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Biomedical subjects

D Harms

Publications and source records attributed to D Harms.

At least 73 records · Page 4Linked to original sources
PubMed1997

Juvenile granulosa cell tumors of the ovary in children and adolescents: results from 33 patients registered in a prospective cooperative study.

Clinical and pathological data from 33 prospective registered patients who suffered from juvenile granulosa cell tumors (JGCT) were evaluated according to treatment and outcome. The median age at the time of diagnosis was 7.6 years (range, 6 months to 17.5 years). Fourteen patients showed signs of a pseudo-precocious puberty. In 1 patient premenarcheal bleeding was the only clinical symptom of the disease. A pelvic tumor or an abdominal distention was found in 6 children, revealing signs of an acute abdomen in 3 children. Tumor staging was performed according to the FIGO (International Federation of Gynecology and Obstetrics) classification for ovarian tumors. Twenty children and adolescents were classified as FIGO stage Ia; 8 children had stage Ic tumors. In 4 patients stage IIc and in 1 patient stage IIIc tumors were observed. For local tumor control all 33 patients underwent tumor resection and oophorectomy, which was complete in 28 patients. Adjuvant combination chemotherapy was used in 1 girl who presented with high mitotic pathological index features in FIGO stage Ia. In 8 other children between FIGO stage Ic and IIIc, treatment was also intensified by multidrug chemotherapy. After a follow-up period of 168 months, an event-free survival of 0.75 +/- 0.07 was observed. From our data we conclude that multidrug chemotherapy including cisplatin-based regimens may be useful to enhance treatment results of JGCT, especially in advanced FIGO stages.

Adolescent↗
PubMed1997

Testicular juvenile granulosa cell and Sertoli cell tumours: a clinicopathological study of 29 cases from the Kiel Paediatric Tumour Registry.

Testicular Sertoli cell tumours (SCT) and juvenile granulosa cell tumours (JGCT) are rare in childhood. This study was designed to investigate the clinical picture, morphology and disease course in a comparatively large series of cases (total number = 29). Of 198 cases of childhood testicular tumour documented in the Kiel Paediatric Tumour Registry 18 were cases of infantile SCT (9.1%) and 11 of JGCT (5.6%). The average age at the time of diagnosis was 4.2 months for infantile SCT and 0.4 months for IGCT. SCT and JGCT often showed infiltrative growth into adjacent testicular tissue, dense cellularity and considerable proliferation activity. Immunohistochemically all cases expressed vimentin intermediate filaments in both tumour types. Next in frequency of expression were cytokeratins (SCT: 7/16; JGCT: 7/10) and smooth-muscle actin (SCT: 9/15; JGCT: 4/10). Follow-up studies (24/29) showed that in cases of tumour manifestation in infancy and after complete tumour removal (usually orchiectomy) no local recurrences and no metastases occurred. The most important conclusion for diagnosis and therapy is that despite infiltrative growth, incomplete differentiation, dense cellularity and considerable proliferation activity, after surgical excision infantile SCT and JGCT have a good prognosis. Adjuvant chemotherapy or more extensive operations with lymphadenectomy are thus not indicated.

Actins↗
PubMed1997

Congenital intracerebral teratoma: a rare differential diagnosis in newborn hydrocephalus.

Congenital hydrocephalus is caused by a broad spectrum of underlying disorders. In the majority of cases it is due to aqueductal stenosis and other distinct congenital anomalies, like Arnold-Chiari malformation. Nevertheless, in the differential diagnosis rare conditions such as cerebral malignancies must also be considered. We present two cases of congenital intracerebral teratoma as a differential diagnosis in congenital obstructive hydrocephalus. A teratoma is suggested when a rapidly growing hydrocephalus with a central calcified and vascularized mass is found sonographically. Regular cerebral structures usually cannot be detected. Early diagnosis in such cases is of clinical importance as the prognosis of congenital intracerebral teratoma is generally very poor.

Brain Neoplasms↗
PubMed1997

Efficiency and toxicity of ifosfamide, cisplatin and doxorubicin in the treatment of childhood hepatoblastoma. Study Committee of the Cooperative Paediatric Liver Tumour Study HB89 of the German Society for Paediatric Oncology and Haematology.

The Cooperative German Paediatric Liver Tumour Study HB89 was conceived to evaluate the efficiency and toxicity of ifosfamide, cisplatin and doxorubicin (IPA) in children with resectable and non-resectable hepatoblastoma (HB) and to determine late sequelae including tubular nephropathy of tumour treatment. The study also assessed the results of a surgical strategy, which adapts the procedure at the initial operation to the tumour's extension in the liver. The relationship of the tumours' histological differentiation to response to chemotherapy was also examined. Patients with a HB restricted to one liver lobe underwent primary resection. Larger tumours were initially treated with IPA chemotherapy and resected at second-look surgery. All patients received IPA adjuvantly after tumour resection. The IPA regimen consisted of ifosfamide 3.5 g/m2 (over 72 h days 1-3), cisplatin 100 mg/m2 (over 5 days 4-8) and doxorubicin 60 mg/m2 (over 48 h, days 9-10). Median follow-up of survivors was 64 months (range 28-82). Long-term disease-free survival (DFS) was for stage I: 21/21; stage II: 3/6; stage III: 28/38; and stage IV: 2/7 (overall 75%). Severe surgical complications occurred in 15% (4/27) of primary and 21% (8/38) of secondary resections with no lethality. 44/45 stage III/IV HB displayed PR after two IPA courses. Drug resistance developed in 8/12 tumours after four or five chemotherapy courses. Acute toxicity was observed in 34/242 (14%) IPA courses. Late sequelae were found in 7/54 (13%) of survivors, and subclinical renal tubulopathy occurred in 7/41 investigated patients (17%). Despite a more favourable prognosis in pure fetal and predominantly fetal histology, statistical analysis revealed no relationship between tumour differentiation and response to chemotherapy. In conclusion, IPA chemotherapy in combination with delayed surgery was highly effective in the treatment of HB.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

The current contribution of molecular factors to risk estimation in neuroblastoma patients.

The association of molecular characteristics with prognosis has been reported, but not their relationship with each other and their impact in the context of known clinical risk factors. In this study, data of 1249 consecutive intent-to-treat-neuroblastoma patients with more than 1 year follow-up were examined by multivariate analysis using loglinear and Cox proportional hazard regression models on a stage-related basis (stages 1-3: 600, 4S: 116, 4: 533). In a first step, risk factors were identified from 18 selected clinical variables, and risk groups defined. The second step investigated whether molecular characteristics (MYCN, LOH 1p, del 1p, CD44, N-ras, NGF-R, bcl-2, APO-1 (CD95)) contributed additional prognostic information to the model. The loglinear model demonstrated several interactions between clinical factors. By the Cox regression model, seven independent clinical risk factors were found for stages 1-3, seven for stage 4 and two for stage 4S. By subsequent introduction of all molecular variables, MYCN amplification only added significant prognostic information to the clinical factors in localised and stage 4 neuroblastoma. The models allowed the definition of risk groups for stages 1-3 patients by age (e beta = 5.09) and MYCN (e beta = 4.26), for stage 4 by MYCN (e beta = 2.78) and number of symptoms (e beta = 2.44) and for stage 4S by platelet count (e beta = 3.91) and general condition (e beta = 2.99). Molecular factors and in particular MYCN contribute significantly to risk estimation. In conjunction with clinical factors, they are powerful tools to define risk groups in neuroblastoma.

Adolescent↗
PubMed1997

In vitro culture studies of childhood myelodysplastic syndrome: establishment of the cell line MUTZ-1.

Myelodysplastic syndrome (MDS) in childhood is considered to be very rare and detailed pathobiological data are scarce. More biological information regarding MDS in children is clearly needed and in vitro culture studies provide one possibility for gaining further pathophysiological insights into this malignancy. Here, we incubated bone marrow samples from 30 children with MDS in liquid suspension culture in order to grow the transformed cells in vitro. In most cultures, the hematopoietic cells died quickly and only fibroblastic (stromal) background layers proliferated temporarily; several normal Epstein-Barr virus (EBV)-transformed B-lymphoblastoid cell lines (B-LCL) were established. Only in one instance, albeit from the peripheral blood and not from the bone marrow, could we establish a cell line, termed MUTZ-1, from the malignant cells of a 5-year-old girl with MDS (FAB subtype refractory anemia with excess of blasts). The MDS arose from a pre-existing Fanconi anemia and progressed quickly to an acute myeloid leukemia (FAB M2). Despite positivity for EBV, MUTZ-1 is not an EBV + B-LCL and further characterization of MUTZ-1 confirmed the derivation from the transformed clonal cells. Immunophenotyping showed a pre B-cell surface marker profile (CD10+ CD19+ cytoplasmic IgM+); receptor gene rearrangement analyses underlined the clonal B-cell nature of MUTZ-1 cells. MUTZ-1 cells exhibit a highly rearranged, unstable karyotype with a high frequency of spontaneous chromatid breaks and exchanges; del(5q) and additional rearrangements involving chromosome 5 [der(15)t(5;15)] were detected. The present data and results from a few other MDS-derived cell lines suggest that the transforming event in MDS seems to occur in an immature pluripotent progenitor cell. The new MDS-derived continuous cell line MUTZ-1 provides a useful in vitro model system for studies on the pathogenetic events leading to MDS.

Adolescent↗
PubMed1997

Prognostic significance of the proliferative activity in neuroblastoma.

The prognostic significance of the immunohistochemically assessed growth fraction in neuroblastomas was determined in relation to tumor grade and tumor stage. A total of 101 cases of neuroblastoma were examined with the monoclonal antibodies PC10 against proliferating cell nuclear antigen (PCNA) and Ki-S5 against the Ki-67 protein. Patients were followed for a mean time of 4.8 years. Expression of both PC10 and Ki-S5 was found to be significantly linked to tumor grade and tumor stage. Prognostically favorable stage IVs was associated with low PCNA and Ki-S5 levels. For ganglioneuroblastoma, significant differences were found between the diffuse and the composite type. In univariate analysis of stage III and IV tumors, Ki-S5 and PCNA scores were significantly correlated with disease-free survival (P < 0.0015), allowing definition of a subset of cases with favorable outcome. As to Shimada's group with poor prognosis, significant differences in the clinical course were found for low and high Ki-S5 scores (P = 0.036) but not for PCNA. In multivariate analysis, only patient age, Shimada's grade, and Ki-S5 scores achieved prognostic significance. We conclude that proliferation marker Ki-S5 may provide substantial prognostic information and might become a useful adjunct for predicting the clinical courses of neuroblastoma.

Adolescent↗
PubMed1997

Detection of rare RNA sequences by single-enzyme in situ reverse transcription-polymerase chain reaction. High-resolution analyses of interleukin-6 mRNA in paraffin sections of lymph nodes.

To study the distribution pattern of interleukin-6 (IL-6)-producing cells in normal human lymph nodes, we applied the in situ reverse transcription-polymerase chain reaction technique. We describe a new modification of this technique for monitoring small amounts of specific nucleotide sequences in conventional paraffin sections. This technique differs in at least two respects from those described earlier. The two decisive steps are: 1) the reverse transcription of mRNA and the subsequent amplification of cDNA by polymerase chain reaction are performed by a new single enzyme capable of both reaction types in one and the same medium without buffer exchange; and 2) for the specific detection of the amplified cDNA, a modified version of the primed in situ labeling technique was used. The technique, carried out on normal human lymph nodes, traces a low load of IL-6 mRNA in fibroblasts, endothelial cells, and a minor population of T lymphocytes in the pulp region. High levels of expression were encountered in about 20% of perisinusoidal pulp macrophages. In addition, moderate activity was detectable in sinus lining cells. Because no major activity was found in the germinal centers of the lymphoid B follicles and in the T zone, it is suggested that the plasma cell differentiation ensuing from primary and secondary B-cell immunization is mainly effected by the sinus lining cells as well as perifollicular and perisinusoidal pulp macrophages capable of producing high amounts of IL-6.

Humans↗
PubMed1996

Treatment of pediatric malignant thymoma: long-term remission in a 14-year-old boy with EBV-associated thymic carcinoma by aggressive, combined modality treatment.

Malignant thymoma, including thymic carcinoma, is extremely uncommon in the pediatric population. It is known to have a very poor outcome. We report on a 14-year-old boy with Epstein-Barr virus (EBV)-associated thymic carcinoma. Sections of the original tumor were analyzed for EBV by in situ hybridization to confirm the histological diagnosis of a lymphoepithelioma-like subtype. High copy numbers of EBV RNA were detected in the tumor tissue, suggesting an etiological role of EBV in our case. Intensive treatment resulted in long-term remission over 12 years. In order to facilitate the difficult management of the rare child with malignant thymoma, a literature search was initiated. Forty well-documented pediatric cases of malignant thymoma were found in the literature. Histological characteristics, clinical features, and therapeutic regimens were reviewed. Having the very limited experience with malignant thymoma in childhood in mind, it is concluded that its aggressiveness makes the most intensive treatment necessary. Long-term remission can be achieved by application of radical surgery, high-dose irradiation, and multiagent chemotherapy. The combination of cisplatinum, etoposide, and ifosfamide seems to be promising.

Adolescent↗
PubMed1996

Interphase cytogenetics on paraffin sections of paediatric extragonadal yolk sac tumours.

Germ cell tumours in children are more often extragonadal than in adults and the most frequent type is the yolk sac tumour. Limited cytogenetic data exist on extragonadal yolk sac tumours in children. We applied in situ hybridization (ISH) to interphase cell nuclei of four paediatric extragonadal pure yolk sac tumours and one yolk sac tumour component of a mixed germ cell tumour using paraffin-embedded tissue sections. The panel of chromosome-specific DNA probes was selected on the basis of their relevance in adult germ cell tumours and consisted of five DNA probes specific for the (peri)centromeric regions of chromosomes 1, 8, 12, and/or 17, X and/or one DNA probe specific for the subtelomeric region of chromosome 1 (p36.3). Only one tumour failed to show numerical and structural chromosome aberrations with the DNA probes used. The other four had an increased incidence of numerical chromosome aberrations with an over-representation of at least one chromosome. The DNA indices determined in the paraffin-embedded tumour material correlated well with the in situ hybridization findings. In only a few cases were chromosomes over-represented, when compared with the corresponding DNA indices. Recently, we have shown that the short arm of chromosome 1 is a non-random site of deletion in paediatric gonadal pure yolk sac tumours. The occurrence of similar deletions in one extragonadal pure yolk sac tumour and in one yolk sac tumour component, in conjunction with two further ISH reports, suggests that the loss of gene(s) in this region is an important event in the pathogenesis of paediatric malignant germ cell tumours of nearly all sites.

Adolescent↗
PubMed1996

Randomized comparison of rotational chemotherapy in high-risk acute lymphoblastic leukaemia of childhood--follow up after 9 years. Coall Study Group.

UNLABELLED: A frequent change of drug combinations may circumvent drug resistance in the treatment of patients with acute lymphoblastic leukaemia (ALL). In study COALL 85/89 201 children with high-risk ALL were randomized to receive over a period of 8 months rotational chemotherapy with six drug combinations given either in slow rotation (SR) (each combination given twice in succession) or in rapid rotation (RR) (each combination given once with a repetition of the drug combinations). Treatment of central nervous system leukaemia consisted of cranial irradiation and intrathecal methotrexate. Both SR and RR treatment groups were then given continuation chemotherapy of oral 6-mercaptopurine and methotrexate until 2 years after the date of diagnosis. The 9-year event-free survival (EFS) rate for the whole group is 69% +/- 3%, and the survival rate 75% +/- 3% at a median follow up of 5.8 years. Failure to achieve remission at day 28 was the most important prognostic factor (EFS 12% +/- 7% vs. 75% +/- 3% in the remission group). In the RR group, 11/100 patients were not in remission at day 28 opposed to 7/101 patients in the SR group. Children aged < 1 year (6/6 relapses) or aged > or = 10 years had a worse prognosis (EFS 64% +/- 5% vs. 77% +/- 4% in patients 1-10 years old). After 5 years EFS was inferior in the RR group attributable to a significantly higher relapse rate in children with a WBC > or = 100/nl. The EFS at 9 years for all patients, however, is similar in both groups (SR 72% +/- 5% vs. RR 67 +/- 5%). CONCLUSION: The COALL 85/89 treatment protocol with early intensive therapy and rotation of different drug combinations offers longterm disease-free survival for children with high-risk ALL. a continuous 4-week exposure to one drug combination may be necessary to achieve optimal results, especially in children with a high leukaemic cell burden.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

[Giant cell fibroblastoma. A rare soft tissue tumor in childhood].

We report on a 9-year-old girl with a giant cell fibroblastoma of the right anterior chest wall. This rare soft tissue tumour occurs predominantly in the first two decades of life. The typical clinical presentation is a solitary, usually 2-6 cm large, non-tender mass of blue-greyish colour which is mostly located on the back, anterior chest wall, thigh or groin. The histology shows a loose infiltrate of predominantly bland spindle cells in dermis and subcutis. Characteristic elements of the tumour are large angiectoid branching spaces lacking any endo- or epithelium, and relatively small multinucleated cells (floret cells). The recurrence rate is high if the tumour is not excised with adequate safety margins. Metastases are not reported. It is of pre-eminent importance to differentiate this rare benign tumor from sarcomas, in order to avoid an inappropriately aggressive therapy.

Biomarkers, Tumor↗
PubMed1996

Rhabdoid tumour of the kidney: a clinicopathological study of 22 patients from the International Society of Paediatric Oncology (SIOP) nephroblastoma file.

We present 22 (0.9%) cases of rhabdoid tumour of the kidney diagnosed amongst 2392 renal tumours in children. The patients ages ranged from 3 weeks to 94 months (median 7 months) and the female:male ration was 1.2:1. Clinically, they presented with an abdominal mass but four (18%) children also had hypercalcaemia and one (4.5%) developed a brain tumour (primitive neuroectodermal tumour). None of the children presented with stage I disease, five (23%) had stage II, ten (46%) stage III, and five (23%) stage IV disease. Two (9%) patients had bilateral tumours. Histologically, the vast majority (20/22) of the tumours exhibited a classical pattern but other histological patterns were also noted. Immunohistochemical studies performed in 12 cases showed vimentin positivity in all cases, CAM 5.2 in eight, epithelial membrane antigen in six, neuron specific enolase in four, S-100 protein in eight, and desmin in one case. In only 12 of the 22 tumours was there agreement between the reporting pathologist and the panel on a diagnosis of rhabdoid tumour of the kidney. Eight tumours originally diagnosed as rhabdoid tumour of the kidney were found to be other renal tumours and in another ten cases the initial diagnosis was changed by the panel to rhabdoid tumour. Metastases developed in 18 (82%) of the children--in eight they were present at the time of diagnosis and in 10 they developed from 2 weeks to 9 months after initial diagnosis. Metastases were found in the lung, abdomen, lymph nodes, liver, bone and brain. Of the 19 children with adequate follow-up, only two (10.5%) with stage II disease are alive, while 17 (89.5%) died 2 weeks to 20 months after the diagnosis.

Adolescent↗
PubMed1996

In vitro fibrinolysis after adding low doses of plasminogen activators and plasmin generation with and without oxidative inactivation of plasmin inhibitors in newborns and adults.

PURPOSE: The aim of this study was to investigate in vitro fibrinolysis after adding low doses of plasminogen activators and to determine the functional role of plasmin inhibitors in newborns and adults. PATIENTS AND METHODS: We have studied the kinetics of in vitro fibrinolysis after adding low doses of urokinase (UK) and recombinant tissue plasminogen activator (rt-PA) by use of a microtiter clot lysis assay. Additionally, we have determined plasmin generation with and without oxidative inactivation of plasmin inhibitors in newborns and adults. RESULTS: The 50% lysis time in the clot lysis assay correlated with the activator dose and was significantly shorter in newborns at rt-PA concentrations of < 0.21 microgram/ml. When UK was used as an activator, the 50% lysis time was slightly but significantly prolonged in newborns at concentrations of 140-200 IU/ml, whereas we could find lower values (non-significant) at 110 and 80 IU/ml. Plasmin generation after oxidative inactivation of plasmin inhibitors was significantly lower in newborns, even when compared with adult plasma, which was diluted 50%. However, in a physiological plasma milieu (containing natural inhibitors), there were no differences in plasmin generation when streptokinase (SK) was used as an activator and only minor differences when UK was used. CONCLUSIONS: Our data indicate a more rapid clot lysis at low UK and rt-PA concentrations in newborns despite significantly reduced plasminogen levels. The results of the plasmin generation experiments suggest a diminished effect of plasmin inhibitors towards fetal plasmin, which raises an explanation for the concentration-related differences in the clot lysis assay. The experience with thrombolytic agents in newborns is limited. Most dosage regimens for thrombolytic therapy in children or adults consist of an initial bolus infusion, followed by low-dose continuous treatment. Based on the results of our clot lysis experiments, we think that especially the continuous infusion of plasminogen activators after bolus administration should not be enhanced in newborns compared to older children or adults.

Adult↗
PubMed1996

The role of alpha 2-antiplasmin in the inhibition of clot lysis in newborns and adults.

The fibrinolytic system is involved in a wide variety of biological phenomena and differs physiologically in newborns compared to older children or adults. Newborn's plasminogen differs from adult plasminogen in carbohydrate composition, cell binding and activation kinetics. The fetal plasminogen has an increased concentration of sialic acid similar to fetal fibrinogen. In a previously reported study on plasminogen activation kinetics, we demonstrated differences in the reaction kinetics between fetal plasmin and plasmin inhibitors as compared to the reaction between adult plasmin and inhibitors. Hitherto, there are no investigations on the role of alpha 2-antiplasmin in the inhibition of clot lysis in newborns. We studied the contributions of purified alpha 2-antiplasmin to the regulation of fibrin clot lysis by use of a microtiter clot lysis assay. The lysis time of clots without adding purified alpha 2-antiplasmin correlated to the activator dose. When purified alpha 2-antiplasmin was incorporated at final concentrations ranging from 10 to 40 micrograms/ml, strong dose-dependent inhibition resulting in a prolongation of 50% lysis time was observed. The inhibition in newborns at all alpha 2-antiplasmin concentrations was less pronounced than that of the adults if 50% lysis time was < 55 min. If 50% lysis time was > 55 min. the prolongation of 50% lysis time was more pronounced in newborn than in adult plasma. The fact that we have less effects of alpha 2-antiplasmin in newborn infants at short reaction times despite the lower plasminogen levels, is consistent with slower reaction kinetics between plasmin and alpha 2-antiplasmin in newborns. These differences raise an explanation for the findings of Idell et al. [Am J Respir Crit Care Med 1994; 149:767-775] in premature baboons with neonatal respiratory distress syndrome (RDS). The knowledge of different reaction kinetics between plasmin and alpha 2-antiplasmin and the role of alpha 2-antiplasmin in the inhibition of clot lysis in newborns can be helpful to elucidate the significance of the fetal fibrinolytic system in neonatal RDS and to establish treatment strategies for fibrinolytic therapy of progressive RDS.

Adult↗