[Adherence to Long-term Follow-up in Paediatric Oncology--Results of a Monocentric Analysis]. / Nachsorgeadhärenz in der Pädiatrischen Onkologie - Ergebnisse einer monozentrischen Analyse.

BACKGROUND: Cured paediatric-oncology patients frequently present with health problems even years after treatment. Hence long-term follow-up (LTFU) is essential. This analysis tries to identify factors that influence regular LTFU attendance. STUDY POPULATION: Between 1991 and 2010, 2 153 children and adolescents were treated at Muenster University Department of Paediatric Hematology and Oncology (UKM). 1 708 patients with permanent residence in Germany and completed therapy have been included into this analysis. METHODS: Patients were reviewed for the duration and regularity of LTFU at UKM. Prospective analyses with postponed starting-points have been conducted as well as descriptive analyses to validate correlations. Prospective data were evaluated by Kaplan-Meier-Analyses, the analysis of multivariate correlations by Cox Proportional Hazard Model. RESULTS: 2 years after the end of therapy 83% of the patients were still in LTFU. After 5 and 10 years this percentage decreased to 67 and 42%. Patients diagnosed after the year 2000 and younger patients attended LTFU for a longer period (p<0,005). There were no significant gender differences. Statutory insured patients stayed longer in LTFU than private health insured (p<0,005). The multivariate examination showed only small differences between systemic diseases and solid tumours. The residential distance had no significant influence. CONCLUSIONS: Younger, more recently treated and statutory insured patients showed a significantly longer LTFU.

Frequent but borderline methylation of p16 (INK4a) and TIMP3 in medulloblastoma and sPNET revealed by quantitative analyses.

Certain risk groups among tumors of the central nervous system (CNS) in children take an almost inevitably fatal course. The elucidation of molecular mechanisms offers hope for improved therapy. Aberrant methylation is common in malignant brain tumors of childhood and may have implications for stratification and therapy. Methylation of p16 (INK4A), p14 (ARF), TIMP3, CDH1, p15 (INK4B )and DAPK1 in medulloblastoma (MB) and ependymoma has been discussed controversially in the literature. DUTT1 and SOCS1 have not previously been analyzed. We examined methylation in MB, sPNET and ependymoma using methylation-specific PCR (MSP), quantitative Combined Bisulfite Restriction Analysis (COBRA) and direct and clone sequencing of bisulfite PCR products. We detected methylation of p16 (INK4A) (17/43), p14 (ARF) (11/42) and TIMP3 (9/44) in MB and others by MSP. CDH1 was not only methylated in MB (31/41), but also in normal controls. Evaluation of MSP results by quantitative COBRA and sequencing yielded methylation between the detection limits of COBRA (1%) and MSP (0.1%). Only p16 (INK4A )and TIMP3 were methylated consistently in medulloblastomas (p16 (INK4A ) 14%, TIMP3 11%) and p16 (INK4A) also in anaplastic ependymomas (1/4 tumors). Methylation ranged from 1-5%. Evaluation of methylation using MSP has thus to be supplemented by quantitative methods. Our analyses raise the issue of the functional significance of low level methylation, which may disturb the delicate growth factor equilibrium within the cell. Therapeutic and diagnostic implications urge into depth analyses of methylation as a mechanism, which might fill some of the gaps of our understanding of brain tumor origin.

[Positron emission tomography (PET) in oncology: a part of medical therapeutic expertise]. / Positronen-Emissions-Tomografie in der Onkologie -- Bestandteil der ärztlichen Behandlungskunst.

Early inclusion of positron emission tomography (PET) in the stepwise oncological diagnosis improves tumor staging and can make further costly diagnostic and inadequate therapeutic measures superfluous. The advantage of this method, in answering the many questions that arise, has been supported by an extensive literature and analysis of interdisciplinary data. Its use is therefore demanded by doctors working in oncology. Surgeons and radiotherapists demand PET studies before local treatment is started so that patients with advanced-stage cancer are spared invasive local therapeutic measures. Oncologists take advantage of PET"s potential to administer stage-related chemotherapy and provide evidence of its efficacy. Expensive treatment regimens can be immediately tested for their efficacy and, if ineffective, can be replaced by a more suitable combination of chemotherapeutic agents. For this purpose combined PET and CT can be considered the (future) standard for oncological diagnosis. Manufacturers have already positioned themselves to provide PET only as part of combined PET/CT equipment. If these advances are not used, patients are deprived of optimal treatment. Furthermore, PET provides considerable potential for cost savings by avoiding expensive measures that do not prolong life. Responsible use of these resources within the health service system requires the early use of PET in the staging of diagnostic methods so that therapeutic options can be weighed through interdisciplinary consultation. The patient can thus be given optimal information and included in therapeutic decisions. It is our obligation as doctors to demand from the decision makers that PET equipment be provided for use in accordance with correct indications and to reimburse the costs as is already the case in other parts of Europe.

Effect of pH on the stability of plant phenolic compounds.

It is not uncommon to treat plant-derived foods and feeds with alkali. Such exposure to high pH is being used to recover proteins from cereals and legumes, to induce the formation of fiber-forming meat analogue vegetable protein, for preparing peeled fruits and vegetables, and for destroying microorganisms. In addition to their profound effects on functional and nutritional properties in such foods, such treatments may also cause other side reactions, including the destruction of natural polyphenolic compounds. Because plants contain a large number of structurally different antioxidant, anticarcinogenic, and antimicrobial polyphenolic compounds, it is of interest to know whether such compounds are stable to heat and to high pH. In this model study, the stability of the following natural polyphenols to pH in the range 3-11 was studied with the aid of ultraviolet spectroscopy: caffeic acid, (-)-catechin, chlorogenic acid, ferulic acid, gallic acid, (-)-epigallocatechin, rutin, and the nonphenolic compound trans-cinnamic acid. This study demonstrates that caffeic, chlorogenic, and gallic acids are not stable to high pH and that the pH- and time-dependent spectral transformations are not reversible. By contrast, chlorogenic acid is stable to acid pH, to heat, and to storage when added to apple juice. (-)-Catechin, (-)-epigallocatechin, ferulic acid, rutin, and trans-cinnamic acid resisted major pH-induced degradation. The results are rationalized in terms of relative resonance stabilization of phenoxide ions and quinone oxidation intermediates. The possible significance of these findings to food chemistry and microbiology is discussed.

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.

Treatment of children with relapsed soft tissue sarcoma: report of the German CESS/CWS REZ 91 trial.

BACKGROUND: The present study was performed to evaluate the possibilities of relapse treatment in patients heavily pretreated for a soft tissue sarcoma. PATIENTS AND METHODS: Prospective, multicenter study in 44 soft tissue sarcoma (STS) patients with first relapse. Primary diagnosis was embryonal rhabdomyosarcoma (RME) in 17 patients, alveolar rhabdomyosarcoma (RMA) in 13, primitive neuroectodermal tumor (PNET) in 6, and miscellaneous soft tissue sarcomas in 8 patients. Initial chemotherapy consisted of carboplatin/etoposide combination (150 mg/m2 each, days 1 to 4) followed by local therapy including surgical treatment and, whenever possible, radiotherapy. RESULTS: In 11/17 patients without primary tumor resection, CR or PR was achieved following the initial two cycles of chemotherapy (61%). The probability of event-free survival (pEFS) for RME patients was 0.41 +/- 0.12 at 5 years, and 0.25 +/- 0.12 for RMA patients. But, in contrast no PNET patient or patient with another soft-tissue sarcoma achieved long-term remission. Additional local radiotherapy significantly (P = 0.002) improved pEFS (3-year estimates of 0.23 +/- 0.2 vs. 0.1 +/- 0.1 in patients without radiotherapy). CONCLUSIONS: In patients with RME, relapse treatment employing a carboplatin/etoposide combination may induce a second remission in approximately 40% of patients. Surgical excision and additional local radiotherapy seem to be essential to maintain a stable remission. In patients with RMA or PNET, however, this treatment strategy is of no long-term benefit.

Hyperthermic isolated limb perfusion with cis-diamminedichloro-platinum. II. An experimental study in dogs with a balloon-occlusion technique for repeated high-dose treatment.

Isolated organ perfusion is attractive for regional high-dose chemotherapy because of its advantage to reduce whole body toxicity. Intraoperative hyperthermic isolated perfusion procedures involving a heart-lung machine have been developed, but repeated treatments carry a high risk of vessel and tissue damage. Therefore, a study of isolated hyperthermic limb perfusion in four dogs was conducted using a balloon-occlusion technique including a hyperthermia unit, two low-flow rotary pumps, a bubble oxygenator, and two polyurethane balloon catheters. After 15 min infusion of cisplatinum the concentrations of serum platinum (Pt) in the isolated limb and in the whole body were measured by atomic absorption spectroscopy. Regional exposure to Pt was more than 10-fold higher than systemic exposure. After 60 min isolated limb perfusion, the area under the curve (AUC) of Pt concentrations in the isolated limb showed values between 767.4 and 1055.6 micrograms/l x 60 min, whereas in the whole body values between 59.8 and 75.9 micrograms/l x 60 min were obtained. Repeated isolated limb perfusions with the balloon-occlusion technique were performed in three dogs without systemic side effects. This model of regional chemotherapy may be useful for preoperative chemotherapy in malignant tumors of the limbs.

Total body hyperthermia in combination with etoposide and melphalan in a child with acute myelomonocytic leukemia.

In vitro and clinical studies have shown antineoplastic effects of hyperthermia alone and in combination with other treatment modalities. Synergistic cytotoxic effects of chemotherapy and hyperthermia have been demonstrated on leukemic cell clones in vitro. It seems that hyperthermia is effective in overcoming chemotherapy resistance. Several groups treated solid tumors by using total body hyperthermia (TBHT). However, only a few studies have been reported investigating the clinical effects of TBHT in myeloproliferative disorders. We report the case of a 7-year-old boy with myelomonocytic leukemia treated with TBHT (2 hours, 42 degrees C) combined with etoposide (600 mg/m2), melphalan (30 mg/m2) and hyperglycemia (200-300 mg/dl). Within 24 hours after TBHT, the leukemic cells decreased after TBHT from 53,000/microliters to zero. Skin leukemic infiltrates, resistant to conventional treatment, also responded well. Although our patient relapsed 34 days after TBHT, these results indicate that TBHT in combination with cytotoxic treatment may be a useful treatment modality in refractory leukemia.

[Regional hyperthermia with systemic chemotherapy in children and adolescents: feasibility and clinical follow-up of 34 intensively pretreated patients with prognostically unfavorable tumor diseases]. / Regionale Hyperthermie mit systemischer Chemotherapie bei Kindern und Jugendlichen: Durchführbarkeit und klinische Verläufe bei 34 intensiv vorbehandelten Patienten mit prognostisch ungünstigen Tumorerkrankungen.

Temperature elevation for a few degrees (degrees C) increases significantly the cytotoxicity of several antineoplastic drugs under experimental conditions. An isolated elevation of the tumour temperature, which is possible since a few years, might be able to improve local tumour control without increasing the systemic toxicity. This study was performed to examine the feasibility of regional hyperthermia with systemic chemotherapy in pediatric patients. The special interests were the level of temperatures that could be achieved as well as the degree of toxicity and undesired side effects. Furthermore there was some hope to attain local tumour control in cases with very poor prognosis. 34 patients up to 18 years were treated in Munich and Essen until the end of 1992. 21 suffered of local relapse, in 11 cases it was the 2nd up to the 7th relapse. In another 11 cases the indication for the combined treatment was tumour progress or non-response to previous therapy. 33 patients were pretreated by aggressive chemotherapy, 20 patients had received radiotherapy before. In 28 cases the tumour was located in the pelvis. The heating device that we use is commercially available. It is based on external electromagnetic radiation which induces heat by absorption within the tissue. Since the temperature distribution inside the tumours is very heterogeneous thermometry is necessary which can only be performed invasively. For this sake we use closed tip catheters which are inserted into the tumour by puncture or surgically. The catheters remain in place for the whole treatment duration of several weeks. Chemotherapy was performed in treatment cycles (3.4/patient) mainly using etoposide, ifosfamide, and carboplatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaphylaxis to L-asparaginase during treatment for acute lymphoblastic leukemia in children--evidence of a complement-mediated mechanism.

L-Asparaginase (l-Asp) is widely used as an effective drug against childhood and adult acute lymphoblastic leukemia (ALL). However, it is immunogenic in humans and may lead to hypersensitivity reactions. The immunological basis of these reactions is not clear. Since the presence of l-Asp specific IgG-antibodies seems to correlate better with clinical reactions than IgE-antibodies and IgG-antibodies are known to be able to fix and activate the complement system, we speculated that the mechanism of anaphylaxis may be complement- rather than IgE-mediated. We analyzed 24 children with ALL (age 2-15 yr) for changes in the complement system during l-Asp infusions. Chemotherapy was administered according to the CoALL 82 protocol which is derived from the CoALL 80 protocol recently published. The formation of specific antibodies of IgM and IgG classes against l-Asp was monitored by a solid phase ELISA. The immunological responsiveness of individual patients varied over a wide range but both types of antibodies were induced. Anaphylactic reactions were observed on eight occasions in eight children. The infusions in the remaining 16 patients were tolerated without clinical reactions. Significant activation of complement was demonstrated in seven of eight reaction occasions and in none of the occasions without reactions. The most important complement activation parameter monitored was the C3 split product C3d measured in EDTA-plasma. We conclude that anaphylaxis to l-Asp in patients with ALL can be explained in most instances on the basis of complement activation induced by the formation of immune complexes of l-Asp and specific antibodies of IgM and IgG classes.

Toxicity associated with combination chemotherapy for osteosarcoma: a report of the cooperative osteosarcoma study (COSS 80).

The treatment-associated toxicity in 189 patients entered in the COSS-80 Study was analyzed. The sequential use of high-dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) and cis-platinum may be additive or synergistic in causing renal toxicity. However, evaluation of the 48-h serum methotrexate level and the incidence of elevated serum creatinine levels throughout treatment failed to indicate prolonged methotrexate elimination or severe kidney damage from this regimen where an interval of 3 weeks between cis-platinum administration and the next course of HDMTX was mandatory. The treatment-related mortality was 3.2% (6 out of 189 patients). Three patients died of septicemia during chemotherapy-induced bone-marrow depression following treatment with adriamycin or the combination of bleomycin, cyclophosphamide, and dactinomycin (BCD). Three deaths occurred following the use of high-dose methotrexate with citrovorum factor rescue. Two of these deaths were associated with delayed excretion of methotrexate. The toxicity is within the range reported in the literature.

Essential laboratory determinations for monitoring high-dose methotrexate treatment with citrovorum factor rescue.

The use of high-dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) has considerably improved the prognosis of some pediatric malignancies. Massive doses of methotrexate (mtx) may lead to severe or even lethal toxicity. Safe administration of this regimen requires a wide pattern of laboratory tests as well as clinical supervision. One hundred and eighteen courses of HDMTX (12 gm/m2 over 6 hours iv) with CFR administered to 12 patients were analysed for changes of routine laboratory tests 0, 6, 24, 48, and 72 hours following infusion. Hgb, WBC, and platelets on average showed no change during the 72 hours follow-up period. Serum SGOT and SGPT were elevated with a maximum 24 hours following infusion and slowly returned to normal. The increase of serum LDH values were less marked and reached a maximum at 48 hours; changes of serum y-GT values were not significant. Evaluation of the elimination of mtx from serum in each individual patient throughout 14 sequential mtx courses gave no evidence of a prolonged serum half life due to impaired renal mtx clearance. There was also no evidence of enzyme induction in the liver resulting in a shortened serum half-life. Changes of serum enzymes also were not increasing throughout treatment. Careful monitoring of serum mtx levels is mandatory when HDMTX with CFR treatment is administered. Elevation of blood urea nitrogen and creatinine levels within 24 hours following mtx treatment identify the patient at risk for slow mtx elimination and severe toxicity requiring salvage by adequate doses of citrovorum factor.