Extremity salvage with a free musculocutaneous latissimus dorsi flap and free tendon transfer after resection of a large congenital fibro sarcoma in a 15-week-old infant. A case report.

A case of complex microsurgical reconstruction of the dorsum of the foot, including tendon transfer following tumor resection, in a 15-week-old male infant is presented. After birth, a 5.5 x 4 cm large tumor was observed on the dorsum of the right foot. Biopsy showed a congenital malignant fibro sarcoma. After initial chemotherapy a radical excision of the tumor at the age of 14 weeks was followed. To cover the defect a musculocutaneous latissimus dorsi flap was taken, the cutaneous part being large enough to cover the defect. Extensor tendons were reconstructed with free tendon transplants. Amputation is usually indicated in these cases. To the best of our knowledge, microsurgical reconstruction in infants at this age with congenital malignant tumors has not yet been reported. The case shows that Plastic surgery can play an important role in pediatric oncology and should routinely be integrated into the multi-modal treatment concepts.

A meta-model of chemotherapy planning in the multi-hospital/multi-trial-center-environment of pediatric oncology.

OBJECTIVE: Chemotherapy planning in pediatric oncology is complex and time-consuming. The correctness of the calculation according to state-of-the-art research is crucial for curing the child. Computer-assistance can be of great value. The objective of our research was to work out a meta-model of chemotherapy planning based on the Unified Modeling Language (UML). The meta-model is used for the development of an application system which serves as a knowledge-acquisition tool for chemotherapy protocols in pediatric oncology as well as for providing protocol-based care. METHODS: We applied evolutionary prototyping, software reengineering techniques and grounded theory, a qualitative method in social research. We repeated the following steps several times over the years: Based on a requirements analysis (i) a meta-model was developed or adapted, respectively (ii). The meta-model served as a basis for implementing evolutionary prototypes (iii). Further requirements were identified (i) from clinical use of the systems. RESULTS: We developed a comprehensive UML-based meta-model for chemotherapy planning in pediatric oncology (chemoMM). We implemented it and introduced evolutionary prototypes (CATIPO and DOSPO) in several medical centers. Systematic validation of the prototypes enabled us to derive a final meta-model which covers the requirements that have turned out to be necessary in clinical routine. CONCLUSIONS: We have developed an application system that fits well into clinical routine of pediatric oncology in Germany. Validation results have shown that the implementation of the meta-model chemoMM can adequately support the knowledge acquisition process for protocol-based care.

Ovarian sex cord-stromal tumors in children and adolescents.

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

High-dose chemotherapy with autologous stem cell rescue in children with nephroblastoma.

Children with Wilms tumor who have a particular risk of failure at relapse or at primary diagnosis were treated with high-dose chemotherapy (HDC) and autologous peripheral blood stem cell rescue in order to improve their probability of survival. From April 1992 to December 1998, 23 evaluable patients received HDC within the German Cooperative Wilms Tumor Studies. Nineteen were given melphalan, etoposide and carboplatin (MEC); the others received different regimens. The dose of carboplatin was adjusted according to renal function. Indications for HDC were high-risk relapse in 20 patients, bone metastases in two patients and no response in one patient. Fourteen of 23 patients are alive after a median observation time of 41 months, 11 of 14 in continuous complete remission, three in CR after relapse post HDC. The estimated survival and event-free survival for these patients are 60.9% and 48.2%. Twelve children relapsed after HDC; nine of them died within 12 months and three are surviving from 20 to 33 months after relapse. The main toxicities were hematologic, mucositis and renal (tubular dysfunction; intermittent hemodialysis in one patient). There were no toxic deaths. About half of the children suffering from Wilms tumor with very unfavorable prognostic factors survive disease-free after HDC for over 3 years. Besides hematological toxicity, mucositis and infections, renal function is at risk during HDC. With dose adjustment on glomerular filtration rate, however, no permanent renal failure was observed.

Rapid development of ganciclovir-resistant cytomegalovirus infection in children after allogeneic stem cell transplantation in the early phase of immune cell recovery.

As recently reported, children having T cell-depleted peripheral blood stem cell transplantation (PBSCT) might be at increased risk for the development of drug resistance. To investigate if delayed immune recovery was a potential risk factor, the recovery of the CD3(+), CD4(+), CD8(+) and CD19(+) cells was related retrospectively to genotypic detected resistance development in three pediatric patients with ganciclovir (GCV)-resistant human cytomegalovirus (HCMV)-infection out of 79 receiving allogeneic PBSCT. Selected control groups consisted of HCMV-seronegative patients without any infection (A, n = 8), asymptomatic infected patients with viral leuko- and plasmaDNAemia (B, n = 4) and patients with HCMV-disease (pneumonia) (C, n = 3). Patient No. 1 with very early resistance development exhibited a rapid immune recovery with higher T cell counts than in group A. Immune recovery of patient No. 2 was delayed, as also observed in groups B and C. Patient No. 3 showed an immune recovery comparable to group A. Resistance developed before (No. 2) or during (Nos 1 and 3) the recovery of the relevant CD3(+), CD4(+), CD8(+) lymphocytes. GCV-resistance development did not necessarily coincide with delayed immune recovery, but appeared in all three cases in the early phase of immune recovery (range: day +44 to day +95). Therefore, children seem to be at special risk for resistance development in the early phase after transplantation before immune cells have recovered. These results suggest that GCV treatment of an HCMV infection in the early posttransplant phase of children after T cell-depleted PBSCT/BMT should promote more stringent resistance screening.

The incidence of hearing impairment after successful treatment of neuroblastoma.

BACKGROUND: Platinum compound based chemotherapy has contributed to improved survival rates in neuroblastoma patients. We studied the association of hearing loss with the use of platinum based drugs. METHODS: Data of children from the two German neuroblastoma study cohorts, NB90 and NB97, were analyzed for the incidence of hearing impairments greater than WHO grade 2. Data from patients surviving more than 1 year after diagnosis without progression or recurrence were used. RESULTS: Of these 1,170 patients, 146 (12.5 %) had persisting hearing impairments. The incidence was low after localized neuroblastoma INSS stage 1 - 3 with 35/650 (5 %) and stage 4S with 2/113 (2 %), but high in stage 4 disease with 109/405 (27 %). Ototoxicity depended on the cumulative cisplatin dose. For doses of 1 - 200 mg/m (2), 201 - 400 mg/m (2), 401 - 600 mg/m (2) and 601 - 800 mg/m (2) we found hearing impairments in 5/39 (12 %), 28/221 (13 %), 61/230 (26 %) and 50/225 (22 %) patients, respectively. The incidence of hearing impairment was not age dependent. In stage 4 patients, there was an additional effect of high dosed carboplatin. 65/188 (40 %) patients developed hearing impairments after carboplatin containing (1,500 mg/m (2)) high dose chemotherapy with autologous stem cell reinfusion compared to only 33/217 (15 %) in patients receiving platinum free maintenance chemotherapy. Substitution of cisplatin (40 mg/m (2) x d, d 1 - 4, 96 h infusion) with carboplatin (100 mg/m (2) x d, d 1 - 4, 1 - 2 h infusion) due to otoxicity during induction chemotherapy did not reduce event free survival. CONCLUSION: One fourth of high risk neuroblastoma survivors suffer from treatment induced hearing impairments. The substitution of cisplatin with carboplatin was not associated with an increased rate of tumor recurrences.

Idarubicin improves blast cell clearance during induction therapy in children with AML: results of study AML-BFM 93. AML-BFM Study Group.

In the randomized trial AML-BFM 93 we compared 60 mg/m2/day daunorubicin with 12 mg/m2/day idarubicin for 3 days each, combined with cytarabine and etoposide during induction. Results showed a significant better blast cell reduction in the bone marrow on day 15 in patients of the idarubicin arm (25 of 144 = 17% of patients with > or = 5% blasts compared to 46 of 149 = 31% of patients after daunorubicin, Pchi2 = 0.01). This was, however, mainly seen in high risk patients treated with idarubicin (19% vs 38%, Pchi2 = 0.007). Cardiotoxicity, WHO grade 1-3 shortening fraction reduction after induction occurred in 6% patients in both arms. Bone marrow toxicity differed slightly with a median recovery time of neutrophils >500/microl of 25 days (daunorubicin) compared to 27 days (idarubicin), P = 0.05. In the total group of patients probabilities of 5 years event-free survival and disease-free survival were similar for patients treated with daunorubicin or idarubicin (49% +/- 4% vs 55% +/- 4% and 57% +/- 4% vs 64% +/- 4%, P logrank 0.29 and 0.15, respectively). However, in patients presenting with more than 5% blasts on day 15 there was a trend for a better outcome after treatment with idarubicin (P logrank 0.06). Together with the early effect seen for high risk patients these results indicate a better efficacy of idarubicin than of daunorubicin during induction with a similar rate of toxicity.

Influence of compression hosiery on physiological responses to standing fatigue in women.

PURPOSE: The purpose of this investigation was to examine the influence of various designs of commercial hosiery, which use graduated compression, on the physiological and performance responses to standing fatigue. METHODS: Twelve healthy women (age = 23.0+/-2.1 yr, height = 165.7+/-5.0 cm, percent body fat = 22.6+/-4.2%, body mass = 60.0+/-8.9 kg) volunteered to participate in this investigation. All subjects completed four identical standing fatigue protocols with different garment conditions each separated by 7 d. The standing fatigue protocol involved a total of 8 h of standing on hard floors during which subjects participated in various tasks and experimental testing procedures. In addition, all activity and dietary profiles of the subjects were carefully controlled 48 h before each experimental session. Before the standing fatigue protocol, subjects completed a battery of tests to establish morning baseline values. Experimental tests included determination of lower leg venous cross-sectional area, blood pressure, heart rate, perceived discomfort ratings, circumferences measurements, total body water, variation in center of pressure during "quiet" standing, vertical jump performance, and specific regional patterns of foot pressures. RESULTS: This investigation demonstrated that commercial hosiery with various forms of graduated compression and construction were effective in mediating a reduction in edema in the ankles and legs while reducing the amount of venous pooling and discomfort in the lower body. Different constructions of garments may mediate these overall effects via different physiological mechanisms related to fluid shifts and muscle tissue damage. CONCLUSION: Wearing various types of graduated compression hose during the day as it relates to women in standing professions may minimize edema and muscle tissue disruption, thereby increasing comfort in the legs.

Drug-resistant human cytomegalovirus infection in children after allogeneic stem cell transplantation may have different clinical outcomes.

Three seropositive pediatric recipients of allogeneic stem cell transplantation out of a group of 42 patients receiving T-cell-depleted, unrelated transplants and 37 patients receiving T-cell-depleted, haploidentical transplants were monitored longitudinally for human cytomegalovirus (HCMV) infection and the emergence of antiviral drug resistance. Early in the posttransplant course, all 3 patients developed HCMV mutations conferring drug resistance to ganciclovir. One child additionally developed multidrug resistance to foscarnet and cidofovir, with mutations in the viral phosphotransferase gene (UL97) and the DNA-polymerase gene (UL54) being found. These data show that resistant HCMV infection does not necessarily correlate with a severe clinical outcome. The early detection of genotypic resistance up to 129 days before the emergence of phenotypic resistance and the dissociation of resistance patterns among different body sites emphasize the importance of genotypic analyses of different DNA specimens for an efficient antiviral therapy. T-cell-depleted children having transplantation might be at an increased risk for the development of drug resistance.

Integrating specialized application systems into hospital information systems--obstacles and factors for success.

Hospital information systems are often huge and heterogeneous systems. To support physicians with their daily clinical work, application systems are developed which are dedicated to particular medical fields or tasks and which have to be integrated into the hospital information system. The integration process is quite complicated, because it makes the information system's infrastructure even more heterogeneous. We developed an application system for documentation and therapy planning in pediatric oncology (DOSPO) and we started to introduce it into the Department of Pediatric Oncology of Heidelberg University Hospital. The fact that DOSPO is developed as a universal system for nationwide use made the integration process more difficult. In any case, the introduction of specialized application systems has to be planned systematically in advance, regarding the prevailing information system's infrastructure, available resources and established processes. To simplify the integration process comprehensive electronic patient records for the future should be designed in a way that they can be enhanced easily by new clinical functions.

Lymphocytic hypophysitis with central diabetes insipidus and consequent panhypopituitarism preceding a multifocal, intracranial germinoma in a prepubertal girl.

UNLABELLED: We report the clinical course of a prepubertal girl with central diabetes insipidus (DI) and consequent panhypopituitarism evolving over a period of 10 years due to lymphocytic hypophysitis and subsequent germinoma. Two years after the diagnosis of central DI was established, MRI revealed a thickened pituitary stalk. Later pituitary enlargement and increasing thickening of the pituitary stalk impinging on the optic chiasm required a trans-sphenoidal biopsy which disclosed active hypophysitis with lymphocytic infiltrates and necrosis. High dose dexamethasone treatment only temporarily halted the disease process. Therefore, stereotactic radiation therapy was performed as a rescue treatment and MRI findings almost reversed. However, the subsequent MRI showed multiple intracranial lesions identified histologically as a germinoma and a standard chemotherapy and radiation was performed. CONCLUSION: The diagnosis of diabetes insipidus in children requires long-term follow up beyond the pubertal age in order to establish the underlying cause. In contrast to lymphocytic hypophysitis in adults, lymphocytic hypophysitis in prepubertal children may represent the first sign of a host reaction to an occult germinoma.

[Multi-national therapy study for Hodgkin's disease in children and adolescents GPOH-DH 95. Interim report after 2 1/2 years]. / Multinationale Therapiestudie für den Morbus Hodgkin bei Kindern und Jugendlichen GPOH-HD 95. Zwischenbericht nach 2 1/2 Jahren.

Based on concepts of the successful German-Austrian pediatric Hodgkin studies DAL-HD 78 until-90, a new trial was initiated addressing the question whether radiotherapy can be further reduced or can be omitted in case of complete remission after initial chemotherapy, aiming at reduction of sequelae after radiotherapy, especially radiogenic second malignancies. In respect to CHEMOTHERAPY patients are stratified into 3 therapy groups (TG) according to stage and gender: 2 courses of OPPA (girls) or OEPA (boys) in TG1 (stage IA/B, IIA), and in addition 2 (TG2: stage IEA/B, IIEA, IIB, IIIA) or 4 (TG3: stage IIEB, IIIEA/B, IIIB, IVA/B) COPP courses. Boys with stage IIIB and IIIEB receive OPPA instead of OEPA. RADIOTHERAPY is administered according to response to chemotherapy independent of stage: patients with complete remission or minimal residues do not receive irradiation; patients with more than 75% tumor regression are irradiated to involved fields at a dose of 20 Gy. Doses of 30 or 35 Gy are given to regions with tumor regression below 75% or residual bulky tumor of > 50 ml, respectively. INTERIM RESULTS: From 8/95 till 1/98 we registered 385 patients under the age of 18 years from Germany, Austria, Switzerland, Sweden and the Netherlands. Therapy has been completed in 334 patients. Three patients with solitary nodular paragranuloma were treated with surgery only. Out of 331 patients 89 (26.9%) achieved a complete remission with chemotherapy. Tumor regression of more than 75% was seen in 193 (58.3%) patients and below 75% in 39 (11.8%) patients. Tumor progression during chemotherapy occurred in 1 (0.3%) patient. Response after chemotherapy was not evaluable for 9 (2.7%) patients. Radiotherapy was omitted in 91 (27.1%) patients: in TG1 50 of 142 (34%) patients, TG2 24 of 98 (24.5%) patients and TG3 18 of 94 (19.2%) patients. Initially involved regions were irradiated at a dose of 20 Gy in 164 of 334 (49.1%) patients. Doses up to 30 Gy or 35 Gy were given to 19 (5.7%) or 57 (17.1%) patients respectively. Events (tumor progression, relapse or death) occurred in 23 of 334 patients until now. The event-free survival rate is 0.91 at 2 1/2 years for all study patients and 0.89 for patients without radiotherapy. Six relapses occurred in 91 patients without radiotherapy. No relapse occurred in TG1 (n = 49), but in 5 of 24 TG2-patients, and in 1 of 18 TG3 patients without radiotherapy. As yet, the results are not significantly inferior compared with trial DAL-HD 82. Therefore this trial aiming at omitting radiation therapy in patients with complete remission after a short lasting chemotherapy will be continued. Longer follow up is necessary for final evaluations and conclusions.

Plasmapheresis in severe septic shock with disseminated intravascular coagulation.

An 18-year-old female with CNS relapse of acute lymphoblastic leukemia after previous complete remission of the disease underwent chemotherapy. Due to the therapy she suffered from profound suppression of bone marrow with consecutive thrombocytopenia and leukopenia. Despite prophylactic treatment, severe septicemia occurred with septic shock, hemolysis and disseminated intravascular coagulation (DIC). As the clinical course became uncontrollable by means of conventional therapy, including broad-spectrum antibiotics, substitution of fresh frozen plasma, antithrombin III and heparin therapy, plasma exchange was used as a rescue therapy. This method succeeded in effective replacement of clotting factors and normalization of coagulation, in removal of fibrinogen degradation products and probably of toxins and shock mediators. The patient recovered from shock.

[Effect of desmopressin (DDAVP) on blood platelet parameters in vivo and in vitro]. / Untersuchungen zum Einfluss von Desmopressin (DDAVP) auf Blutplättchenparameter in vivo und in vitro.

Coagulation assays including DDAVP test were carried out in 15 patients preoperatively, evaluating several parameters of platelets during the assays. After DDAVP infusion we observed a decreased spontaneous aggregation in whole blood, an increased retention to glass beads, and in a number of cases a raised in vitro-formation of thromboxane. By application of DDAVP, a significant enhancement of spontaneous aggregation in whole blood and left shift to smaller volumes of the platelet volume distribution were demonstrated in vitro. It is concluded that DDAVP has an indirect inducing effect on aggregation, probably by release of ADP from red blood cells.

[Kinetic fibrinogen determination with batroxobin (reptilase)]. / Kinetische Fibrinogenbestimmung mit Batroxobin (Reptilase).

A kinetic turbidity-producing method for fibrinogen determination on the basis of reptilase reagent (batroxobin) is described. The method, which is in good agreement with method by Clauss shows comparable precision, is marked out by the possibility of objective photometric measurement. Reagent stability, use of undiluted test plasma and single-point calibration are further advantages. The method is insensitive to heparin. With regards to FDP it is less disturbed than the method by Clauss. In case of adaptation to a modern photometer a clear rationalization effect can be achieved.

[Measurement of spontaneous platelet aggregation in citrated whole blood by application of the hematologic automatic Coulter S plus VI]. / Zur Messung der spontanen Thrombozytenaggregation im Citratvollblut (SPAV) unter Verwendung des hämatologischen Automaten Coulter S plus VI.

A method for measurement of the spontaneous platelet aggregation in citrated whole blood (SPAV) was tested using the Coulter Counter S plus VI and a simple mechanism for sample rotation. The underlying principle of the procedure consists in the sequential measurement of the decrease of free platelets in a specimen of citrated whole blood which ist rotated at 37 degrees C for 20 minutes. SPAV offers advantages compared to other methods for spontaneous aggregation in platelet rich plasma. First experiences about application of the SPAV-procedure are presented.

[Pulmonary blastoma in childhood--a case report and review of the literature]. / Das pulmonale Blastom im Kindesalter--Eine Kasuistik und eine Ubersicht über die Literatur.

The paper deals with a pulmonary blastoma with CNS involvement in a young child 2 years after resection of congenital cysts from the other lung. Further 25 pulmonary blastomas in infants are compiled from the literature serving as the basis for a discussion of epidemiology, pathogenesis, classification, definition and prognosis as well as diagnostic and therapeutic problems involved in these rare malignant lung tumours.