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Biomedical subjects

N Graf

Publications and source records attributed to N Graf.

At least 19 recordsLinked to original sources
PubMed1998

Abdominal irradiation in unilateral nephroblastoma and its impact on local control and survival.

PURPOSE: The influence of abdominal radiotherapy was analyzed in 122 patients with unilateral Wilms tumor eligible for local irradiation according to postoperative SIOP-stage. MATERIAL & METHODS: 122 of 454 children with Wilms tumor diagnosed between January 1989 and March 1994 in Germany were eligible for abdominal irradiation after preoperative chemotherapy and tumor resection according to SIOP9/GPOH protocol. There were 88 children with standard histology (SH; local Stage IIN+ and III) and 34 children with unfavorable histology (UH; anaplastic, clear cell and rhabdoid, local Stages II and III). Local irradiation was given postoperatively parallel to polychemotherapy according to protocol with appropriate dose reductions of Actinomycin D (dactinomycin) during the course of radiotherapy. Fifteen Gy to the tumor bed were prescribed in standard histology, with 30 Gy to regional lymph nodes, if histologically positive. Thirty Gy were given in unfavorable histology. Boost doses up to 15 Gy were possible for macroscopic residuals. Ages ranged between 6 months and 21 years (median 4.2 years). RESULTS: Only 98 of 122 eligible children were irradiated. Reasons for ommission of radiotherapy were: Stage III only due to intraoperative biopsy (n = 6), due to resected cava thrombus (n = 5); young age (n = 2); undergrading/understaging (n = 7); other reasons (n = 4). There were 19 abdominal recurrences (4 of 88 with SH; 15 of 34 UH). In 5 patients, local recurrence was the only site of failure. There were 6 local failures in 24 nonirradiated but eligible children (25%) vs. 13 of 98 in irradiated children (13%); p = 0.15. In SH 0 of 15 nonirradiated vs. 4 of 73 treated children (p = NS) and in UH 6 of 8 nonirradiated vs. 9 of 26 irradiated children developed local recurrence (p < 0.05). Of 19 children with local recurrence as one site of failure, 18 have died. This comprises 67% of 27/122 children with fatal outcome in the observation period. In the patients eligible for abdominal radiotherapy, projected 3-year relapse-free survival is 85% for the group of children with standard histology and 41% for the children with unfavorable histology. CONCLUSION: Despite impressive overall results for this multicenter trial in unilateral nephroblastoma, local recurrence remains a grave prognostic parameter. Evaluation of irradiated vs. eligible but not irradiated children suggests that radiotherapy to the tumor bed is of considerable impact for local control in the risk groups eligible for abdominal irradiation as defined in the SIOP9/GPOH protocol.

Adolescent↗
PubMed1998

Allele loss in Wilms tumors of chromosome arms 11q, 16q, and 22q correlate with clinicopathological parameters.

An extended analysis for loss of heterozygosity (LOH) on eight chromosomes was conducted in a series of 82 Wilms tumors. Observed rates of allele loss were: 9.5% (1p), 5% (4q), 6% (6p), 3% (7p), 9.8% (11q), 28% (11p15), 13.4% (16q), 8.8% (18p), and 13.8% (22q). Known regions of frequent allele loss on chromosome arms 1p, 11p15, and 16q were analyzed with a series of markers, but their size could not be narrowed down to smaller intervals, making any positional cloning effort difficult. In contrast to most previous studies, several tumors exhibited allele loss for multiple chromosomes, suggesting an important role for genome instability in a subset of tumors. Comparison with clinical data revealed a possible prognostic significance, especially for LOH on chromosome arms 11q and 22q with high frequencies of anaplastic tumors, tumor recurrence, and fatal outcome. Similarly, LOH 16q was associated with anaplastic and recurrent tumors. These markers may be helpful in the future for selecting high-risk tumors for modified therapeutic regimens.

Alleles↗
PubMed1998

US, CT and MR imaging characteristics of nephroblastomatosis.

OBJECTIVES: To describe the imaging features of nephroblastomatosis with US, CT and MR, to point out characteristics of differentiation between nephrogenic rests (NR) and Wilms' tumour (WT) and to determine the most appropriate imaging modality. MATERIALS AND METHODS: We reviewed the US, CT and MR images of 29 cases of histopathologically confirmed nephroblastomatosis sent to our department for reference evaluation (German nephroblastoma study). The series included 17 kidneys with NR, 6 kidneys with WT and 32 kidneys with both NR and WT. RESULTS: NR presented as multinodular, peripheral, cortical lesions, the diffuse form of distribution being less common. Foci were homogeneous and of low echogenicity, density or signal intensity. The lesions were most clearly depicted with contrast-enhanced CT and T1-weighted (T1-W) MR images. Lesions smaller than 1 cm were rarely identified by US. The most reliable criterion to differentiate NR from WT was their homogeneity. CONCLUSIONS: Contrast-enhanced CT and T1-W MR images are of similar potential and superior to US in the diagnosis of nephroblastomatosis. Due to the significant radiation dose of serial CT, MR imaging should be the method of choice wherever it is available. The cost-effectiveness and availability of US makes it ideal for serial follow-up of known lesions.

Case-Control Studies↗
PubMed1998

Down's syndrome in childhood acute lymphoblastic leukemia: clinical characteristics and treatment outcome in four consecutive BFM trials. Berlin-Frankfurt-Münster Group.

Clinical characteristics, treatment response and outcome were evaluated in children with Down's syndrome (DS) and acute lymphoblastic leukemia (ALL) as compared to other children with ALL (NDS). Sixty-one DS and 4049 NDS patients, receiving intensive antileukemic treatment during four consecutive trials (ALL-BFM 81, 83, 86 and 90) of the Berlin-Frankfurt-Münster Group (BFM), were retrospectively analyzed. DS and NDS children did not differ with respect to sex, leukocyte count, CNS leukemia and cytogenetic translocations. The DS cohort was slightly older (P=0.04), presented predominantly with the common while lacking the T immunophenotype (P=0.005), had a lower frequency of hyperdiploidy (P=0.004) and tended to have a better initial steroid response (P=0.057). Therapy-associated morbidity especially during high-dose methotrexate and a subsequent need for treatment modification occurred in 43% of all DS patients. Event-free survival (EFS) was slightly worse in children with DS (58+/-8% vs 70+/-1%, P=0.14), mainly due to rather late bone marrow recurrences. However, EFS in DS patients was comparable to the NDS group once they either received treatment with no major modifications (65+9% vs 70+/-1%, P=0.66) or were <6 years of age, irrespectively of therapy modifications (73+/-9% vs 74+/-1%, P=0.7). Cox regression analysis revealed that DS was an adverse prognostic factor for patients having completed therapy (P=0.0107), but was not prognostic at diagnosis (P=0.103). Age > or = 6 years, suboptimal treatment and infectious problems contributed to the slight inferior EFS in children with ALL and Down's syndrome. Therefore, most of these patients can be successfully treated if receiving intensive antileukemic treatment with no major modifications, but they require more sophisticated management of toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

[Wilms' tumor].

Today the prognosis in children with nephroblastoma is excellent. With the combination of surgery, chemotherapy and radiation more than 80% of children can be cured. Because of acute toxicity and late effects of treatment (scoliosis, cardiotoxicity, fertility problems and second malignancies) a major issue in the management of children with this kind of malignancy is the reduction of chemotherapy and radiation. This is done in prospective multicenter studies. In 1989 the GPOH did join the SIOP 9 study for the treatment of Wilms' Tumors. All the SIOP studies mainly investigated the preoperative treatment. With the introduction of a centralized radiodiagnostic center in Germany (Prof. Tröger, Heidelberg) a high certainty in making the right diagnosis preoperatively without histological proof could be achieved. It could be shown in SIOP 9, that four weeks of preoperative chemotherapy with actinomycin-D and vincristine is as effective as eight weeks. 60% of patients with a localized nephroblastoma will have stage I disease at the time of surgery. The response to preoperative chemotherapy is of prognostic value. As a result of the NWTS and SIOP studies the postoperative stage and histological subtype are very important regarding prognosis. By reducing the dose of actinomycin-D to 2/3 in children under 12 kg of body weight problems with venous occlusive disease could be minimized. In the now ongoing study SIOP 93-01/GPOH postoperative treatment for patients with stage I disease and intermediate malignancy is randomized to a short and a long branch.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

A novel site of DNA amplification on chromosome 1p32-33 in a rhabdomyosarcoma revealed by comparative genomic hybridization.

Cytogenetic analysis of a human embryonal rhabdomyosarcoma revealed a near-diploid karyotype with structural chromosome aberrations not involving the typical rearrangements of rhabdomyosarcomas, plus a large number of double minutes. Comparative genomic hybridization revealed a previously undescribed site of DNA amplification on the short arm of chromosome 1 (band 1p32-33).

Child↗
PubMed1995

12q13, a new recurrent breakpoint in acute non-lymphoblastic leukemia.

The karyotypes of 312 successfully analyzed samples of children with acute non-lymphoblastic leukemia (ANLL), which were sent to us by 72 German hospitals, were examined in order to find new recurrent chromosome abnormalities of possible clinical relevance. Whereas most of the patients had one of the specific aberrations of ANLL or a normal karyotype, random numerical or structural changes were found in 61 children (20%). Four of them showed an abnormality involving band 12q13: t(12;17)(q13;q21), t(12;21)(q13;q21), t(2;12)(p13;q13), and t(5;12)(p11;q13). Despite the fact that FAB subtypes were different (M0, M1 M6, AHL), the blasts of all patients were characterized by immaturity and were difficult to classify. The breakpoint 12q13 might be of clinical importance in ANLL, because the four patients in our study, as well as the 21 patients with this aberration found in the literature, had a very poor prognosis.

Child↗
PubMed1995

Microsurgery of cerebral lesions under stereotactic conditions.

Microsurgical excision of cerebral lesions was carried out under CT-guided stereotactic conditions. For lesions located in critical cortical areas, cerebral teleangiography under stereotactic conditions provided the coordinates of the vascular elements related to the structures and adjacent to the lesion without X-ray distortion. Small size cortical and subcortical lesions were targeted using the stereotactic biopsy probe as a guide. In twenty-four patients stereotactic microsurgery was used for following lesions: 8 cavernomas, 8 metastases, 7 gliomas, and 1 tuberculoma. Unpredictable permanent neurological complications did not occur, but predicted transient impairment after surgery in functional territories was tolerated with the complete removal of the lesion. The advantages of microsurgery using stereotactic coordinates are: precise knowledge of the location of brain structures and exact targeting of intracerebral lesions, better evaluation of surgical risks, easy spatial orientation, and minimization of the surgical damage to the healthy brain tissue.

Adolescent↗
PubMed1994

Autosomal recessive chronic granulomatous disease with absence of the 67-kD cytosolic NADPH oxidase component: identification of mutation and detection of carriers.

Chronic granulomatous disease (CGD) is characterized by the failure of phagocytic leukocytes to kill certain bacteria and fungi. This is caused by deficiencies in one of the components of NADPH oxidase, the enzyme in phagocytic leukocytes that generates superoxide. In a rare, autosomal recessive form of CGD, a 67-kD cytosolic component of NADPH oxidase (p67-phox) is missing. Until now, mutations in the gene coding for this protein have not been identified. We now report on a 10-year-old girl with lymph node and liver abscesses who was recognized as an A67(0) CGD patient by lack of NADPH oxidase activity in her granulocytes, a cytosolic defect in a cell-free oxidase system, and lack of immunoreactive material with an antiserum against the p67-phox protein. mRNA for this protein was present in normal amounts in her monocytes. This p67-phox mRNA was reverse-transcribed, and the coding region was amplified by polymerase chain reaction in six overlapping fragments and was sequenced. The patient appeared to be homozygous for a G-233-->A mutation, resulting in a nonconservative amino acid change (78Gly-->Glu). This mutation was also found in the genomic DNA of this patient but not in that of 38 normal donors. Both parents and a sister proved to be carriers of the disease, as deduced from the mutation in only one allele. The carrier state was also manifested by intermediate superoxide production by their intact granulocytes and in the cell-free system.

Amino Acid Sequence↗
PubMed1994

Methotrexate pharmacokinetics and prognosis in osteosarcoma.

PURPOSE: The influence of methotrexate (MTX) pharmacokinetic parameters on the efficacy of high-dose MTX (HDMTX) in osteosarcoma was analyzed. PATIENTS AND METHODS: MTX serum peak values from 198 patients in 1,703 treatment courses and more detailed pharmacokinetic data from 185 patients in 1,045 treatment courses from the Cooperative Osteosarcoma Study Group (COSS) studies COSS-80, COSS-82, and COSS-86 were investigated. RESULTS: A mean threshold peak level of > or = 1,000 mumol/L for the repeated MTX courses of individual patients was found to correlate significantly to prognosis in study COSS-80 (18% v 64% actuarial 10-year disease-free survival [DFS], P = .0001). Six courses of HDMTX per patient who achieved peak values > or = 1,000 mumol/L were found to be sufficient for a full effect to be seen in DFS in COSS-80. The MTX peak level was found to correlate closely to the area under the curve (AUC). However, AUC was a less powerful determinator of prognosis than the mean threshold MTX peak value. In patients who received cisplatin (DDP) as one of the additional drugs to MTX, the peak values and AUC were significantly increased (1,396 v 1,276 mumol/L, P = .011; 6,684 v 5,820 h.mumol/L, P < or = .002) and only a few patients (6%) did not achieve mean threshold MTX peak values. In addition, following restriction of hydration fluid after the MTX infusion from 4.5 to 3.0 L/m2 per 24 hours, the early MTX half-life (t1/2) and the AUC, but not the MTX peak value, were significantly increased (3.4 v 3.05 hours, and 6,760 v 5,998 h.mumol/L, respectively, P < or = .002). CONCLUSION: MTX pharmacokinetics significantly influence the efficacy of MTX in osteosarcoma. Individual adaptation of the MTX dose to ensure a threshold peak serum level > or = 1,000 mumol/L does not seem necessary at a fixed dose of 12 g MTX/m2, restriction of hydration fluid to 3 L/m2 per 24 hours, and concomitant use of DDP within the drug regimen.

Actuarial Analysis↗
PubMed1993

[Intracellular measurement of anthracyclines with flow cytometry].

The intracellular drug uptake of anthracycline antibiotics, including the anthrachinone analogue mitoxantrone, was investigated. Measurement of drug uptake for each of the white cell subpopulations is possible by Flow cytometry (FCM). Cell separation was carried out by two different methods, using Lysing solution and Ficoll. Ficoll was found to be the best for further investigations in cell kinetics. Stock solutions of each drug, ranging from 0.5-3 micrograms/ml, were incubated with cell suspensions of healthy donors. In the case of doxorubicin, daunorubicin and epirubicin a linear correlation between drug concentration in the incubation medium and intracellular drug level was found. In further studies drug concentration was constant (1 microgram/ml or 3 micrograms/ml) and the intracellular drug uptake was measured at various incubation times. Examinations were carried out with the two different cell separation methods, mentioned above. In healthy donors the reproducibility of FCM measurement was examined. In conclusions of the results observed in experiments, FCM seems to be a suitable, reproducible technique for determination of cellular anthracycline concentrations with the exclusion of aclacinomycin A and mitoxantrone because of their physical properties.

Aclarubicin↗
PubMed1992

The BFM-protocol for HIV-negative Burkitt's lymphomas and L3 ALL in adult patients: a high chance for cure.

During a period of 9 years we used the pediatric BFM-NHL protocol for treatment of 14 adult patients with Burkitt's lymphoma or L3 acute lymphoblastic leukemia. Ten of 14 patients obtained a complete remission including 5/8 with stage-IV disease or B-ALL. After a median follow-up of 55 months none of these ten patients relapsed. The projected survival after 8 years is 71%. Toxicity was moderate, with one early death; a tumor lysis syndrome occurred in four patients. From our experience we conclude that the BFM-NHL protocol is very effective in adult patients, with a high cure rate and acceptable toxicity, even in advanced stages of disease.

Adolescent↗
PubMed1992

[The diagnosis of bone marrow lesions in the MR tomogram in children with diseases of the hematopoietic system with special reference to post-therapy changes].

119 MR-examinations of both tibiae, knees and the lower part of both femur were performed in 41 children suffering from bone marrow disease (27 ALL, 4 AML, 3 NHL, 1 agranulocytosis, 6 anaemia). T1- and T2-spin-echo sequences and a T2-gradient-echo sequence were used. Bone marrow changes in leukaemia were diffuse before therapy and patchy after therapy. Due to their different signal in T2-weighted images, differentiation of the post-therapeutic patchy findings into infiltrations, fibrosis, necrosis and siderosis seems to be possible. In future, MRI will be the method of choice for screening and controlling bone marrow disease if the examination time is shortened by using only a T1-spin-echo sequence and a T2-gradient-echo sequence.

Adolescent↗
PubMed1992

[MR tomography of the lower limbs of children with diseases of the hematopoietic system].

In 41 children with disorders of the hematopoetic system 119 MR examinations of both tibiae and knees were performed (T1 and T2 spin-echo sequences and a T2 gradient-echo sequence). Before therapy bone marrow changes in leukemia were diffuse, and patchy during and after therapy. Signals in T2-weighted images were different for infiltrations, fibrosis, necrosis and siderosis. In 3 children suspected of suffering from osteomyelitis, Ewing-sarcoma or coxitis, MR examination was the first to show the correct diagnosis. Therefore in children indications for MR tomography should be handled more generously to win time for therapy. Using only a T1 spin-echo sequence and a T2 gradient-echo sequence screening of more than one region is capable of controlling bone marrow diseases.

Acute Disease↗
PubMed1992

[Neurocysticercosis in an 8-year-old girl].

We report about an 8-year-old girl with signs of elevated intracranial pressure. X-ray, CT and MRT scan showed an inner hydrocephalus as well as an intracranial calcification. By western blot analysis a Taenia solium cysticercosis could be diagnosed. In spite of spontaneous remission of the symptoms we treated with Praziquantel. Resection of the cyst was not necessary. Diagnostic and therapeutic problems of cysticercosis are discussed.

Animals↗
PubMed1992

[Value of serum sialic acid determination in children].

In order to find out whether sialic acid (SA) is suitable as a tumor marker this compound was determined in the sera of 48 healthy and of 168 sick children. In healthy children under six months of age lower concentrations of SA were found (x = 41 +/- 5 mg/dl) than in subjects aged six months to 18 years (x = 68 +/- 8 mg/dl). Inflammatory diseases of various etiologies lead to a significant increase in both age groups (x = 93 +/- 28 mg/dl), the same could be observed in subjects up to 14 days after surgery. In children with malignant disorders the concentration of SA was significantly higher (x = 83 +/- 27 mg/dl) than in the healthy subjects, but not higher than in patients with inflammatory diseases. We conclude that SA might play a role in the follow up protocol of patients with malignant tumors.

Adolescent↗
PubMed1991

[Polyvalent immunoglobulins in prevention of viral infections in children with neoplastic diseases treated with immunosuppressive therapy].

31 children with leukemias, lymphomas and solid tumors treated by polychemotherapy received prophylactic i.v. polyvalent immunoglobulins during 48 hours after exposion with varicella-zoster-virus, rubella-virus or mumps-virus. None of the 23 children with immunity against the exposed virus developed the infection. 8 children had no antibodies against the exposed virus. The prophylaxis with the polyvalent immunoglobulin protected them against chickenpox (6 children) and rubella (2 children). All children showed an elevation of the IgG level in plasma and the antibody titers against measles-, mumps-, rubella- and varicella-zoster-virus after application of the immunoglobulin. A study with a larger number of patients is necessary to confirm our results, that polyvalent immunoglobulins with high titers against exposed viruses are effective in prevention of this diseases in immunocompromised children.

Adolescent↗