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.

Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related differences.

One of the most relevant concerns in long-term survivors of paediatric acute lymphoblastic leukaemia (ALL) is the development of neuropsychological sequelae. The majority of the published studies report on patients treated with chemotherapy and prophylactic central nervous system (CNS) irradiation, little is known about the outcome of patients treated with chemotherapy-only regimens. Using the standardised clinical and neuropsychological instruments of the SPOG Late Effects Study, the intellectual performance of 132 paediatric ALL patients treated with chemotherapy only was compared to that of 100 control patients surviving from diverse non-CNS solid tumours. As a group, ALL and solid tumour survivors showed normal and comparable intellectual performances (mean global IQ 104.6 in both groups). The percentage of patients in the borderline range (global IQ between 70 and 85) was comparable and not higher as expected (10% cases and 13% controls, expected 16%). Only 2 (2%) of the former ALL and 1 (1%) of the solid tumour patients were in the range of mental retardation (global IQ<70). Former known risk factors described in children treated with prophylactic CNS irradiation, like a younger age at diagnosis of ALL and female gender, remained valid in chemotherapy-only treated patients. The abandonment of prophylactic CNS irradiation and its replacement by a more intensive systemic and intrathecal chemotherapy led to a reduction, but not the disappearance of late neuropsychological sequelae.

Evidence for HLA-linked susceptibility factors in childhood leukemia.

To test the hypothesis that susceptibility to leukemia can be governed by (a) recessive gene(s) associated with the major histocompatibility complex (MHC) in man, we performed an analysis of the inheritance of HLA antigens in 55 families in which one of the children developed ALL. We found among the parents of affected children a highly significant increased compatibility at the DR locus (p = 0.003). A similar increase was observed in sharing HLA antigens of the B locus (p = 0.02). The observed number of homozygotes among the patients was twice the expected value in families where the parents shared a B and a DR antigen. In segregation analysis, heterozygotes for the shared parental HLA antigen were significantly more prevalent among the healthy siblings. Our genetical analysis indicates that mating of certain shared alleles of the HLA system (especially of the DR locus) is associated with the risk for the offspring to develop ALL in childhood. This situation favors the expression of recessive genes associated with the MHC, and presumably those involved in the susceptibility to acute leukemia. Because familial leukemia is a rare event, the susceptibility to childhood ALL must also implicate genes outside the MHC and important environmental factors.

Preleukemic proliferative changes in murine bone marrow after single and multiple 7,12-dimethylbenz(a)anthracene (DMBA)-applications.

The effect of a leukemia-inducing treatment on early changes in kinetic parameters of murine bone marrow cells were investigated. Mice were treated i.p. one, four and eight times at biweekly intervals with 1 mg DMBA. Up to nine weeks after the last injection, CFU-S number, proliferation ability of bone marrow cells (PF), cell doubling time (td) and the compartment ratio (CR) were measured. Following multiple DMBA injections, CFU-S number and PF were decreased whereas CR and td increased, thus indicating persisting stem cell injury and proliferative compensation in the hemopoietic amplification compartment. A single DMBA injection had no effect. It is concluded that a first DMBA injection induces cytotoxic (and genotoxic) damage in the bone marrow leading simultaneously to a strong proliferation stimulus and a hindered proliferation ability of HSC, some of which will be predisposed for further mutagenic treatment. The following DMBA injections meet strongly proliferating HSCs, thus enhancing the probability for the loss of proliferation control/terminal differentiation.

Two cases of sudden death by rupture of traumatic and bacterial aneurysms.

Unexpected subarachnoid hemorrhage with a fatal outcome was seen in two patients in intensive care in association with trauma and an intracranial inflammatory abscess. The cause of SAH was disclosed at autopsy: traumatic and bacterial aneurysms of the basilar artery respectively. In the reported cases the symptoms of SAH did not suggest an origin.

Primary cerebral anaplastic T-cell-lymphoma (type Ki-1): review and case report.

We describe the clinical course of a 20-year-old man who suffered generalized convulsive seizures with postictal aphasia and hemiparesis of the right side. Computed tomography (CT) displayed a left postcentral lesion with prominent perifocal edema and only a little contrast medium enhancement. The completely removed tumor proved to be a primary cerebral non-Hodgkin lymphoma consisting of T-cells. Only ten days after the operation the patient once more presented a clinical deterioration. A nuclear magnetic resonance imaging (MRI) displayed an annular structure in the area previously operated upon, suspected to be an abscess. The second operation disclosed a large recurrence of the primary T-cell lymphoma extending diffusely into the white matter. On account of the rapid recurrence, a whole brain irradiation was started twelve days after the second operation. Four cycles of chemotherapy followed. Immunohistochemical studies of the anaplastic large lymphoma cells showed staining with the pan T-cell markers (UCHL1, CD3) and with the CD30 (Ki-1) antibody. The B-cell markers (L26, LN1) were negative. The EMA (epithelial membrane antigen) was only partially expressed. Further investigation excluded the presence of systemic lymphoma manifestation. 24 months after the last operation the patient remained free of symptoms. The last MRI displayed no evidence for the recurrence of a lymphoma. In reference to this unusual clinical course the few previously reported cases of the extremely rare primary cerebral T-cell lymphoma are reviewed.

[Computed tomographic assessment of orbital fractures in traumatic damage of the optic nerve]. / Computertomographische Beurteilung von Orbitafrakturen bei traumatischer Schädigung des Nervus opticus.

Ten patients with orbital fractures and optic nerve trauma are reported. Fractures of the optic canal could be demonstrated by computed tomography in six cases and fractures of the orbital apex in another three cases. Surgical decompression of the optic canal was performed in seven cases. Computed tomography enhanced decision for surgery in cases of intraorbital haematoma with exophthalmus and narrowing of the canal by bony fragments, especially in those patients presenting with incomplete or progressive visual disturbance.

Epidural abscess following frontal sinusitis--demonstration of communication by epidural contrast medium and coronal computerized tomography.

A case of epidural abscess following sinusitis is presented with rhinorrhoea after irrigation of the abscess cavity postoperatively. Coronal computerized tomography and instillation of contrast medium through the catheter showed communication between epidural space and left frontal sinus.

Mesenchymal liver hamartoma in a newborn; case report.

A newborn boy had a severe, unexplained apnoea. On clinical examination a palpable abdominal mass was found extending over the right hemiabdomen. Further investigations by Ultrasound, CT scan and MRI revealed a liver tumor (7 x 5 x 9 cm). Histology from an open liver biopsy confirmed the diagnosis of a benign mesenchymal hamartoma. Operative resection of the tumor was performed when the patient was 2 1/2 months old. Postoperative management and clinical follow-up for twelve months were without complications. Primary liver tumors are rarely found in children. About half of them are malignant and associated with high mortality rates (e.g.hepatoblastoma). The most common benign liver tumors are mesenchymal hemangiomas and hamartomas. In this group of tumors prognosis has improved mainly due to progress in imaging techniques and progress in liver surgery during recent years.

[Cooperation of the family physician with the oncology center in the care of the children with tumors]. / Die Zusammenarbeit des Hausarztes mit dem onkologischen Zentrum bei der Betreuung des tumorkranken Kindes.

With a cure rate of over 50% pediatric oncology contrasts with the adult oncology. The success is the result of a multimodal approach with surgery, radiotherapy and chemotherapy to almost all forms of childhood cancer as outlined in various national and international protocols. These are evaluated permanently concerning efficacy and toxicity at one organisation (in Switzerland: the pediatric section of the "Schweizerische Arbeitsgruppe für klinische Krebsforschung"). For the care of the children with malignancy however a specialist physician team at a tumor center is not enough. Without the cooperation of the family doctors of the area proper referral of the patients and long term treatment can not be realized. Good information and adequate teaching appears to be necessary to give these patients optimal care.

[Acute leukemias and tumors of childhood--a problem solved?]. / Akute Leukämien und Tumoren des Kindesalters--Problem gelöst?

Cancer is a rare disease in children, in whom some 200 new cases are recorded every year in Switzerland including about 20 in the eastern part of the country. In contrast to cancer in adults, many malignancies of the child have prospects of cure. This improved prognosis is mainly the result of interdisciplinary cooperation within the framework of controlled national and international protocols. Progress in the treatment of two representative forms of cancer (acute lymphocytic leukemia and Wilms tumor) is illustrated. 50% of all children from the eastern part of Switzerland with acute lymphocytic leukemia and 70% of those with Wilms tumor have been cured in the past 7 years. These impressive advances are unfortunately overshadowed by late sequelae of the therapy, which are described and must be taken into account in future therapeutic approaches.

[Familial primary chronic type ventilation]. / Familiäre primäre chronische Hypoventilation

Primary hypoventilation (Ondine's curse), due to diminished sensitivity ofthe respiratory center to CO2, is very rare. Up to now only a few patients have been observed, ten of whom were children. Familial occurrence was reported in 1976 for the first time. The cases are described of a 10-year-old girl and her mother who both showed the typical clinical and pathophysiological symptoms. Our own observation also suggests that this unknown defect of respiratory regulation could be inherited. Sedation, anesthesia, or severe respiratory tract infection are life-threatening situations in these patients. Pulmonary hypertension and right heart failure are possible long-term complications.

Increased prothrombin activation in a patient with congenital afibrinogenemia is reversible by fibrinogen substitution.

We describe a patient with congenital afibrinogenemia who showed elevated prothrombin activation fragments (F1 + 2) indicating increased thrombin formation. This finding was unexpected since it has hitherto been thought that patients with congenital hypo- or afibrinogenemia have no evidence of increased utilization or accelerated consumption of coagulation factors. No other possible reasons for the elevation of F 1 + 2 were found. Upon fibrinogen substitution F1 + 2 decreased and were again increasing when fibrinogen concentration in plasma fell to very low levels. These findings raise the question of whether increased thrombin formation should be understood as a compensatory mechanism in congenital afibrinogenemia.

Meningeal relapse after long-term remission in acute childhood lymphocytic leukemia.

Central nervous system (CNS) relapse is reported in three children with acute lymphocytic leukemia who received intermittent prophylactic CNS therapy with intrathecal methotrexate. The children were on monochemotherapy either with methotrexate or 6-mercaptopurine for 2 1/2 years. The CNS relapse occurred 2 1/2, 10 and 11 months after cessation of all chemotherapy. Irradiation and/or intensive chemotherapy including drugs as BCNU and Ara-C which are known to cross the blood-brain barrier were not given. Preventive CNS radiotherapy should be considered in all children who did not receive an adequate prophylactic CNS therapy even after long-term remission before chemotherapy is stopped.

[Optimation and simplification of clinical tumor cytodiagnosis by means of cytocentrifugation]. / Optimierung und Vereinfachung der klinischen Tumorzytodiagnostik mittels Zytozentrifugation

Since the introduction of cytocentrifugation, the methods of clinical cytology have become more refined. The following advantages should be stressed: 1. speed and ease of processing, 2. highest possible cellular yield, 3. good preservation of cellular characteristics. In the light of predominantly CSF analyses in the field of pediatric oncology the above mentioned findings are clearly illustrated (ALL, AML, reticulum cell sarcomatosis, Ewing sarcoma, leptomeninx sarcoma, retinoblastoma, Letterer-Siwe's disease, familial erythrophagocytic lymphohistiocytosis, plexus papilloma). Malignancies are clearly distinguishable from benign conditions (toxic glial reactions, virus meningitides, CNS hemorrhages etc.). The higher cellular yield permits very early diagnosis of meningeal leukemia. This qualitative improvement of cytological diagnostic methods may considerably influence the choice of therapeutic procedures in the treatment of malignancies.

[The use of trans-cranial Doppler sonography in a neurosurgical intensive care unit. Intracranial pressure, intracranial circulatory arrest]. / Zum Einsatz der transkraniellen Dopplersonographie auf einer neurochirurgischen Intensivstation. Hirndruck, intrakranieller Zirkulationsstillstand.

Transcranial Doppler Sonography (TCD) is a noninvasive simple bedside procedure to control continuously cerebral blood flow velocity in basal brain arteries in comatose patients of an intensive care unit (ICU). This measure can already be performed at ICU, to determine timing of angiography for confirming intracranial circulatory arrest when an organ explantation of patients judged clinically brain-dead is intended. TCD is also carried out to assess cerebral circulation in patients with intracranial hypertension. 64 patients are repeatedly evaluated by TCD and have been continuously monitored for ICP at the same time. According to our results a strong correlation between the flow parameters derived from TCD and the ICP exists when the ICP surpasses the level of 25 mmHg. Furthermore repeated control-TCD-examinations of 150 comatose patients in our ICU have elucidated the significant prognostic value of the pulsatility index representing the cerebrovascular resistance. Thereby important informations concerning further clinical course of patients suffering from intracranial hypertension are available. Additionally a clinical example of complete failure of cerebrovascular autoregulation shortly after hypoxic brain damage is demonstrated.

Histiocytosis X in 9 children: clinical aspects and laboratory evaluations including an analysis of monocytopoiesis.

Nine children with histiocytosis X were observed. The course of the disease largely depended upon the degree of dissemination at the time of diagnosis. Bone and skin involvement healed completely with a relatively simple therapy using prednisone in combination either with vincristine or vinblastine. Complete or long lasting partial remissions could be achieved up to involvement of 4 organs. Three patients demonstrating histiocyte infiltrations in 5 organs died. They all were less than 2 years of age. Hyperproliferation of monocytopoiesis was present in all patients manifesting itself by a rise in the fraction of mononuclear phagocytes in bone marrow. This variation was paralleled by monocytosis in the peripheral blood in 5 of 7 cases. Serum muramidase levels were increased in 5 of 6 patients. However, there was no clearcut correlation to the degree of disease dissemination.