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Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families.

Female patients with childhood, adolescent, and young adult cancer are at increased risk for fertility impairment when treatment adversely affects the function of reproductive organs. Patients and their families desire biological children but substantial variations in clinical practice guidelines reduce consistent and timely implementation of effective interventions for fertility preservation across institutions. As part of the PanCareLIFE Consortium, and in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in female patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. This clinical practice guideline leverages existing evidence and international expertise to develop transparent recommendations that are easy to use to facilitate the care of female patients with childhood, adolescent, and young adult cancer who are at high risk for fertility impairment. A complete review of the existing evidence, including a quality assessment, transparent reporting of the guideline panel's decisions, and achievement of global interdisciplinary consensus, is an important result of this intensive collaboration.

Purpose: The number of persons who have successfully completed treatment for a cancer diagnosed during childhood and who have entered adulthood is increasing over time, and former patients will become aging citizens. Methods: Ten years ago, an expert panel met in Erice, Italy, to produce a set of principles concerning the cure and care of survivors of childhood and adolescent cancer. The result was the Erice Statement (Haupt et al. Eur J Cancer 43(12):1778–80, 2007) that was translated into nine languages. Ten years on, it was timely to review, and possibly revise, the Erice Statement in view of the changes in paediatric oncology and the number and results of international follow-up studies conducted during the intervening years. Results: The long-term goal of the cure and care of a child with cancer is that he/she becomes a resilient and autonomous adult with optimal health-related quality of life, accepted in society at the same level as his/her age peers. “Cure” refers to cure from the original cancer, regardless of any potential for, or presence of, remaining disabilities or side effects of treatment. The care of a child with cancer should include complete and honest information for parents and the child. Conclusions and implication for cancer survivors: Some members of the previous expert panel, as well as new invited experts, met again in Erice to review the Erice Statement, producing a revised version including update and integration of each of the ten points. In addition, a declaration has been prepared, by the Childhood Cancer International Survivors Network in Dublin on October 2016 (see Annex 1).

Introduction: Irradiation of brain tumors (BT) in children can lead to the loss of pituitary function, predominantly manifesting as deficiencies in GH and ACTH. Objective: To assess the incidence and nature of pituitary deficiency in relation to initial tumor location in children after radiotherapy of BT. Methods: Twenty survivors (16 males and 4 females) of radiation-treated BT aged 1.4–10.9 (median 3.6) yr at diagnosis were studied, 10 with supratentorial and 10 with infratentorial BT. Radiation doses to the hypothalamus-pituitary (HP) area ranged from 30 to 54 (median 45) Gray. Follow-up was 9.4–16.9 (median 12.2) yr. Basal pituitary hormone levels were measured every 6 months. When growth failure became evident or pituitary deficiency was suspected, provocation tests of the HP axis were performed to assess GH, ACTH, and TSH function. Results: GH deficiency (GHD) developed in 17/20 (85%) children. In 10 patients, it occurred 4 yr after radiotherapy and in 2, 11 and 12 yr after radiotherapy. Six (30%) patients developed secondary hypothyroidism and 4 (20%) developed ACTH deficiency. Precocious puberty occurred in 2 girls. The course of development and the severity of hormone deficiencies were similar for supratentorial and infratentorial tumors. Conclusion: The major hormonal effect of BT irradiation in children is GHD, which may sometimes take more than 10 yr to manifest. We confirm findings by others that ACTH insufficiency occurs less frequently in children than reported for adults. Tumor location has no prognostic significance regarding the loss of HP function.

Summary Objective The role of chemotherapy in thyroid sequelae after cancer treatment has not been studied systematically, especially in sarcoma patients. The aim of this study was to determine the incidence of post-therapeutic thyroid disorders and their contributing factors in a cohort of paediatric sarcoma patients. Design Late effects of sarcoma treatment have been collected prospectively within the Late Effects Surveillance System (LESS) in Germany, Austria and Switzerland since 1998. Patients We studied 340 relapse-free paediatric patients (median age at diagnosis 12·2 [interquartile range (IQR) = 7·3–15·6 years] treated for osteosarcoma, soft tissue sarcoma or Ewing's sarcoma within the COSS-96, CWS-96/CWS-2002P or EICESS-92/EURO-E.W.I.N.G.-99 therapy trials. In addition to polychemotherapy, 127 patients were irradiated (mean cumulative dose 47 ± 9·7 Gy), including 51 patients with irradiation to the head/neck region. Median follow-up was 24·6 (IQR = 11·9–44·9) months. Measurements We reviewed the results of yearly examinations of serum TSH and fT4 levels and thyroid ultrasound examinations. Results The incidence of thyroid disorders was 37% (19/51, 95% CI 24–52%) in patients with head/neck irradiation, and 11% (32/289, 95% CI 8–15%) in patients without irradiation to the head/neck. Thyroid disorders were more frequent in patients treated with idarubicin (P = 0·027) and trofosfamide (P = 0·016). We also found a significant association between raised TSH levels and treatment with trofosfamide (P = 0·008) or idarubicin (P = 0·037) (n = 250). Conclusions The incidence of thyroid disorders in the head/neck-irradiated group was high. Even without head/neck irradiation, we found an increased proportion of patients with thyroid disorders, possibly as a result of chemotherapy.

Durch die Behandlungserfolge der Kinderonkologie hat die Erkennung, Behandlung und Vermeidung von Spatfolgen sowie die Verbesserung der Nachsorge einen besonderen Stellenwert erlangt. Im Rahmen des „late effects surveillance systems“ (LESS) der Gesellschaft fur Padiatrische Onkologie und Hamatologie (GPOH) werden seit 1995 systematisch wesentliche Spatfolgen bei den Patienten der GPOH-Therapieoptimierungsstudien erfasst. Zum heutigen Zeitpunkt werden prospektiv uber 2500 ehemalige Ewing-Sarkom- und Osteo-, und Weichteilsarkompatienten entsprechend den Nachsorgeempfehlungen der GPOH regelmasig nachuntersucht. Die wichtigsten bislang bekannten Spatfolgen sind Kardiotoxizitat v. a. nach einer Anthrazyklintherapie, Oto- und Nephrotoxizitat nach Cisplatin, Tubulopathien nach Ifosfamid und endokrine Storungen mit ihren Auswirkungen auf Wachstum, Schilddruse, Pubertatsentwicklung und Fertilitat. Neue Kenntnisse der strukturierten Nachsorge sind Grundlage einer vertikalen Vernetzung zwischen Arzten in Klinik und Praxis bei der Betreuung ehemals krebskranker Kinder und Jugendlicher.

1/f noise in HgCdTe photodiodes has been attributed to a variety of sources, most of which are associated with some form of excess current. At DRS, we have measured the 1/f noise in vertically integrated (VIP) and high-density vertically integrated photodiodes (HDVIP), over a wide range of compositions and temperature, for strictly well-behaved diffusion current limited operation. It is found that (1) the 1/f noise current is directly dependent on dark current density; (2) material composition and temperature are irrelevant, except in as much as they determine the magnitude of the current density; (3) in high-quality diodes, the 1/f noise is independent of background flux; and (4) surface passivation is relevant. These observations have been compared to the 1/f noise theory of Schiebel, which uses McWhorter’s fluctuation of the surface charge tunneling model to modulate diode diffusion current. Agreement is obtained with Schiebel’s theory for realistic surface trap densities in the 1012/cm2 range, which will obviously be characteristic of the passivation used. The relevance of this work relative to high operating temperature phtodiodes is discussed.

Exponential-gain values well in excess of 1,000 have been obtained in HgCdTe high-density, vertically integrated photodiode (HDVIP) avalanche photodiodes (APDs) with essentially zero excess noise. This phenomenon has been observed at temperatures in the range of 77–260 K for a variety of cutoff wavelengths in the mid-wavelength infrared (MWIR) band, with evidence of similar behavior in other IR bands. A theory for electron avalanche multiplication has been developed using density of states and electron-interaction matrix elements associated with the unique band structure of HgCdTe, with allowances being made for the relevant scattering mechanisms of both electrons and holes at these temperatures. This theory is used to develop an empirical model to fit the experimental data obtained at DRS Infrared Technologies. The functional dependence of gain on applied bias voltage is obtained by the use of one adjustable parameter relating electron energy to applied voltage. A more quantitative physical theory requires the use of Monte Carlo techniques incorporating the preceding scattering rates and ionization probabilities. This has been performed at the University of Texas at Austin, and preliminary data indicate good agreement with DRS models for both avalanche gain and excess noise as a function of applied bias. These data are discussed with a view to applications at a variety of wavelengths.

Fanconi's anaemia (FA) shows great variability in phenotypic symptoms. We report on two FA siblings of German ancestry with the very rare form of the complementation group FA-D. Both presented with a similar phenotype and mild disease severity but with different growth. In the sister, growth velocity was normal, puberty and menarche occurred spontaneously. Her final height was within her parental target height. The younger brother had a reduced growth velocity, height SDS values below -5.5 SDS, a markedly retarded bone age, and delayed puberty. At the age of 12.9 years, growth hormone deficiency (GHD) was diagnosed and treatment with growth hormone was initiated. Our cases emphasize the heterogeneity of symptoms in FA even in siblings with the same genotype. In FA-children with severe growth retardation, GHD must also be considered.

Background: Lymphoma and leukemia are the commonest malignant diseases in patients with chromosomal breakage syndromes and immunodeficiency (Ataxia teleangiectasia (AT) and Nijmegen breakage syndrome (NBS)). With improved management of infections, malignant disease is more frequently diagnosed and has become one of the commonest causes of death in pediatric AT and NBS. Patients and methods: In three consecutive multicenter therapy trials for pediatric non-Hodgkin's lymphoma (NHL) (NHL-BFM), 1569 patients with newly diagnosed NHL have been registered between 1986 and 1997. Nine patients with AT (n = 5) and NBS (n = 4) were identified and analysed. Results: Median age of patients with AT and NBS at diagnosis of NHL was nine years. NHL-entities differed from non-AT/NBS-patients: diffuse large B-cell lymphomas, n = 7 (78%); ALCL, n = 1; lymphoblastic T-cell lymphoma, n = 1. Cervical nodes, paranasal sinuses and epipharynx were the sites most frequently involved. Stages were: I and II in three patients, III in five and IV in one patient. All patients received polychemotherapy according to tumor-entity and stage, none received radiation. Dose reductions according to individual tolerance concerned mainly ethotrexate, alkylating agents and epipodophyllotoxines. One patient died of toxic complications, two patients relapsed and died, one patient suffered from second malignancy. Five of nine patients are in 1. CCR after a median folluow-up of five years. Conclusions: Patients with AT and NBS suffer from rare entities of pediatric NHL. Curative treatment is possible and should be attempted. Intensity of therapy should be adjusted to individual risk factors and tolerance. Alkylating agents, epipodophyllotoxines should be omitted, dose of MTX should be limited to 1 g/m 2 . Further cooperative trials using standardized approaches are required.

The number of subjects that have successfully completed treatment for a cancer diagnosed during childhood and are entering adulthood is increasing over time. Members of the International Berlin-Frankfurt-Munster (I-BFM) Early and Late Toxicity Educational Committee (ELTEC) invited 45 paediatric cancer experts (representing oncologists, psychologists, nurses, epidemiologists, parents, and survivors) from 13 European countries (with five additional experts from North America) to Erice, Sicily (from October 27 to 29, 2006) to discuss the circumstances in which the word 'cure' should be used when speaking about children with cancer, and when and why continuing follow-up and care may be required. The objective of the gathering was to generate from the personal and professional experience of the participants an overview statement of the group's philosophy of cure and care of survivors of childhood cancer. The ten points reflect what the group considers essential in the survivors' cure and care.

Monitoring of therapy-related late effects after acute lymphoblastic leukemia (ALL) therapy in childhood has become an increasingly important area in posttherapeutic patient surveillance. The usefulness of conventional electroencephalographic (EEG) investigations as part of these attempts is controversially discussed. However, EEG recordings have become a popular approach for judgement on the functional integrity of the central nervous system in this subject group. The present report focuses on this problem and discusses the question whether and to what extent conventional EEG recordings were correlated with further measures of central nervous system (CNS) integrity and therapeutic differences. EEGs were recorded in 110 subjects, asymptomatic long-term survivors of ALL in childhood, during a large retrospective multicenter study evaluating CNS late sequelae following antileukemic therapy in Germany and Austria. EEG findings were correlated with demographic data, illness- and treatment-related parameters, as well as with data on the morphological, neurological and psychological status of the participating subjects. At the time of follow-up the EEG was abnormal in 47 cases (42.7%). The most frequent EEG abnormalities observed were disturbances of the background activity (n=45, 95.8%), followed by hypersynchrone activities (n=10, 21.3%) and interhemispheric differences/focal slowings (n=6, 12.8%). With exception of age at diagnosis, none of the observed EEG abnormalities showed a correlation with any of the aforementioned illness- or treatment-related parameters. Eighty percent of the observed EEG abnormalities were found in children younger than 5 years at diagnosis. Children less than 2 years of age as well as those above 5 years at onset of disease showed a significantly reduced prevalence of EEG disturbances compared to subjects between 2 and 5 years at diagnosis. Neither the degree of illness nor therapy-specific differences showed any relationship to EEG outcome. There was no specific EEG finding for a specific morphological substrate, neurological or psychological deficiency and vice versa. Overall, there was no beneficial effect of routine EEG testing in children following therapy for ALL. According to our data, the evaluation of conventional EEG recordings of otherwise asymptomatic ALL long-term survivors is not a very helpful measure for predicting the degree of behavioral deficiencies, neurological disturbances, or morphological CNS abnormalities, which may be present or will develop in this special subject group. Med. Pediatr. Oncol. 29:121–131, 1997. © 1997 Wiley-Liss, Inc.

Periodontitis is a primarily bacterial infection that is common in dentate individuals, while denture stomatitis is a predominantly fungal infection that is common among denture wearers. Both infections may increase a patient's risk for chronic systemic infection dissemination, and may in turn increase the risk of chronic, inflammatory-based systemic diseases. Systemic diseases for which chronic oral infections are believed to confer attributable risk include atherosclerotic and coronary disease, stroke, chronic obstructive pulmonary disease, diabetes, and hypertension. It appears that invasive oral pathogens trigger a systemic inflammatory response via mediators released by the cardiovascular system and liver, putting the patient at increased risk for these diseases. Data comparing gene expression between denture wearers with and without denture stomatitis (and associated Candida albicans infections) has demonstrated unique up- and down-regulation patterns for a number of genes. It appears that down-regulated genes (whose functions are thereby diminished) are associated with reduced epithelial barrier integrity. By contrast, there appears to be an association between up-regulated genes (which have enhanced function) and inflammatory responses that facilitate the ability of C. albicans to bind with and penetrate the oral mucosa. Molecular biological approaches suggest that future therapeutic development could target reducing either the local inflammatory processor, the binding and attachment of C. albicans to the oral mucosa, or both. Ongoing investigations are attempting to incorporate interventions into matrices, to provide a local and sustained presence to therapeutic interventions.

Maternal infections during pregnancy have been demonstrated to often results in preterm labor, preterm rupture of membranes, and spontaneous preterm birth (SPB), which is usually associated with low birth weights (ie,2,500 g). Our research focus has been to determine whether periodontal infections can provide sufficient challenge to affect pregnancy--either via disseminating periodontal organisms or bacterial toxins in the blood, or as a consequence of infection-induced hormonal and cytokine abnormalities. We have completed independent case-control studies in humans to examine the relationship between periodontal status and SPB, all of which suggest that the periodontal status is worse in SPB mothers as compared with normal-term delivery controls (2,500 g). Additional research is needed to confirm and clarify the relationship between periodontal infection and SPB, but current findings suggest that periodontal disease may be as deleterious to the pregnant mother and developing fetus as smoking or alcohol abuse.

The authors report the observation of an incoherent tunnelling phenomenon in Al/ZnS/p-Hg1-xCdxTe metal-insulator-semiconductor (MIS) capacitors in the temperature range 15

Late effects after radiotherapy in childhood and adolescence have mainly been characterized retrospectively with small patient numbers. Therefore the German Group of Pediatric Radiation Oncology (APRO) established the "RegIster for the evaluation of late Side effects after radiation in childhood and adolescence" (RiSK). After a pilot phase starting in 2001 documentation has been performed all over Germany since 2004. This analysis shows the first results of "RiSK".Radiation parameters including detailed organ doses as well as toxicity evaluations were collected prospectively from centers all over Germany in the study center. Standardized documentation forms were used. Documentation is planned for all children who receive radiotherapy in one of the German pediatric therapy trials.Until December 31st 2006, 696 documentations of radiotherapy and 526 acute as well as 836 late follow-up documentation forms have been collected. Altogether, 41 patients with late grade 3 and 16 patients with late grade 4-side effects were identified. Side effects mainly concerned joints with functional impairment (after combined radiotherapy and surgery), the bowel, skin and subcutis as well as blood parameters under continued chemotherapy. Patients with late side effects of a higher grade were mainly treated for Ewing's or soft tissue sarcomas (n=235 patients), representing 33.8% of all patients in this study.Fortunately, up to now only a few late grade 3 or 4 side effects of radiotherapy are shown for almost 700 documented patients. For further results, especially for the characterization of dose-effect-relationships, this study has to be continued with a higher patient number and a longer follow-up.

Summary We have reported previously that naive T cells from relapsing-remitting multiple sclerosis (RRMS) patients have T cell receptor (TCR) repertoire shifts, but the basis of these TCR repertoire shifts was uncertain. Here, we questioned whether RRMS patients have altered naive CD4 and CD8 T cell homeostasis by studying homeostatic proliferation and thymic production in RRMS patients and healthy controls. We measured thymic production by quantifying signal joint T cell receptor excision circles (sjTRECs). Both naive T subsets from controls showed an age-associated decrease in sjTRECs, i.e. evidence of progressive thymic involution, but we detected no age-associated decrease in sjTRECs in RRMS patients. Instead, naive CD8 T cells from patients had lower sjTRECs (P = 0·012) and higher Ki-67 proliferation levels (P = 0·04) than controls. Naive CD4 T cell sjTRECs did not differ between patients and controls. However, in RRMS these sjTRECs correlated strongly with CD31, a marker expressed by newly generated CD4 T cells but not by naive CD4 T cells that have undergone homeostatic proliferation. HLA-DR2 positivity correlated negatively with naive CD4 T cell CD31 expression in RRMS (P = 0·002). We conclude in RRMS that naive T subsets have homeostatic abnormalities due probably to peripheral (non-thymic) mechanisms. These abnormalities could have relevance for MS pathogenesis, as naive T cell changes may precede MS onset.

Mit Hilfe einer multimodalen, interdisziplinar durchgefuhrten Behandlung konnen viele krebskranke Kinder und Jugendliche geheilt werden. Inzwischen leben in Deutschland uber 25 000 Geheilte, von denen die Mehrzahl das Erwachsenenalter erreicht haben. Dabei handelt es sich vor allem um ehemalige Leukamie- und Lymphompatienten, seltener um Uberlebende nach einer Hirntumor- oder Sarkombehandlung.

The aim of this study was to analyze cisplatin-induced ototoxicity in a recent study trial. Seventy-four patients who had received cisplatin for the treatment of osteosarcoma (median cumulative dose: 360 mg/m2) were investigated prospectively for ototoxicity in a multicenter trial. Hearing function was tested by audiometry. We evaluated the incidence and dependencies of hearing loss. After cessation of therapy, 51% of the patients showed a hearing loss of >20 dB in the frequency range of 4-8 kHz. Only in one patient a hearing loss was found at 2 kHz, and in none at 1 kHz. At a cumulative cisplatin dose of < or = 240 mg/m2, almost no ototoxicity was found. Incidence and magnitude of hearing loss increased significantly with a higher cumulative dose. Furthermore, hearing thresholds were significantly poorer in children

Visual-evoked potentials (VEPs) were studied in 92 asymptomatic long-term survivors of acute lymphoblastic leukemia (ALL) in first complete remission 6-7 years after cessation of therapy in order to detect therapy-related disturbances in conduction velocity capacities within central nerve fibers. Subjects were grouped with respect to CNS prophylaxis: a) ith. MTX and 18 Gy cranial irradiation (group A, n = 58), b) ith. MTX and iv. MHD-MTX, no cranial irradiation (group B, n = 34). At follow-up VEPs were abnormal in 10 subjects (10.9 %) with comparable rates in both CNS prophylaxis groups (A: 7/58 [12.1 %], B: 3/34 [8.8 %]; p = 0.56). Participants with radiological signs of leukodystrophy (n = 14), all within the irradiated CNS prophylaxis group, showed significantly prolonged P100 latencies and had a 6.1-fold increased relative risk to develop VEP disturbances. No correlation could be established between VEP outcome and illness- or treatment-related parameters. VEP outcome was not correlated with age at diagnosis or gender. Thus, VEP recordings showed a close relationship with radiation-induced CNS white-matter disturbances. However, their value for clinical practice, routinely performed follow-up evaluations or standardized posttreatment surveillance studies is negligible.

Therapy-related acute myeloid leukemia (t-AML) characterized by the t(9;11)(p22;q23) translocation is one of the most frequent secondary malignancies. The timing of the initiation of translocation and of development of the malignant t(9;11) clone during chemotherapy is presently unknown. In the present study, we backtracked bone marrow samples from three children during treatment for acute lymphoblastic leukemia (ALL). Two patients developed a t(9;11)-positive t-AML 19 and 30 months after therapy start, whereas the third patient, diagnosed with a rare t(9;11)-positive ALL, suffered from an ALL relapse 23 months after initial diagnosis. The genomic MLL-MLLT3 (MLL-AF9) fusion site was amplified by a multiplex, nested long-range PCR and used as a clonal marker for quantification of the MLL-MLLT3-positive cells during chemotherapy. The t(9;11)-positive clone was detectable 13 and 18 months after therapy start in both t-AML cases, which was 6-12 months before clinical diagnosis of the secondary malignancy. In the t(9;11)-positive ALL patient, the identical leukemic clone reoccurred during maintenance therapy after a short molecular remission, 8 months before clinically overt ALL relapse. The time course and characteristics of the genomic breakpoints in the present t-AML cases support the hypothesis of translocation formation as a result of defective breakage repair after topoisomerase II cleavage.

Chromosomal translocations are a characteristic feature of leukaemia and other malignant diseases. As clonal markers, they can be applied to identify and quantify the number of malignant cells by polymerase chain reaction (PCR) methods. The translocation t(4;11) is present in60% of infant leukaemia. In order to facilitate the sequencing of chromosomal breakpoints, we developed an optimized set of 30 PCR primers and a new approach, designated as asymmetric multiplex PCR (am-PCR). Due to the high number of primers, small breakpoint-spanning DNA fragments are obtained in one nested multiplex PCR reaction. All PCR products contain an identical binding site for the initiation of direct sequencing. By using am-PCR, the translocation t(4;11) was examined in bone marrow and blood samples from children with acute leukaemia. Compared with previously described methods for the determination of genomic breakpoints, am-PCR may be advantageous with regard to its simplicity and rapidity. Breakpoint-spanning sequences were also evaluated with regard to their applicability as unique clonal markers to design primers and probes for minimal residual disease quantification by real-time PCR. This approach can easily be adapted to other chromosomal translocations in malignant diseases for the detection and analysis of clone-specific DNA markers.

The term periodontal medicine encompasses the study of the contribution of periodontal infections on several systemic conditions such as atherosclerosis, myocardial infarction, stroke, diabetes, and premature delivery. The early reports of a linkage between periodontitis and systemic conditions are gaining further support from additional epidemiological studies. The evidence continues to suggest that maternal periodontitis may bean important risk factor or risk indicator for pregnancies culminating in preterm low birth-weight deliveries. Potential mechanisms by which infectious challenge of periodontal origin and systemic inflammation may serve as a potential modifier of parturition are discussed. Furthermore, preliminary data are presented, supporting a hypothetical model in which periodontal pathogens disseminate systemically within the mother and gain access to the foetal compartment. Several aspects of this hypothetical model remain to be elucidated. Only the clarification of the mechanisms of pathogenesis of both periodontitis and premature deliveries will ultimately allow for accurate diagnoses and successful therapies. The concept of diagnosing and treating a periodontal patient to minimise the deleterious effects of this chronic infectious and inflammatory condition on systemic conditions represents both an unprecedented challenge and opportunity to our profession.

Children with metastatic retinoblastoma are considered to have a poor prognosis after conventional chemotherapy. We used high-dose chemotherapy (HDC) with peripheral hematopoietic stem cell transplantation in such patients in an attempt to improve their survival. Four patients with bone marrow metastases and one child with extraorbital disease were treated with HDC after achieving complete remission by enucleation and conventional chemotherapy. The child with extraorbital tumor was the only one to receive local irradiation. The conditioning regimen included thiotepa (900 mg/m(2)), etoposide (40 mg/kg) and carboplatin (1.5 g/m(2)) in four patients, and BCNU (300 mg/m(2)), cyclophosphamide (6.8 g/m(2)) and etoposide (1.6 g/m(2)) in one child. Hematologic recovery occurred without delay in all patients. The main toxicities were diarrhea, mucositis and infectious complications. No toxic deaths or any major late toxicities were observed. The child treated with the BCNU regimen developed a meningeal relapse 10 months after HDC, which was partially resected and treated with conventional chemotherapy, but not with radiotherapy. He is in complete remission (CR) 105 months off treatment. The other patients are in CCR for 107, 57, 9 and 8 months after HDC. HDC with thiotepa, etoposide and carboplatin may represent a curative option for children with extrabulbar or disseminated retinoblastoma responsive to chemotherapy. It may control occult CNS disease. The necessity to irradiate these children and the curative potential of this strategy for patients with bulky CNS disease remain to be determined.

To study cardiac function and the incidence of anthracycline-induced cardiotoxicity in children following treatment according to the nephroblastoma studies SIOP No.9/GPOH and SIOP 93-01/GPOH.Analysis of clinical status, echocardiography, and ECG findings prior to administration of anthracyclines (median cumulative doxorubicin dose: 250 mg/m(2) [range: 90-411 mg/m(2)] and after a median posttherapeutic interval of 2.9 years [range: 0-10.2 years]. Data on cardiac function before and/or after therapy could be obtained of 186 patients.Posttherapy left ventricular fractional shortening was reduced in 4/157 (2.5%) patients. Out of the 4 children, 2 had clinically reduced tolerance to exercise and received anticongestive therapy. Abnormal ECG findings that were not detectable prior to therapy were found in 7/124 (5.6%) children.The incidence of abnormal findings is low in our study group in comparison to data from the literature and might be due to the comparably short posttherapeutic interval.

In a girl with bilateral Wilms' tumor veno-occlusive disease occurred during chemotherapy. The diagnosis was established by reversed flow in the portal vein displayed by color and pulsed Doppler sonography. After successful conservative treatment normalization of flow in the portal vein could be shown by both Doppler techniques.

The variety of endocrine late-effects after brain tumour therapy in childhood is well known. Growth is usually impaired first due to a hypothalamo-pituitary growth hormone (GH) deficiency or a radiation-induced neurosecretory dysfunction of GH secretion. Generally, all hypothalamo-pituitary axes can be affected. Disturbances of puberty, gonadal function, thyroid function and adrenal function can manifest after a long posttherapeutic interval. A retrospective analysis of the auxological and endocrinological data assessed within the German brain tumour study HIT 91 showed that endocrinological follow-up of these patients was not satisfactory. Therefore we have developed a concept for the new brain tumour study: auxological and laboratory parameters will be assessed before oncological therapy and in regular intervals (4, 12, 18, 24 months after the end of tumour therapy). 24 months after the end of tumour therapy all hypothalamo-pituitary axes are to be evaluated with pharmacological stimulation tests.

The recommendation for first-line therapy for hypertension remains a beta blocker or diuretic given in a low dosage. A target blood pressure of less than 140/90 mm Hg is achieved in about 50 percent of patients treated with monotherapy; two or more agents from different pharmacologic classes are often needed to achieve adequate blood pressure control. Single-dose combination antihypertension therapy is an important option that combines efficacy of blood pressure reduction and a low side effect profile with convenient once-daily dosing to enhance compliance. Combination antihypertensives include combined agents from the following pharmacologic classes: diuretics and potassium-sparing diuretics, beta blockers and diuretics, angiotensin-converting enzyme (ACE) inhibitors and diuretics, angiotensin-II antagonists and diuretics, and calcium channel blockers and ACE inhibitors.

Lymphoma and leukemia are the commonest malignant diseases in patients with chromosomal breakage syndromes and immunodeficiency (Ataxia teleangiectasia (AT) and Nijmegen breakage syndrome (NBS)). With improved management of infections, malignant disease is more frequently diagnosed and has become one of the commonest causes of death in pediatric AT and NBS.In three consecutive multicenter therapy trials for pediatric non-Hodgkin's lymphoma (NHL) (NHL-BFM), 1569 patients with newly diagnosed NHL have been registered between 1986 and 1997. Nine patients with AT (n = 5) and NBS (n = 4) were identified and analysed.Median age of patients with AT and NBS at diagnosis of NHL was nine years. NHL-entities differed from non-AT/NBS-patients: diffuse large B-cell lymphomas, n = 7 (78%); ALCL, n = 1; lymphoblastic T-cell lymphoma, n = 1. Cervical nodes, paranasal sinuses and epipharynx were the sites most frequently involved. Stages were: I and II in three patients, III in five and IV in one patient. All patients received polychemotherapy according to tumor-entity and stage, none received radiation. Dose reductions according to individual tolerance concerned mainly ethotrexate, alkylating agents and epipodophyllotoxines. One patient died of toxic complications, two patients relapsed and died, one patient suffered from second malignancy. Five of nine patients are in 1. CCR after a median follow-up of five years.Patients with AT and NBS suffer from rare entities of pediatric NHL. Curative treatment is possible and should be attempted. Intensity of therapy should be adjusted to individual risk factors and tolerance. Alkylating agents, epipodophyllotoxines should be omitted, dose of MTX should be limited to 1 g/m2. Further cooperative trials using standardized approaches are required.

The purpose of this invited review is to describe and discuss methods currently in use to quantify the progression of attachment loss in epidemiological studies of periodontal disease, and to make recommendations for specific analytic methods based upon the particular design of the study and structure of the data. The review concentrates on the definition of incident attachment loss (ALOSS) and its component parts; measurement issues including thresholds and regression to the mean; methods of accounting for longitudinal change, including changes in means, changes in proportions of affected sites, incidence density, the effect of tooth loss and reversals, and repeated events; statistical models of longitudinal change, including the incorporation of the time element, use of linear, logistic or Poisson regression or survival analysis, and statistical tests; site vs person level of analysis, including statistical adjustment for correlated data; the strengths and limitations of ALOSS data. Examples from the Piedmont 65+ Dental Study are used to illustrate specific concepts. We conclude that incidence density is the preferred methodology to use for periodontal studies with more than one period of follow-up and that the use of studies not employing methods for dealing with complex samples, correlated data, and repeated measures does not take advantage of our current understanding of the site- and person-level variables important in periodontal disease and may generate biased results.

Bislang ist die Diagnostik von Knochentumoren eine Domäne der Radiologie. In der vorliegenden Arbeit werden sonographische und farbdopplersonographische Befunde bei 5 Patienten mit bioptisch gesichertem Osteosarkom beschrieben. Bei allen Patienten fand sich ein ausgedehnter Weichteiltumor mit echogenen osteosklerotischen Bezirken und echoarmen Kavernen. Charakteristisch waren außerdem deutliche Kortikalisdefekte im Bereich des Tumors. Beim Übergang von gesundem zu befallenem Knochen fanden sich typische Periostabhebungen. Farbdopplersonographisch gelang der Nachweis einer deutlich vermehrten Durchblutung des Tumors im Vergleich zu gesundem Gewebe. Sonographie und Farbdopplersonographie stellen eine wichtige Ergänzung zur konventionellen Radiologie dar. Mit der Sonographie können Struktur, Ausdehnung und Durchblutung von Osteosarkomen dargestellt werden.

Nonresponders (NR) are patients (pts.) with no or insufficient response to initial treatment, which may be caused by either initial risk factors or poor therapy realization. In study AML-BFM 87, 49 NR of 307 patients (16%) did not achieve remission until the end of intensive chemotherapy and were analysed to assess the specific contribution of prognostic factors, therapy realization and complications of therapy. THERAPY AND METHODS: Therapy started with an 8-day induction therapy followed by a 6-week consolidation and two 5-day intensification blocks with high-dose cytosine-arabinoside and VP-16. Maintenance therapy was given for a total duration of 1.5 years. To evaluate the impact of treatment intensity in NR, we compared the dose compliance (DC = dose given/intended dose), the dose intensity (DI = dose per time given), the treatment results, and toxicity of the individual therapy phases in responders (CR) and NR.In 19 of 49 NR therapy was stopped before starting intensification blocks. Twenty-six NR received at least one block of intensification, and seven patients between three and six intensification blocks. Six children entered maintenance therapy. Twelve patients received a bone marrow transplant (9 allogeneic, 3 autologous). Six (5 after bone marrow transplantation) of 49 NR are still alive for 64 to 108 months. In nearly all patients induction therapy could be applied according to protocol (mean DC: 98%, range 85%-100%), whereas therapy realization was more difficult in the 2nd phase of therapy (mean DC: 92%, range 12%-113%). Deviations from the protocol in the treatment blocks (changes of dose and/or schedule) were mainly attributable to persistence of blasts (n = 33) and septic complications (n = 24). The mean relative DI of 1.01 was according to protocol. Bleeding and infectious complications in the individual therapy phases varied from 7% to 61%. NR compared to CR patients suffered significantly more often from bleeding during the first and second part of consolidation and from infections during the second part of consolidation. Withdrawal from protocol in NR was mainly due to persistence of blasts (n = 16), followed by bone marrow transplantation or other therapies (n = 13), and sepsis (n = 11).It is difficult to discriminate between nonresponse associated with blast persistence followed by complications and subsequent discontinuation of therapy and nonresponse due to insufficient therapy in patients with complications. Our analyses revealed that therapy with 2 intensifications according to protocol was feasible in 13 NR. Patients' condition permitting, therapy should not be stopped prematurely, in order to sustain the option of BMT after blast cell reduction.

Advances in the therapy of malignant brain tumors in children have led to a significant improvement in survival rates over the last few decades. As a result, the recognition and treatment of late effects have become more important. In addition to secondary tumors and deficiencies in cognitive and intellectual skills, the resulting endocrine disturbances play an important role.Own data and literature review.Deviations from the normal growth hormone secretion are usually recognized first and are most common, and have already been observed after conventional whole brain irradiation with 18 Gy. With some delay, other hypothalamo-pituitary deficiencies may occur, including panhypopituitarism. Puberty may come too early or too late or may not appear at all. Girls in particular, frequently experience an early and rapid pubertal development after brain tumor therapy, which may lead to further reduction in height due to an accelerated bone maturation. Functional disturbances of the thyroid and adrenal glands due to hypothalamic or pituitary deficiency are less common, and usually seen only after a radiation dose of over 40 Gy.Survivors of childhood brain tumors must be considered as long-term survivors, in whom the first therapy-induced long-term side effects appear almost immediately after the end of therapy. Maximum quality of life for the individual patient can only be achieved by long-term care and close cooperation of specialists in the different medical disciplines involved.

Background: Craniospinal radiotherapy for malignant brain tumors can result in a variety of neuroendocrine disturbances, among which are the development of growth hormone deficiency and early puberty, which can markedly reduce adult height. Methods: The authors report the case of a girl who received craniospinal radiotherapy for a medulloblastoma at the age of 3.4 years. At 9.1 years, growth hormone therapy was started, and spontaneous onset of puberty (Tanner stage B2) occurred at age 10.3 years. Interval until menarche was short, at only 0.9 years. Results: Although chronologic age at appearance of Tanner stages was within the normal range, the patient showed a rapid acceleration in skeletal maturation, resulting in adult short stature. Conclusion: Bone age seems to be a more precise parameter for biologic maturation in some patients after craniospinal irradiation than is clinical assessment of pubertal stages. Thus, if progression of bone age and decreasing final height predictions are noted, puberty should be stopped with gonadotropin-releasing hormone analogs, even if pubertal development seems to be adequate for chronologic age, because this increases the remaining time for growth hormone treatment.

Study objective was to evaluate retrospectively central nervous system (CNS) morbidity of children with acute lymphoblastic leukemia treated with intensive chemotherapy and cranial radiotherapy for a first isolated or combined CNS relapse. Neurological (Touwen), neuropsychological (CFT 20, Wechsler scales, d2 attention test) and neuromorphological (CT, MRI) assessments were performed in 17 children (9 girls, 8 boys) aged between 7 and 14 years. Patients were off therapy for median 4 years; cranial radiotherapy for CNS relapse (12-24 Gy) was given to all patients 2 to 9 years ago (median 5.5 years). Ten patients had received preventive cranial radiotherapy during front-line treatment, previously. In this group, the cumulative radiation dose ranged between 30 and 39 Gy. Patients received 12 to 30 intrathecal methotrexate doses (median 22). Compared with normative levels for age (100 points) performance IQ (89.9) and full scale IQ (92.0), Culture Fair IQ (88.3) and attention and concentration (90.9) were significantly impaired. Verbal IQ (95.5) was not significantly different from normal expectations. Neurological investigations of 16 patients showed mild signs in 7 (44%) of them, mostly of fine-motor skills and coordination, but no major motor disability. In MRI and CT, white matter changes or ventricular enlargement were noted in 10 of 16 patients (63%). Parent-completed questionnaires indicated problem behaviors in 5 children. Cumulative doses of methotrexate correlated significantly with neuropsychological test results. Children irradiated twice as well as girls had poorer cognitive functions, not being statistically significant. Despite pathological test results, all children attended a normal school and did not exhibit obvious impairment in daily life. In conclusion, CNS relapse and attendant therapy, mostly consisting of a second course of cranial radiotherapy, caused measurable intellectual deficits and CNS morbidity, which did not result in severely impaired performance. Periodic psychological und clinical examinations are recommended for recognition of delayed morbiditiy and early intervention.

Monitoring of therapy-related late effects after acute lymphoblastic leukemia (ALL) therapy in childhood has become an increasingly important area in posttherapeutic patient surveillance. The usefulness of conventional electro-encephalographic (EEG) investigations as part of these attempts is controversially discussed. However, EEG recordings have become a popular approach for judgement on the functional integrity of the central nervous system in this subject group. The present report focuses on this problem and discusses the question whether and to what extent conventional EEG recordings were correlated with further measures of central nervous system (CNS) integrity and therapeutic differences. EEGs were recorded in 110 subjects, asymptomatic long-term survivors of ALL in childhood, during a large retrospective multicenter study evaluating CNS late sequelae following antileukemic therapy in Germany and Austria. EEG findings were correlated with demographic data, illness- and treatment-related parameters, as well as with data on the morphological, neurological and psychological status of the participating subjects. At the time of follow-up the EEG was abnormal in 47 cases (42.7%). The most frequent EEG abnormalities observed were disturbances of the background activity (n = 45, 95.8%), followed by hypersynchrone activities (n = 1.0, 21.3%) and interhemispheric differences/focal slowing (n = 6, 12.8%). With exception of age at diagnosis, none of the observed EEG abnormalities showed a correlation with any of the aforementioned illness- or treatment-related parameters. Eighty percent of the observed EEG abnormalities were found in children younger than 5 years at diagnosis. Children less than 2 years of age as well as those above 5 years at onset of disease showed a significantly reduced prevalence of EEG disturbances compared to subjects between 2 and 5 years at diagnosis. Neither the degree of illness nor therapy-specific differences showed any relationship to EEG outcome. There was no specific EEG finding for a specific morphological substrate, neurological or psychological deficiency and vice versa. Overall, there was no beneficial effect of routine EEG testing in children following therapy for ALL. According to our data, the evaluation of conventional EEG recordings of otherwise asymptomatic ALL long-term survivors is not a very helpful measure for predicting the degree of behavioral deficiencies, neurological disturbances, or morphological CNS abnormalities, which may be present or will develop in this special subject group.