Epidemiology and clinical characteristics of pandemic (H1N1) 2009 influenza infection in pediatric hemato-oncology and hematopoietic stem cell transplantation patients.

BACKGROUND: For children with hemato-oncologic diseases, especially after hematopoietic stem cell transplantation (HSCT), the risk for developing complications related to pandemic influenza A (H1N1) 2009 (pH1N1) infection is largely unknown. METHODS: A retrospective chart study was performed of pH1N1 cases diagnosed between October 2009 to January 2010 in the hemato-oncologic unit of the University Children's Hospital of Düsseldorf, Germany. FINDINGS: In total, 21 children were diagnosed with laboratory-confirmed pH1N1; in 16 patients with malignancies (acute leukemia 7, lymphoma 4, solid tumors 2, others 3) and in 5 with benign hematologic disorders. Five patients had undergone prior HSCT, although 1 patient was diagnosed during conditioning therapy with high-dose chemotherapy in preparation for haploidentical HSCT. Most frequent symptoms were fever (>38.5°C) and cough (in 100%), and rhinorrhea (57%). The 2 patients acquiring pH1N1 infection under high-dose or intensive chemotherapy did not require intensive care or mechanical ventilation, and both recovered under antiviral therapy. Oseltamivir was administered to 11 patients; in 1 patient, therapy was switched, on a compassionate-use basis, to intravenous zanamivir because of lack of clinical improvement after oseltamivir therapy. Complications were hospitalization (19%), demand of oxygen supplementation, delay/interruption of antineoplastic therapy, and prolonged administration of antibiotics and antipyretics. CONCLUSION: In the investigated patient population, pH1N1 was mild in most cases, but was associated with substantial morbidity in a proportion of patients and led to interruption and delay in anticancer treatment.

Invasive aspergillosis in pediatric oncology patients: a rare event with poor prognosis--case analysis to plan better targeted prophylactic or therapeutic measurement.

Despite the implementation of new antifungal drugs, invasive aspergillosis (IA) still remains a considerable challenge in pediatric oncology with a severe mortality. Prophylactic and therapeutic measurement have to be evaluated in these rare but poor prognostic patients. Therefore the entire group of patients at risk of developing IA has to be defined before cooperative prospective trials. In a retrospective analysis including all our patients with malignancies we looked for patients with proven/probable IA. Cases of the period from 2003 to 2008 were analyzed in detail.In the period between 2003 to 2008 24 of 755 patients were affected by proven/ probable IA. Compared to former studies incidence increased from 1.3%in 1980 to 3.4% in 2008. AML patients with or without allogeneic/haploidentical stem cell transplantation were at highest risk (24% and 25% respectively, in comparison to 1% in ALL-patients). Survival after 2 years was 50% for patients with AML and IA. In patients with high risk to develop IA the effect of intensified, intravenous antimycotic prophylaxis has to be proven prospectively in a cooperative and randomized setting.

Symptoms of childhood acute lymphoblastic leukemia: red flags to recognize leukemia in daily practice.

BACKGROUND: The aim of this study is to identify clinical "red flags" that may assist the general pediatrician in detecting patients with an acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Medical history and clinical findings of 189 children and adolescents, diagnosed with ALL between 1/1995 and 7/2004, were analyzed retrospectively. RESULTS: Only 50% of patients presented with symptoms known in children with leukemia (fever, fatigue, paleness, hemorrhage); 5% were diagnosed accidentally in the absence of any clinical symptoms. The majority of patients had a medical history up to few weeks; in 11% of patients up to several months without impairing curability. 95% of the patients presented at diagnosis with enlargement of lymphnodes, liver and/or spleen. The characteristic laboratory constellation included mono-, respectively bi- or trilinear pathology of the blood count and with blasts in the blood smear. CONCLUSION: The clinical diagnosis of ALL relies on physical examination and the blood count including microscopic examination. Therefore, the alertness of the treating paediatrician with regard to clinical findings and a pathologic blood count is more important than elaborate laboratory investigations. In uncertain cases, a close follow-up examination may help to unmask ALL, which will most likely be stratified in the low-risk-group.

Long time survival after reduced chemotherapy ina 15-year-old patient with AML and Candida krusei sepsis and eye involvement.

A 15-year-old boy with AML develops a fulminant candida krusei sepsis complicated by acute blindness due to enophthalmitis and subsequent bleeding during prolonged pancytopenia after induction therapy. Despite a low dose prophylaxis with oral nystatine and i. v. amphotericin B (ampho B) three times a week (0.8 mg/kg). Under an early intensified therapy with ampho B (1.5 mg/kg/d) combined with 5-flucytosin (160 mg/kg/d)the sepsis could be controlled and visual acuity slowly improved. A vitrectomy is due to the bleeding unavoidable. Despite a therapy delay of 4 weeks and omission of two cycles of the intensification treatment the patient is in continuous complete remission for longer than 10 years after diagnosis. If it is within the treatment protocols manageable to detect patients with increased sensitivity against cytostatic drugs and correspondingly highly sensitive leukemic cells, such complications could be avoided due to primary treatment adaptation.

Serial intense chemotherapy combining topotecan, etoposide, carboplatin and cyclophosphamide (TECC) followed by autologous hematopoietic stem cell support in patients with high risk soft tissue sarcoma (STS).

In nine patients (pts) with soft tissue sarcoma refractory to conventional therapy (incomplete response or relapse) intensified chemotherapy was administered combining 0.75 mg/m (2) topotecan, 100 mg/m (2) etoposide, 100 mg/m (2) carboplatin and 200 mg/m (2) cyclophosphamide on day 1-5 (TECC). To avoid prolonged intervals between the serial TECC courses autologous hematopoietic stem cell supports (median 1.0 x 10(6) CD34+ cells per kg body weight (bw), range 0.5-2.8 x 10(6) CD34+ cells/kg bw, SD 0.6 x 10(6) CD34+ cells/kg bw) were given on day 7. All pts received granulocyte colony stimulating factor (GCSF) from day 8 in addition. All together 39 TECC courses (minimum 2 courses, maximum 6 courses per pt) were administered, with a median interval of 32 (range 21-52) days until recovery. Leukopenia (<1000/microl) occurred 9 days (range 3-13 days; SD 2.4 days) after end of chemotherapy and persisted for 9 (range 3-15 days; SD 3 days) days. In 31/39 TECC courses readmission to hospital was required for supportive therapy mainly due to neutropenic fever. In this period pts received 0.83 (range 0-1) red blood cell units and 2.35 (range 1-4) platelet units. C-reactive protein in neutropenic pts as an indicator for infection after TECC chemotherapy was detectable after 36 of 39 chemotherapy courses leading to further supportive therapy (median 10.4 mg/dl, range 1.1-28.3 mg/dl; SD 6.67 mg/dl). Duration of total inpatient treatment per TECC course including supportive therapy was in median 13.5 days (range 7-53 days; SD 4.3 days). Only two children had a prolonged infection (77 and 100 days). Clinical and objective tumor responses, defined as complete remission, very good partial response and partial response were observed in 9/9 pts at eight weeks after the last TECC course and were maintained at six months in 7/9 pts. Median time to progression and median overall survival time after TECC chemotherapy were 20.3 months and 25.2 months, respectively. These data provide evidence that in very high risk pts refractory to standard high risk therapy, a combination of TECC chemotherapy and stem cell support is feasible in pts with incomplete remission respectively relapsed STS pts and demonstrates promising antineoplastic activity. Therefore, this regimen warrants further investigation in prospective trials.

Trends in infections in children with malignant disease in 2000: comparison of data of 1980/81.

Children with cancer have an overall chance of survival of 70-80%. Despite significant advances in supportive care during the last years, infections remain a major cause of therapy-associated morbidity and death. Between January and December 2000, oncology patients (ONC) treated on a pediatric oncology ward after chemotherapy (n = 109), loco-regional thermochemotherapy (n = 13), or hematopoietic stem cell (HSCT) transplantation (n = 35) suffered a total of 249 febrile infectious complications (HSCT 40/ONC 209). These episodes were analyzed retrospectively and compared with 125 ONC patients with 133 febrile infections in 1980/81. The relative incidence of fever of unknown origin (FUO) decreased from 1980/81 to 2000 (p <.001). The frequency of bloodstream infections (BSI) in febrile episodes was comparable in both periods with 37% (50/135) in 1980 and 29% (72/249) in 2000. In both periods, gram-positive bacteria were the most frequent organisms, whereas gram-negative organisms were detected in approximately 20% of BSI. In 1980/81 microbiologically (MDI) or clinically documented infections (CDI) were not detected, whereas in 2000 27% of all infectious were MDI/CDI. During the last 20 years, improved diagnostic tools have resulted in an increased detection rate of infectious agents causing febrile episodes in pediatric cancer patients. The comparison of the two observation periods did not reveal a change in the microbiologic spectrum. Despite the fact that in 2000 more patients were treated with intensified chemotherapy because of relapse, infection-related mortality was unchanged compared to 1980/81. This observation may indicate a sufficient preemptive antibacterial therapy followed by better diagnostic tools and goal-oriented treatment.

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.

Combined trimethoprim and caspofungin treatment for severe Pneumocystis jiroveci pneumonia in a five year old boy with acute lymphoblastic leukemia.

Caspofungin was used for the first time with trimethoprim/sulfamethoxazole (TMP/SMX) for treatment of high risk Pneumocystis jiroveci pneumonia (PCP) in a pediatric immunocompromised patient. Despite the need for mechanical ventilation, the pediatric patient with relapsed acute lymphoblastic leukemia improved within nine days of treatment and showed no major side effects. The apparent relative lack of toxicity and of pharmacokinetic drug interactions makes caspofungin an attractive agent.

Serum cystatin C is a suitable marker for routine monitoring of renal function in pediatric cancer patients, especially of very young age.

BACKGROUND: Monitoring renal function is crucial in children undergoing chemotherapy. To date, a combination of routine serum creatinine (SCR) monitoring with occasional determination of creatinine clearance ratio (CCR) is widely used as clinical standard for this purpose. Both methods have their limitations regarding diagnostic value (SCR) or practicability (CCR), especially in young children. Diagnostic alternatives, such as glomerular filtration rate (GFR) estimation formulas have not been proved to be superior. The aim of the study was to evaluate whether serum cystatin C (CysC) may have a diagnostic impact on pediatric patients. PROCEDURE: CysC, SCR, several GFR estimation formulas (Counahan-Barratt, Ghazali-Barratt, Schwartz, Shull, Traub), and CCR were studied in 80 pediatric cancer patients (age range: 0.17-17.9 years) during their chemotherapy. Special attention was given to children under the age of 3 in whom accurate urine collection for CCR is difficult. RESULTS: All parameters correlated similarly well with CCR. Total accuracy was 66% and 67% for CysC and SCR, respectively. In very young children (<3 years), correlation with CCR was for CysC r = -0.74 with an area under the curve (AUC) of 0.646, and for SCR r = -0.27 with AUC = 0.594. Total accuracy was 60% for CysC, 50% for SCR. CONCLUSIONS: CysC represents a suitable marker for monitoring renal function in pediatric cancer patients. In young children (<3 years), CysC may have a better diagnostic value than SCR. Future studies should show if CysC can improve renal monitoring by replacing SCR, especially in very young children.

Asparagine concentration in plasma after 2,500 IU/m(2) PEG-asparaginase i.v. in children with acute lymphoblastic leukemia.

UNLABELLED: Polyethylene glycol conjugated asparaginase (PEG-ASNase) can be substituted in cases of hypersensitivity to native Escherichia coli asparaginase. We measured asparagine (asn) levels in plasma after a single dose of 2,500 IU/m(2) i.v. PEG-ASNase (Oncaspar) in consolidation treatment of ALL and compared those with data from the previous protocol COALL-05-92. This protocol was similar to COALL-06-97, except that children had been given 45,000 IU/m(2) C-ASNase instead of PEG-ASNase. PATIENTS AND METHODS: Between May 2000 and December 2001 seventy-one children (38 boys, 33 girls) with newly diagnosed ALL treated according to the multicenter protocol COALL-06-97 were investigated in this study. Four hundred and seventy-four plasma samples (71 patients) were analysed by ion exchange chromatography after column derivatization with o-phthaldialdehyde. For comparison data (350 plasma samples) from 51 patients treated according to the protocol COALL-05-92 were available. The same method for detection of asn in plasma was used. RESULTS: The median asparagine level in plasma after 2,500 IU/m(2) PEG-ASNase i.v. was below the limit of detection for at least 5 weeks in 81 % of the patients. When divided into high risk (HR) and low risk (LR) group, HR patients who had previously received one dose more of C-ASNase showed a markedly shorter depletion than the LR patients compatible with a higher risk of antibody formation and consequent silent inactivation after a higher number of exposures to ASNase. In the previous protocol COALL-05-92 median asn levels in plasma after 45,000 IU/m(2) native C-ASNase i.v. were below the limit of detection for at least 5 weeks in 65 % of the patients. CONCLUSIONS: 2,500 IU/m(2) PEG-ASNase led to an equally long depletion of asn in plasma as did 45,000 IU/m(2) native C-ASNase i.v. used in COALL-05-92.

Severe hyperhomocysteinaemia and 5-oxoprolinuria secondary to antiproliferative and antimicrobial drug treatment.

A hitherto healthy 7-year-old girl underwent antiproliferative and antibiotic treatment owing to the diagnosis of T-cell lymphoma and concomitant bacterial infection. She developed an encephalopathic crisis associated with metabolic acidosis, hyponatraemia and severe hyperhomocysteinaemia and 5-oxoprolinuria. Laboratory tests normalized completely after recovery. Primary defects in glutathione metabolism could be excluded.

Oncological management of pediatric cancer patients belonging to Jehovah's Witnesses: a two-institutional experience report.

OBJECTIVES: Aim of this study was to analyze the feasibility of oncological treatment in pediatric patients belonging to Jehovah's Witnesses and to describe the changing policy in performing transfusions and supportive care measures at two German pediatric cancer institutions. PATIENTS AND METHODS: Over a period of 16 years 21 treatments according to the current cooperative protocols were performed in 14 children of Jehovah's Witnesses. Various hematological supportive care measures such as supplementation with iron, human erythropoietin, interleukin 11, granulocyte colony-stimulating factor and autologous or allogeneic stem cell rescue had been applied. For comparison matched pairs treated in our hospitals not belonging to Jehovah's Witnesses and 50 pediatric and adult oncological patients belonging to Jehovah's Witnesses reviewed from the international literature were analyzed with respect to transfusions and outcome. RESULTS: So far, 9 of 14 children are surviving 16-195 months (median 26 months). During the primary therapy they received markedly less transfusions than the control cohort (-39,1% red blood cell transfusions and -37,5% platelet transfusions). The review of 50 reported cases showed that oncological therapy can also be successfully performed with a restricted transfusion regimen in children and particularly in adults. CONCLUSION: Pediatric cancer patients belonging to Jehovah's Witnesses can be treated similarly to other patients. A restrictive transfusion policy and the broad application of hematopoietic supportive care measures may reduce transfusions. This treatment policy and a continuous collaboration with the Hospital Liaison Committee for Jehovah's Witnesses appears to create an oncological treatment situation with a high compliance of patients and parents where court orders may not be necessary.

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.

Ovarian sex cord-stromal tumors in children and adolescents.

PURPOSE: To develop diagnostic standards and a risk-adapted therapeutic strategy for ovarian sex cord-stromal tumors (OSCST). PATIENTS AND METHODS: Fifty-four patients were prospectively enrolled as follow-up patients onto the German Maligne Keimzelltumoren protocols. Surgical protocols and histopathology were reviewed centrally (53 patients with complete data). Surgery included ovariectomy in 18 patients, salpingo-ovariectomy in 34 patients, and hysterectomy in one patient. Patients with stage IA tumors were followed-up at regular intervals, whereas nine patients with stage IC and six patients with stage II to III tumors were treated with cisplatin-based chemotherapy. RESULTS: International Federation of Gynecology and Obstetrics stage was IA in 27 patients, IC in 21 patients, II in three patients, and III in three patients. After a median follow-up of 59 months (range, 6 to 193 months), event-free survival +/- SD was 0.86 +/- 0.05 (47 of 54 patients) and overall survival was 0.89 +/- 0.05 (49 of 54 patients). Prognosis correlated with stage (event-free survival +/- SD: IA, 1.0 [27 of 27 patients]; IC, 0.76 +/- 0.09 [16 of 21 patients]; and II/III, 0.67 +/- 0.19 [four of six patients]; P =.02). Ten of 15 patients treated with chemotherapy, including four of six stage II to III patients, are alive after a median follow-up of 33 months. CONCLUSION: On the basis of a standardized clinical and histopathologic assessment, risk-adapted therapeutic strategies for OSCST can be evaluated. Considering our experience, we would recommend that stage IA tumors be followed up at regular intervals, whereas we would recommend cisplatin-based chemotherapy in stage IC tumors with preoperative rupture or malignant ascites, especially those with high mitotic activity. Finally, cisplatin-based chemotherapy also seems to be effective in advanced-stage tumors.

Therapy of advanced ovarian juvenile granulosa cell tumors.

BACKGROUND: Gonadal sex cord-stromal tumors are rare tumors that develop from the gonadal non-germ cell component such as granulosa, Sertoli or Leydig cells. Among these, juvenile granulosa cell tumors (JGCT) constitute the largest subgroup of ovarian sex cord-stromal tumors during childhood and adolescence. In local disease (FIGO stage I), the beneficial role of tumor-ovarectomy is well established. In contrast, life expectancy in patients with advanced JGCT (FIGO stage >/= II) is short even after complete tumor resection. The current literature provides only limited and inconclusive data regarding the value of adjuvant chemotherapy in such patients with advanced disease. PATIENTS AND METHODS: Therefore, we analyzed the patients with FIGO stage >/= II JGCT who were prospectively documented as follow-up patients of the German MAKEI trials for non-testicular germ cell tumors and received the recommended cisplatin-based chemotherapy in an adjuvant setting. From 1988 until 2000, 7 patients (age, 4;2 - 18;11 years, median 14;8 years) were registered. Three patients were stage IIc, one stage IIIa, and three stage IIIc. 5 patients underwent laparatomy with adnectomy, which was complete in only two patients. Two patients received laparoscopic tumor resection, which was incomplete in both. All patients received 4 or 6 cycles of adjuvant cisplatin-based three-agent chemotherapy in analogy to the current therapeutic concept applied in malignant germ cell tumors. One patient with a large tumor and multiple peritoneal metastases additionally received 40 Gy abdominal irradiation. RESULTS: All patients achieved complete clinical remission after initial surgery and adjuvant chemotherapy. 4 out of 7 patients are currently remaining in first continuous complete remission after 15 to 111 months follow-up. One patient developed a metachronous tumor of the contralateral ovary after 126 months follow-up and is still alive but currently in therapy of another recurrence. Another patient suffered a tumor recurrence after 12 months but achieved a second complete remission with cisplatin chemotherapy after a follow-up of currently 4 months. One patient achieved complete clinical remission but suffered a diffuse peritoneal tumor recurrence with massive ascites and finally died as a result of tumor progression. In summary, at the time of this report 6 of 7 patients are alive after a median of 47 (15 - 138) months. CONCLUSION: This analysis clearly demonstrates that advanced JGCT can be successfully treated with surgery followed by adjuvant cisplatin-based chemotherapy. Therefore, this study reveals encouraging therapeutic perspectives in these otherwise fatal tumors that merit further investigation in a prospective cooperative trial.

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.

Treatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96.

PURPOSE: To evaluate therapeutic options for recurrent malignant sacrococcygeal germ cell tumors (GCT) following three-agent, cisplatinum-based, first-line chemotherapy and tumor resection. PATIENTS AND METHODS: Twenty-two patients were evaluated in 22 first-, 14 second-, five third-, and two fourth-relapse situations. One patient, who relapsed with pure teratoma, was excluded from the analysis of adjuvant treatment. RESULTS: Seventeen patients presented with an isolated local recurrence, two patients showed a distant relapse, and three patients suffered from a combined local and distant recurrence. Twelve patients achieved complete remission (CR) after surgery (n = 12) and adjuvant platinum chemotherapy (n = 10). Seven of these patients remain in continuous CR, and five patients relapsed. All patients who achieved only a partial remission developed a second relapse. Three of 14 patients could be cured after a second (or further) relapse. Altogether, 10 patients survived disease free, and 12 patients died as a result of tumor progression (n = 11) or therapy-related complications (n = 1). The completeness of salvage surgery and clinical remission status after first salvage treatment were the most important prognostic parameters. In addition, patients in first or second relapse with locally advanced or poorly responding tumors benefited from preoperative chemotherapy in combination with regional hyperthermia (RHT). In some patients after microscopically incomplete resection, irradiation at doses > 45 Gy contributed to a favorable outcome. CONCLUSION: The complete resection of the local recurrence represents the cornerstone of salvage treatment. Preoperative platinum-based chemotherapy, combined with RHT in some patients, facilitates complete tumor resection. Radiotherapy should be reserved for those patients with microscopically incomplete tumor resection. As the chance of cure decreases with further relapses, it is important to establish a stringent therapeutic strategy to avoid significant treatment delays and, most importantly, insufficient local therapy.

Estimated number of children with cancer eligible for hyperthermia based on population- and treatment-related criteria.

Patients with recurrent, progressed or otherwise, therapy resistant malignancies, whose diseases are not amenable to standard therapies, may benefit from hyperthermia (HT). Based on the number of 1600 newly diagnosed malignancies, in patients < 15 years of age, per annum of which 70% are successfully treated on the standard treatment protocols of the German Society of Pediatric Oncology and Hematology (GPOH) and allowing for various drop-outs for reasons such as lack of established protocols, insufficient state of health and others, this means that as many as 100 children per annum can be expected to be enrolled into phase I/II trials in Germany. In view of the promising results in adults, phase I/II HT studies have also been performed in children and adolescents with recurrent or advanced malignancies including Ewing's tumours, aggressive fibromatosis, and germ cell tumours. Recent results in paediatric studies indicate the feasibility of both regional deep HT and whole body HT, and the best case analysis reveals promising response rates (CR + PR) as well as some long-term remissions. Technical modifications, due to the smaller body diameters, led to mean intratumoural temperatures in paediatric patients similar to those reported for adults in whom an improved outcome was demonstrated. The results in children and adolescents even suggest that introduction of HT into standard treatment protocols may be promising to improve tumour response and event-free survival in patients with poor risk malignancies of childhood.

Acute myelogenous leukemia after treatment for malignant germ cell tumors in children.

PURPOSE: To identify the long-term sequelae of therapy for malignant germ cell tumors (GCTs). PATIENTS AND METHODS: Between 1980 and 1998, 1,132 patients were prospectively enrolled onto the German nontesticular GCT studies. A total of 442 patients received chemotherapy using combinations of the drugs cisplatin, ifosfamide, etoposide, vinblastine, and bleomycin, and 174 patients were treated with a combination of chemotherapy and radiotherapy. Median follow-up duration was 38 months (range, 6 to 199 months). RESULTS: Six patients developed therapy-related acute myelogenous leukemia (t-AML). There was no t-AML among patients treated with surgery (n = 392) or radiotherapy only (n = 124). The Kaplan-Meier estimates of the cumulative incidence (at 10 years) of t-AML were 1.0% for patients treated with chemotherapy (three of 442) and 4.2% for patients treated with combined chemotherapy and radiotherapy (three of 174). Notably, four of these six patients had been treated according to a standard protocol with modest cumulative chemotherapy doses. Five patients had received less than 2 g/m(2) epipodophyllotoxins, and four patients had received less than 20 g/m(2) ifosfamide. Four patients presented with AML, two with myelodysplasia in transformation to AML. In five patients, cytogenetic aberrations were found, four of which were considered characteristic for t-AML. Four patients died despite antileukemic therapy. One patient is alive but suffered a relapse of his GCT, and one patient is alive and well. No secondary solid neoplasm was observed. CONCLUSION: In patients with AML after treatment for GCT, several pathogenetic mechanisms must be considered. AML might evolve from a malignant transformation of GCT components without any influence of the chemotherapy. On the other hand, the use of alkylators and topoisomerase II inhibitors is associated with an increased risk of t-AML. Future studies will show if the reduction of treatment intensity in the current protocol reduces the risk of secondary leukemia in these patients.