Avascular osteonecrosis after hyperthermia in children and adolescents with pelvic malignancies: a retrospective analysis of potential risk factors.

PURPOSE: In children with locally advanced or recurrent malignant tumours, prognosis can be improved by regional deep hyperthermia (RHT) in combination with platin-based chemotherapy. However, because of the increasing number of patients that achieve long-time remission with this therapy, it is necessary to evaluate long-term sequelae of thermochemotherapy. During the years 1993-2004 one has observed avascular osteonecrosis (AON) of the femoral head after RHT in seven children with pelvic germ cell tumours or rhabdomyosarcomas. METHODS: Although AON may develop in patients with malignancies treated with chemo- or radiotherapy alone, RHT might nevertheless contribute to the occurrence of AON. In order to determine potential risk factors for AON after RHT, this study analysed the relationship of AON to the patient's age, medical history and treatment parameters such as thermal dose equivalent and power output. RESULTS AND CONCLUSIONS: In the present study AON was associated with young age as well as intensity of hyperthermia indicated by high power levels that exceed 20 W per kg body weight and/or application of eight or more heat sessions as well as additional radiotherapy. Based on this observation, it was assumed that an optimized three dimensional thermal field modelling may be helpful to avoid hazardous temperatures in the femoral heads during RHT treatment and to reduce AON of the femoral heads.

An approach for cure: PEI-chemotherapy and regional deep hyperthermia in children and adolescents with unresectable malignant tumors.

BACKGROUND: Elevated temperatures of 40 - 44 degrees C increase the actions of various anticancer drugs including N-lost derivatives, cytotoxic antibiotics and platinum analoga. In clinical usage thermochemotherapy (TCH) should facilitate surgical resection and ameliorate local tumor control. PATIENTS AND METHODS: From 07/1993 to 12/2002 a total of 39 patients have been enrolled onto a phase-II study (female = 24, male = 15, age 1 - 37.5 years, median 5.2). Among these, 24 patients had extracranial non-testicular germ cell tumors and 15 patients soft tissue or chondrosarcomas. INDICATION: locoregional relapse (n = 29) or unresectable tumor after neoadjuvant chemotherapy (n = 10). Among these two groups, there were ten patients with poor response or progressive disease under primary or relapse chemotherapy. Ten out of the 29 relapse patients had more than one relapse. Tumor site: pelvis (30), abdomen (4), head and neck (2), proximal leg (2) and lumbar spine (1). Thermochemotherapy (TCH): 1800 - 2000 mg ifosfamide/m (2) and 100 mg etoposide/m (2) on days 1 - 4 and 40 mg cisplatin/m (2) on days 1 + 4 combined with regional deep hyperthermia (42 - 44 degrees C, 1 h) on days 1 + 4. RESULTS: In 39 protocol patients a total of 166 TCH courses (332 heat sessions) were applied. 20 patients achieved complete response, and 10 patients achieved partial response. TCH was followed by surgical tumor resection in 28/39 patients and/or radiotherapy in 13/39 patients. At a median follow-up of 27 months, outcome in this high-risk patient population was 22 NED, 3 AWD, 12 DOD, 2 DOC. Five year event free (EFS) and overall survival (OS) for the whole study cohort was 0.39 +/- 0.11 (20/39 patients) and 0.52 +/- 0.11 (25/39 patients), respectively. CONCLUSION: TCH shows substantial therapeutic efficacy and facilitates complete tumor resection in 14 out of 28 operated patients. Multimodal treatment including TCH, surgical resection and/or radiotherapy leads to sustained remission in the majority of patients with locoregional tumor recurrence. The therapeutic effect is most pronounced, if TCH is administered at first relapse. Due to the clinical and histologic heterogeneity the number of patients eligible for TCH is limited. Therefore, a more valid assessment of treatment efficacy can only be made by a matched-pair comparison in cooperation with the clinical registers.

In vitro test-system for chemo- and thermosensitivity: an analysis of survival fractions and cell-cycle distributions in human Ewing's sarcomas as a modelfor tumors in pediatric oncology.

BACKGROUND: Tumor cell resistance to anticancer drugs is the primary reason for treatment failure in childhood cancer. Resistance can exist at the onset of treatment or can become clinically apparent under selective pressure of drug exposure. In vitro predictive tests are important for the experimental study of drug resistance. Although in vitro studies appear to be fairly good for predicting drug resistance, they are rarely used in the routine management of individual cases. An exception that proves the rule is the MTT- (3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazoliumbromide) assay in children with acute lymphoblastic leukemias (ALL), which can be correlated with the clinical outcome in this group of patients. In the present study we used a predictive test-system to evaluate the synergistic cytotoxic effects of chemotherapy +/- hyperthermia with respect to cell cycle disturbance. METHODS: As a tumor model two well defined human Ewing's sarcoma cell lines VH64 and SK-ES-1 were treated for 1 h with cis-diamminedichloroplatinum II (cDDP) (0.1, 0.5, 1, 3, 5 micro g/ml) or 4'-demethyl-epipodophyllotoxin-5-(4,6-0-)-ethylidene-beta-D-glycopyranoside (VP-16) (1, 5, 10, 20, 50 micro g/ml) +/- hyperthermia (42 degrees C, 43 degrees C); control: 37 degrees C, without chemotherapy. Cell survival was tested using the XTT- (2,3-bis[2-Methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide) assay. Assay conditions were optimized for each tumor cell line, extinction was measured 72 h post treatment at 450 nm in an ELISA-reader. Cell cycle fractions (G0/G1-, S-, G2/M-phase) were determined immediately, 12 h and 24 h after treatment by labeling proliferating tumor cells with bromodeoxyuridine (BrdU) and measuring DNA-content with propidium-iodide (PI) and analyzed by flow cytometry. RESULTS: Survival fractions: Hyperthermia alone at 43 degrees C reduced tumor cell survival to 51 % in SK-ES-1 and 74 % in VH64. cDDP (5 micro g/ml): reduction of survival fraction to 23 % in SK-ES-1 and 33 % in VH64. cDDP (5 micro g/ml) + hyperthermia (43 degrees C): enhanced reduction of tumor cell survival compared to 37 degrees C to 11 % in SK-ES-1 and 8 % in VH64. VP-16 (50 micro g/ml): survival fraction of 18 % in SK-ES-1 and of 31 % in VH64. In contrast to cDDP, chemosensitivity of the tumor cells to VP-16 could not synergistically be enhanced by using hyperthermia. Cell cycle analysis: Hyperthermia alone at 43 degrees C induced an accumulation in G2/M and a slight reduction in G0/G1-phase 24 h after treatment, whereas the S-phase was not markedly affected. cDDP (5 micro g/ml) alone led to a prominent S-phase arrest and a G0/G1 decrease 24 h after treatment. Simultaneous application of cDDP (5 micro g/ml) + hyperthermia (43 degrees C) however significantly reduced S-phase cells. VP-16 (50 micro g/ml) alone induced a temporary S-phase arrest 12 h after treatment and a delayed G2/M-arrest after 24 h. Additional hyperthermia at 43 degrees C did not show further effects on VP-16 induced cell cycle disturbances. CONCLUSIONS: Test-system discloses treatment-specific alterations in tumor cell survival and cell cycle distribution, e. g. synergistic enhancement of cDDP cytotoxicity by heat application, which might predict chemo- and thermosensitivity.

Effects of hyperbaric oxygen and normobaric carbogen on the radiation response of the rat rhabdomyosarcoma R1H.

PURPOSE: Hypoxic tumor cells are an important factor of radioresistance. Hyperbaric oxygen (HBO) and normobaric carbogen (95% oxygen, 5% carbon dioxide) increase the oxygen delivery to tumors. This study was performed to explore changes of tumor oxygenation during a course of fractionated irradiation and to determine the effectiveness of normobaric carbogen and HBO during the final phase of the radiation treatment. METHODS AND MATERIALS: Experiments were performed on the rhabdomyosarcoma R1H growing on WAG/Rij rats. After 20 X-ray fractions of 2 Gy within 4 weeks, oxygen partial pressure (pO2) was measured using the Eppendorf oxygen electrode under ambient conditions, with normobaric carbogen or HBO at a pressure of 240 kPa. Following the 4-week radiation course, a top-up dose of 10-50 Gy was applied in 2-10 fractions of 5 Gy with or without hyperoxygenation. RESULTS: HBO but not carbogen significantly increased the median pO2 in irradiated tumors. The radiation doses to control 50% of tumors were 38.0 Gy, 29.5 Gy, and 25.0 Gy for air, carbogen, and HBO, respectively. Both high oxygen content gas inspirations led to significantly improved tumor responses with oxygen enhancement ratios (OERs) of 1.3 for normobaric carbogen and 1.5 for HBO (air vs. carbogen: p = 0.044; air vs. HBO: p = 0.02; carbogen vs. HBO: p = 0.048). CONCLUSION: Both normobaric carbogen and HBO significantly improved the radiation response of R1H tumors. HBO appeared to be more effective than normobaric carbogen, both with regard to tumor oxygenation and response to irradiation.

[MRI follow-up study of aseptic osteonecrosis (AON) in children treated with chemotherapy for malignant diseases]. / MRT-Verlaufsbeurteilung aseptischer Knochennekrosen (AON) bei Kindern mit chemotherapierter maligner Grunderkrankung.

PURPOSE: The aim of the study was to evaluate by MRI the course of aseptic osteonecrosis (AON) after chemotherapy in children with different malignancies. MATERIAL AND METHODS: Retrospective analysis of 72 MRI studies in 20 children (age: 3.2-18.4 years) presenting with AON after chemotherapy. 8 children were treated exclusively with relief of weightbearing structures, whereas 12 children were additionally treated with hyperbaric oxygen therapy (HBO). Within a range of 3-76 months each patient received 1-6 follow-up exams. The acquired series included multi planar spin-echo as well as fatt-suppressed inversion recovery sequences. The MRI examinations were evaluated by a point-score system (1-6) by two radiologists. RESULTS: AON was most commonly seen in the pedal bones (26.4%), in the hip (23.6%), and in the knee joints (19.4%). Initial findings revealed an average score of 3.1 points. Based upon these initial findings, subsequent analyses show a statistically significant (p < 0.05) score increase of 0.6 score-points. For the observed intervals a: < 6 months, b: 6-12 months, and c: > 12 months the mean scores were: a: 3.3, b: 3.7, and c: 4.5 points. During the observed time period 5 patients were surgically treated in the affected bone areas. CONCLUSION: The majority of chemotherapy associated AON which initially present with advanced findings showed in MRI a progression with frequent destruction of the joint surface over their further course. More discrete forms of AON, especially osteoedema, can be positively influenced by conservative therapy.

MRI evaluation of aseptic osteonecrosis in children over the course of hyperbaric oxygen therapy.

PURPOSE: The study aimed at MRI evaluation of aseptic osteonecrosis (AON) in children over the course of hyperbaric oxygen (HBO) therapy. MATERIAL AND METHODS: Retrospective analysis of 72 MRI studies in 20 children presenting with AON during chemotherapy. Two groups were differentiated: Gr. I (n = 8) was treated exclusively with relief of weightbearing structures, Gr. II (n = 12) was additionally treated with HBO therapy. The MRI examinations were evaluated by a point-score system (1-6 points) by two radiologists. RESULTS: Gr. II initially showed more severe findings (average score: 3.4) in comparison to Gr. I (average score: 2.65). During the follow-up time period the average scores rose to 3.2 score-points in Gr. I and 4.1 points in Gr. II. No statistically significant difference was evident between the two groups in the course of AON. CONCLUSION: The majority of chemotherapy associated AON which initially present with advanced findings show a progression in MRI over their further course. HBO therapy in addition to the relief of affected weightbearing structures statistically shows no significant improvement in MRI morphology during the course of the treatment.

Hyperthermia for the treatment of patients with malignant germ cell tumors: a phase I/II study in ten children and adolescents with recurrent or refractory tumors.

BACKGROUND: Extracranial nontesticular germ cell tumors (GCTs) are rare malignancies in children and adolescents. Cisplatin-containing regimens and complete tumor resection are important determinants for a favorable outcome; however, patients with recurrent tumors that cannot be eradicated by surgical procedures and chemotherapy have a poor prognosis. Noninvasive electromagnetic technologies for superficial and regional deep hyperthermia (RHT) are under investigation to enhance local tumor control in various malignancies. The objectives of this Phase I/II study were to examine 1) whether RHT can be used in combination with platinum-based chemotherapy with acceptable toxicity in children and adolescents and 2) whether this combined regimen can induce objective tumor response in patients with malignant nontesticular GCT that persisted or recurred locoregionally after validated, intensive, cisplatin-based chemotherapy +/- surgery as unsuccessful first-line treatment. METHODS: The authors studied the effects of RHT induced by electromagnetic waves in combination with platinum-based chemotherapy in ten children and adolescents with recurrent or refractory GCTs. RESULTS: Seven of ten patients with recurrent or refractory GCTs had objective responses. Of these, two patients had a partial response and five patients had a complete response. CONCLUSIONS: The results of the current study found that combined RHT and platinum-based chemotherapy can be used in children and adolescents. This regimen was found to induce objective tumor response in 70% of study patients with recurrent or refractory GCTs. The results thus far are encouraging and the study has been extended to patients with a poor response to first-line treatment.

[An interventional study against cigarette smoking among Dusseldorf high school students 1992-94]. / Interventionsstudie gegen das Zigarettenrauchen von Düsseldorfer Hauptschülern 1992-94.

Between 1992 and 1994, an interventional program was held in the secondary schools ("Hauptschulen") in Düsseldorf contra cigarette smoking. The program was conducted in the following way. Half of the schools (intervention schools) were involved in this program which consisted of 15 sessions. The other schools served as control groups. During the first year of this program school-teachers and a physician taught students about the function and the abilities of the healthy heart and lung. The students developed adversions to smoking. In addition, the students learned by role-plays how to say no to a cigarette without embarrassment. These role-plays were videotaped. During the second year of this program the role-plays were repeated and teaching about the heart and the lungs was augmented. Also, every student got the opportunity to meet and talk with a famous athlete. Furthermore, smoking-cessation programs were hold in four intervention schools. The program started in the sixth grade with a questionnaire administered to 878 schoolchildren. During this time the average age of the children was 13 years. Because of a large fluctuation, the questioning could be repeated with only 630 of these children (71.8%) after 2 years. At the end of the study the number of smokers had increased two times greater in the control schools than in the intervention schools (boys: 20.5% points vs 9.4% points; girls: 44.3% points vs 21.0% points). Obviously, the continuation of the program during the second year was important in making the program successful. Among the participants of the intervention program there was a trend to stop smoking. But the program was not able to prevent non-smokers from starting the habit. On the other hand, of the children who started smoking during the program, more girls in the intervention schools quit smoking than in the control schools. At the end of the program more girls than boys (mean age 15 years) smoked. Almost one-fourth of the boys, and from the control schools one-third of the girls were already daily smokers. The smokers obtained cigarettes from kiosks, from friends, vending machines, vendors or shops, but seldom from their homes.

Successful liver treatment of a juvenile granulosa cell tumor in a 4-year-old child by regional deep hyperthermia, systemic chemotherapy, and irradiation.

Juvenile granulosa cell tumors (JGCT) of the ovary are rare in children and adolescents. About 90% are diagnosed in early-stage FIGO I with favorable prognosis. More advanced stages (FIGO II-IV) have a poor clinical outcome and chemotherapy alone cannot avoid tumor progression. Regional deep hyperthermia (RHT) induced by microwave technique has been established as an additional modality for treatment of different tumors. However, in cases with liver involvement there are technical problems which have not yet been solved. We report on a 4-year-old child who suffered from diffuse liver metastases 10 months after JGCT of the left ovary. After chemotherapy including ifosfamide, etoposide, and carboplatin in combination with RHT and consolidation radiotherapy, the patient has been in complete remission for 1 year of follow-up. This Case Report indicates the feasibility of combining surgery, chemotherapy, hyperthermia, and radiation therapy (which can also be an effective treatment modality for advanced granulosa cell tumor) for the treatment of liver metastases of JGCT, but does not allow comparisons of these treatments.

[Preventive long-term intravenous immunoglobulin infusion in children with acute lymphatic leukemia. I. Anticomplementary activity of gamma globulin preparations is a function of the preparation and IgG concentration prior to infusions]. / Prophylaktische Langzeit-i.v.-Immunglobulin-Infusion bei Kindern mit akuter lymphatischer Leukämie. I. Die antikomplementäre Aktivität der Gammaglobulinpräparate ist eine Funktion des Präparates und der IgG-Konzentration prae infusionem.

The influence of intravenous gammaglobulin infusions (ivGG) on hemolytic complement function and the concentration of serum C3 and its split product C3dg was studied in 20 children with acute lymphocytic leukemia (ALL) undergoing ivGG prophylaxis. IvGG was infused once monthly over a period of 20 months using two different preparations commercially available. Serum and EDTA-plasma were collected before initiation of ivGG therapy (time 1), after 10 and 20 months (time 2 and 3), before and immediately after the infusions. IvGG was infused in connection with chemotherapy (according to the CoAll 82 protocol). 16 of 60 sera collected prior to infusions contained less than 700 mg/dl IgG. Mean IgG concentrations could be raised to 198 mg/dl (time 1), 219 mg/dl (time 2), and 213 mg/dl (time 3), respectively. -CH 50 prior to infusions was below normal in 15 of 59 sera, afterwards in 25 of 59 sera. AP 50 before (after) infusions was decreased in 29 of 59 (36 of 60) sera, C3 in 18 of 60 (24 of 60) sera. C3dg was slightly elevated in one EDTA-plasma prior to ivGG infusions and in 5 of the plasmas following infusions. IvGG infusions resulted in a significant loss of hemolytic activity of serum complement (p less than 0.01, F-test). The effect was more profound if IgG concentrations before infusions were less than 700 mg/dl, but this was true for only one of the two used ivGG preparations. The long term follow up over two years showed no significant changes of complement functions (F-test), indicating complete recovery of complement function from short term anticomplementary effects.