten mit und ohne Ganzlungenbestrahlung; 5-Jahres-Gesamtüberleben: 0,61 für Ganzlungenbestrahlung vs. 0,49 für Nicht-Ganzlungenbestrahlung, p = 0,36).Schlussfolgerung:Diese Daten weisen auf einen Vorteil und eine akzeptable Toxizität bei Ganzlungenbestrahlung im präsentierten Kollektiv hin. Solange keine Ergebnisse von prospektiven randomisierten Studien vorliegen, unterstützen die hier gezeigten Daten die Indikation zur Ganzlungenbestrahlung bei Patienten mit solitären primären Lungenmetastasen eines Ewing-Tumors.

Organ movements and dose exposures in teletherapy of prostate cancer using a rectal balloon.

Background and Purpose:During radiotherapy of localized prostate cancer, organ movements for the dose exposure of organs at risk like rectum, urinary bladder and urethra play, inter alia, a significant role. One possibility of internal organ stabilizing is offered by the usage of a rectal balloon during radiotherapy. The influence on organ movements and dose allocation of the organs at risk is unknown.Patients and Methods:Twelve patients (Table 1) were characterized based on planning-CTs regarding organ movements and organ doses using a rectal balloon, inflated with 0 ml and 60 ml air. For the determination of the organ doses, three-dimensional conformal radiation plans (3-field-pelvis box) with a cumulative dose of 59.4 Gy were created, and the dose-volume-histograms for the anterior rectal wall, the posterior rectal wall, the rectal mucosa, the whole rectum, as well as the urinary bladder were compared (Figures 1 and 2).Results:The application of a 60 ml air-filled rectal balloon during each fraction of teletherapy led to significant organ movements of the anterior and posterior rectal wall and to a reduction of the transversal prostate diameter, as well as to a changed organ dose exposure of the organs at risk. A ventral shift of the anterior rectal wall (maximum 0.8 cm, mean 0.4 cm) was shown, as well as a dorsal shift of the posterior rectal wall (maximum 1.2 cm, mean 0.7 cm), associated with a transversal prostate diameter decrease (maximum 0.8 cm, mean 0.3 cm) (Table 2, Figure 3). The organ dose of the anterior rectal wall increased significantly (maximum 1.3 Gy, mean 0.5 Gy) during application of a rectal balloon, the one of the posterior rectal wall decreased significantly (maximum 18.6 Gy, mean 6.5 Gy). Related to the entire rectal mucosa and the rectum as a complete organ, a decrease of the maximum doses was shown (rectal mucosa: maximum 9.1 Gy, mean 3.0 Gy; rectum: maximum 9.4 Gy, mean 3.7 Gy). The organ dose of the urinary bladder did not show significant changes (Tables 3 and 4, Figures 4 to 7).Conclusion:The application of a rectal balloon in teletherapy of localized prostate cancer leads to significantly changed dose exposition of organs at risk. The decreased dose exposure of the posterior rectal wall and the rectal mucosa is opposed by the higher organ dose of the anterior rectal wall. It has to be shown weather documented organ dose exposure is associated with short and long-term consequences.Hintergrund und Ziel:Bei der Strahlentherapie des lokalisierten Prostatakarzinoms spielen unter anderem die Organbewegungen für die Dosisexposition der Risikoorgane Rektum, Harnblase und Harnröhre eine entscheidende Rolle. Eine Möglichkeit der internen Organstabilisierung stellt die Verwendung eines Rektumballons bei der Strahlentherapie dar. Der Einfluss auf die Organbewegungen und die Dosisverteilung an den jeweiligen Risikoorganen ist unklar.Patienten und Methodik:12 Patienten (Tabelle 1) wurden auf der Grundlage von Planungs-Computertomogrammen hinsichtlich Organbewegungen und Organdosen unter Verwendung eines Rektumballons mit 0 ml und 60 ml Luftfüllung charakterisiert. Für die Bestimmung der Organdosen wurden dreidimensionale konformale Bestrahlungspläne (3-Felder-Beckenbox) mit einer Gesamtdosis von 59,4 Gy erstellt und die Dosis-Volumen-Histogramme für die Rektumvorderwand, die Rektumhinterwand, die Rektumschleimhaut, das gesamte Rektum sowie die Harnblase verglichen (Abbildungen 1 und 2).Ergebnisse:Die Verwendung eines mit 60 ml Luft gefüllten Rektumballons bei der Teletherapie führte zu signifikanten Organbewegungen im Bereich der Rektumvorderwand, Rektumhinterwand und zu einer Reduzierung des transversalen Prostatadurchmessers sowie zu veränderten Organdosen der Risikoorgane. Es zeigte sich eine Ventralverschiebung der Rektumvorderwand (Maximum 0,8 cm, Mittel 0,4 cm) sowie eine Dorsalverschiebung der Rektumhinterwand (Maximum 1,2 cm, Mittel 0,7 cm), verbunden mit einer Reduktion des transversalen Prostatadurchmessers (Maximum 0,8 cm, Mittel 0,3 cm) (Tabelle 2, Abbildung 3). Die Organdosis der Rektumvorderwand nahm unter Verwendung eines Rektumballons signifikant zu (Maximum 1,3 Gy, Mittel 0,5 Gy), die der Rektumhinterwand signifikant ab (Maximum 18,6 Gy, Mittel 6,5 Gy). Bezogen auf die gesamte Rektumschleimhaut und das Rektum als Gesamtorgan zeigte sich eine Reduktion der Maximaldosen (Rektumschleimhaut: max. 9,1 Gy, Mittel 3,0 Gy, Rektum: maximal 9,4 Gy, Mittel 3,7 Gy). Die Organdosis der Harnblase zeigte keine signifikante Veränderung (Tabellen 3 und 4, Abbildungen 4–7).Schlussfolgerung:Die Verwendung eines Rektumballons bei der Teletherapie des lokalisierten Prostatakarzinoms führt zu signifikant veränderter Dosisexposition von Risikoorganen. Geringeren Organdosen an Rektumhinterwand und Rektumschleimhaut steht eine höhere Organdosis der Rektumvorderwand entgegen. Inwieweit die unterschiedlichen Organdosen einen Einfluss auf Akut- und Spätfolgen haben, muss Gegenstand weiterer Untersuchungen sein.

Whole Lung Irradiation in Patients with Exclusively Pulmonary Metastases of Ewing Tumors

Background:In the European Intergroup Cooperative Ewings Sarcoma Study (EICESS) 92, whole lung irradiation (WLI) was performed in patients with primary lung metastases. This retrospective analysis evaluates the pulmonary function and the outcome of patients with exclusively pulmonary metastases.Patients and Methods:Between 1990 and 1999, 99 patients were registered into the EICESS-92-study trial with exclusively pulmonary metastases of Ewing tumors. The multimodal treatment regimen included polychemotherapy and local therapy to the primary tumor. WLI was performed with a dose between 12–21 Gy. 70 patients were treated with WLI, 13 of them received a further boost to their primary tumor in the thorax up to a cumulative dose of 54 Gy.Results:Pulmonary function tests were available for 37 patients treated with WLI (± boost). None, mild, moderate or severe pulmonary complications were seen in 43%, 29%, 21% and 7% of patients treated with WLI without further boost (median follow-up 25.2 months). Patients with an additional radiation boost or surgery to the thorax showed slightly higher rates of complications. Overall survival (OAS) showed a trend towards better results for patients with WLI (5-year-OAS: 0.61 for WLI vs. 0.49 for no WLI, p = 0.36).Conclusion:These data indicate a benefit and acceptable toxicity for WLI in the presented collective of patients. As long as there is no randomized prospective analysis, the present data confirm the indication for WLI in Ewing tumor patients with primary exclusively lung metastases.Hintergrund:In der European Intergroup Cooperative Ewings Sarcoma Study (EICESS) 92 wurde bei Patienten mit primären Lungenmetastasen eine Ganzlungenbestrahlung durchgeführt. Für diese retrospektive Analyse wurden Lungenfunktion und Behandlungsergebnisse von Patienten mit ausschließlich pulmonaler Metastasierung analysiert.Patienten und Methodik:Von 1990 bis 1999 wurden 99 Patienten mit primären Lungenmetastasen ohne weitere Metastasierung von Ewing-Tumoren in der EICESS-92-Studie registriert. Das multimodale Therapieregime beinhaltete Polychemotherapie und Lokaltherapie für den Primarius. Die Ganzlungenbestrahlung wurde mit Dosen von 12 bis 21 Gy durchgeführt. 70 Patienten erhielten eine Ganzlungenbestrahlung, 13 davon mit einem weiteren Boost auf den Primarius im Thorax bis maximal kumulativ 54 Gy.Ergebnisse:Lungenfunktionsanalysen waren bei 37 Patienten mit Ganzlungenbestrahlung (± Boost) zu erheben. Keine, milde, moderate oder schwere pulmonale Einschränkungen waren in 43%, 29%, 21% und 7% der Patienten mit alleiniger Ganzlungenbestrahlung zu erheben (mediane Nachbeobachtungszeit 25,2 Monate) (Tabellen 2 und 3: Vergleich der Patientencharakteristika von Patienten mit/ohne Funktionseinschränkungen (Tabelle 2) bzw. mit/ohne Lungenfunktionsprüfung im Verlauf (Tabelle 3). Patienten mit einem zusätzlichen Boost oder einer Operation am Thorax (Tabelle 1) zeigten etwas höhere Komplikationsraten. Im Trend zeigte das Gesamtüberleben für die Patienten, die eine Ganzlungenbestrahlung erhalten hatten, bessere Ergebnisse (Abbildung 1: Gesamtüberleben bei Patienten mit und ohne Ganzlungenbestrahlung; 5-Jahres-Gesamtüberleben: 0,61 für Ganzlungenbestrahlung vs. 0,49 für Nicht-Ganzlungenbestrahlung, p = 0,36).Schlussfolgerung:Diese Daten weisen auf einen Vorteil und eine akzeptable Toxizität bei Ganzlungenbestrahlung im präsentierten Kollektiv hin. Solange keine Ergebnisse von prospektiven randomisierten Studien vorliegen, unterstützen die hier gezeigten Daten die Indikation zur Ganzlungenbestrahlung bei Patienten mit solitären primären Lungenmetastasen eines Ewing-Tumors.

Evaluation of Different Biomarkers to Predict Individual Radiosensitivity in an Inter-Laboratory Comparison–Lessons for Future Studies

Radiotherapy is a powerful cure for several types of solid tumours, but its application is often limited because of severe side effects in individual patients. With the aim to find biomarkers capable of predicting normal tissue side reactions we analysed the radiation responses of cells from individual head and neck tumour and breast cancer patients of different clinical radiosensitivity in a multicentric study. Multiple parameters of cellular radiosensitivity were analysed in coded samples of peripheral blood lymphocytes (PBLs) and derived lymphoblastoid cell lines (LCLs) from 15 clinical radio-hypersensitive tumour patients and compared to age- and sex-matched non-radiosensitive patient controls and 15 lymphoblastoid cell lines from age- and sex- matched healthy controls of the KORA study. Experimental parameters included ionizing radiation (IR)-induced cell death (AnnexinV), induction and repair of DNA strand breaks (Comet assay), induction of yH2AX foci (as a result of DNA double strand breaks), and whole genome expression analyses. Considerable inter-individual differences in IR-induced DNA strand breaks and their repair and/or cell death could be detected in primary and immortalised cells with the applied assays. The group of clinically radiosensitive patients was not unequivocally distinguishable from normal responding patients nor were individual overreacting patients in the test system unambiguously identified by two different laboratories. Thus, the in vitro test systems investigated here seem not to be appropriate for a general prediction of clinical reactions during or after radiotherapy due to the experimental variability compared to the small effect of radiation sensitivity. Genome-wide expression analysis however revealed a set of 67 marker genes which were differentially induced 6 h after in vitro-irradiation in lymphocytes from radio-hypersensitive and non-radiosensitive patients. These results warrant future validation in larger cohorts in order to determine parameters potentially predictive for clinical radiosensitivity.

HEMITHORAX IRRADIATION FOR EWING TUMORS OF THE CHEST WALL

PURPOSE In the Cooperative Ewings Sarcoma Study 86 and the European Intergroup Cooperative Ewings Sarcoma Study 92, hemithorax irradiation (RT) was performed in patients with Ewing tumors of the chest wall involving the pleura or contaminating the pleural cavity. In a retrospective analysis, the outcomes of these patients were evaluated and compared with those of patients with chest wall tumors who did not receive hemithorax RT. METHODS AND MATERIALS Between 1985 and 1996, 138 patients presented with nonmetastatic Ewing tumors of the chest wall. They were treated in a multimodal treatment regimen that included polychemotherapy and local therapy depending on the tumor characteristics. Hemithorax RT was performed at a dose of 15 Gy for patients <14 years old and 20 Gy for patients >or=14 years old. Forty-two patients received hemithorax RT (Group 1) and 86 patients did not (Group 2). The data were insufficient for the other 10 patients. RESULTS Comparing both groups, the initial pleural effusion, pleural infiltration, and intraoperative contamination of the pleural space were significantly more frequent in Group 1. The event-free survival rate after 7 years was 63% for patients in Group 1 and 46% for patients in Group 2 (not statistically significant). The 7-year local relapse rate (including combined local-systemic relapses) was 12% in Group 1 and 10% in Group 2; the corresponding systemic relapse rates were 22% and 39%. CONCLUSION Patients with chest wall tumors who received hemithorax RT were negatively selected; yet the rate of event-free survival was better for patients who received hemithorax RT than for those who did not (although the difference was not statistically significant). This result was due to a reduction of metastases, mainly lung metastases. Local control was equivalent between the two groups. These favorable results have caused us to continue using hemithorax RT to treat high-risk patients with Ewing tumors of the chest wall.

Ovarian Function Following Pelvic Irradiation in Prepubertal and Pubertal Girls and Young Adult Women

Purpose:To analyze the effect of pelvic radiotherapy on ovarian function in prepubertal and pubertal girls and young adult women.Patients and Methods:In a retrospective monoinstitutional analysis, patients < 30 years of age at diagnosis were included who had been irradiated between 1979 and 1998. The main tumor types were Hodgkin’s disease (38%), Ewing’s sarcoma (20%) and nephroblastoma (11%). Patients were classified into three groups according to the position of the ovary in relation to the radiation portals. Group 1 was defined by direct irradiation of both ovaries. Group 2 patients were included with both ovaries potentially located in the radiation portals. In group 3, at least one ovary was not directly irradiated. The median follow-up was 128 months.Results:16 of 55 analyzed patients were categorized in group 1. In ten of these patients, hormone status was evaluable. The ovarian doses were ≥ 15 Gy. Except for one patient treated with 15 Gy all developed hormone failure. Eight of 14 patients of group 2 were evaluable. Seven of these patients developed ovarian failure. 19 of 24 patients in group 3 were evaluable. Nine of these patients developed ovarian failure. The observed difference in the rate of ovarian failure between the groups is statistically significant (p = 0.045).Conclusion:All patients receiving > 15 Gy to the ovaries developed hormone failure. In one case of a patient receiving an ovarian dose of 15 Gy, hormone failure was not found. In case of pelvic irradiation excluding at least one ovary, approximately half of the patients developed ovarian dysfunction, probably also due to the effects of polychemotherapy.Ziel:Analyse des Einflusses einer Beckenbestrahlung auf die Ovarialfunktion bei Mädchen und jungen Frauen.Patienten und Methodik:In einer retrospektiven monoinstitutionalen Analyse wurden Patientinnen evaluiert, die in den Jahren 1979–1998 in der Klinik für Strahlentherapie des Universitätsklinikums Münster bestrahlt worden waren und bei Therapie < 30 Jahre waren. Die häufigsten Tumorentitäten waren Morbus Hodgkin (38%), Ewing-Sarkome (20%) and Nephroblastome (11%). Die Patientinnen wurden in drei Gruppen eingeteilt. Bei Patientinnen der Gruppe 1 wurden beide Ovarien bestrahlt. Bei Patientinnen der Gruppe 2 wurden beide Ovarien potentiell bestrahlt, und in Gruppe 3 wurde mindestens ein Ovar nicht bestrahlt. Die mediane Nachbeobachtungszeit beträgt 128 Monate.Ergebnisse:Von den analysierten Patientinnen wurden 16 in Gruppe 1 klassifiziert. Bei zehn dieser Patientinnen war der Hormonstatus evaluierbar. Die Ovarialdosis lag bei ≥ 15 Gy. Bis auf eine Patientin, die mit 15 Gy bestrahlt wurde, entwickelten alle weiteren Patientinnen eine Ovarialinsuffizienz. Von 14 Patientinnen der Gruppe 2 waren acht evaluierbar. Sieben davon wiesen eine Ovarialinsuffizienz auf. 19 von 24 Patientinnen in Gruppe 3 waren evaluierbar. Neun davon entwickelten eine Ovarialinsuffizienz. Der Unterschied zwischen den drei Gruppen in Bezug auf das Auftreten einer Insuffizienz ist signifikant (p = 0,045).Schlussfolgerung:Alle Patientinnen, die mit > 15 Gy an den Ovarien belastet wurden, entwickelten eine Hormoninsuffizienz. Eine Patientin mit 15 Gy Ovarialbelastung wies keine Ovarialinsuffizienz auf. Wenn mindestens ein Ovar nicht bestrahlt wurde, lag die Insuffizienzrate bei etwa 50%, wahrscheinlich mitbedingt durch die Chemotherapie.

Cell heterogeneity and subpopulations in solid tumors characterized by simultaneous immunophenotyping and DNA content analysis

BACKGROUND Heterogeneity in human malignant tumors is a well-described phenomenon and of interest with regard to subpopulations with differences in clonality, metastatic potential, and response to therapy under different treatment regimes. The aim of this study was the simultaneous characterization of surface markers and DNA content of solid tumors to identify tumor cell subpopulations and to study the association between the expression of antigens and DNA content. METHODS In the present study, six different malignant tumors grown as xenografts in nude mice were characterized by five-parameter flow cytometry. Immunophenotyping was performed using a variety of direct fluorescence-conjugated antibodies. In all cases, simultaneous detection of DNA content was done after staining with 7-aminoactinomycin D. RESULTS Tumor cells were characterized by light scatter properties, antigen expression, and DNA content. Tumor cell heterogeneity, subpopulations, and DNA content-dependent antigen expression were identified. CONCLUSIONS This method offers the possibility of characterizing solid tumors according to their immunophenotype and DNA content. The results obtained can be used to identify changes in immunophenotypic and DNA profiles of tumor cell populations before and after therapy and might be useful to define parameters predictive for response to therapy.