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.

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.

Constitutional balanced chromosomal rearrangements and neoplasm in children.

A predisposition to tumor development is currently associated with some, but not all, constitutional chromosomal abnormalities. In a series of 578 children, in which conventional cytogenetic investigation was performed on material from various benign and malignant tumors, four boys and one girl were also found to have constitutional balanced chromosomal rearrangements. The figure of 5 in 578 is notable because the reported incidence of balanced rearrangements in newborns is approximately 1 in 450. Thereby suggesting that some, if not all, children with balanced constitutional chromosomal rearrangements have an increased predisposition for neoplasms developing.

Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group.

Trial ALL-BFM 90 was designed to improve outcome in patients with childhood acute lymphoblastic leukemia (ALL) by using a reduced treatment regimen. Patients were stratified into a standard-risk group (SRG), a medium-risk group (MRG), both defined by adequate early treatment response; and a high-risk group (HRG), defined by inadequate response to the cytoreductive prednisone prephase, induction failure, or Philadelphia-chromosome-positive ALL. Four treatment modifications were evaluated: dose intensification in induction by a more rapid drug sequence; administration of L-asparaginase during consolidation therapy in the MRG (randomized); enforced consolidation by rotational elements in the HRG; and reduction in the dose of anthracyclines and use of only 12-Gy preventive cranial radiotherapy in the MRG and HRG, with the aim of avoiding toxicity. Among all 2178 patients (

Prognostic value of cerebrospinal fluid cytology in pediatric medulloblastoma. Swiss Pediatric Oncology Group.

BACKGROUND: Although the demonstration of leptomeningeal dissemination is the most important predictor of poor outcome in children with medulloblastoma, there is lack of consensus on the prognostic value of a positive cerebrospinal fluid (CSF) cytology (i.e., stage M1). PATIENTS AND METHODS: Eighty-six pediatric medulloblastoma patients treated in Switzerland between 1972-1991 were retrospectively studied regarding the influence of M-stage on prognosis. 39 were M0, 13 M1, 15 Mx, 17 M2, and 2 M3. RESULTS: Five- and 10-year overall survival rates were 76% and 54% for M0, 68% and 50% for Mx, 36% and 25% for M1, and 22% and 22% for M2-3 (P < 0.001), respectively. No significant survival differences were observed between M1 and M2-3 patients. Among 26 patients with only postoperative CSF cytologies, seven were positive. Their outcome was similar to that of six preoperatively staged M1 and significantly different from that of M0 patients (P = 0.001). In 14 patients both pre- and postoperative CSF cytology was performed. Total agreement was observed between the pre- and postoperative results (six positive and eight negative). Among the 19 M2-3 patients CSF cytology was positive in eight, negative in five, and unknown in six. CONCLUSIONS: A positive CSF cytology either pre- or postoperatively predicts for a poor outcome, similar to that observed in stage M2-3 patients. A postoperative cytology is likely to be concordant with cytologic results obtained preoperatively, and seems to have the same prognostic significance. A negative cytology, however, does not exclude a more advanced stage.

A further case of a t(11;20)(p15;q11.2) translocation in an acute myeloid leukemia (FAB M2).

PURPOSE: The clinical implications of many cytogenetic abnormalities in acute myeloid leukemia (AML) are now well established. However, questions about the significance of rarer abnormalities still exist, particularly in childhood disease. PATIENTS AND METHODS: We report a case of a 9 1/2-year-old girl who had AML of the FAB M2 subtype. A diagnostic bone marrow aspirate and subsequent bone marrow aspirates were investigated using conventional cytogenetic methods. RESULTS: Cytogenetic analysis of the diagnostic bone marrow aspirate showed a t(1;20)(p15;q11.2) translocation as the sole acquired abnormality. After one course of chemotherapy, the patient achieved hematopoietic and cytogenetic remission which has been sustained for 1 year after presentation. CONCLUSION: This report demonstrates that rare non-random cytogenetic abnormalities are still to be described in AML, and that care should be taken when ascribing clinical significance to cytogenetic findings in childhood disease based on those of older patients.

Cytogenetic abnormalities in Langerhans cell histiocytosis.

We present the cytogenetic investigations of five histiocytic tumour lesions from children. In four cases there was a confirmed diagnosis of Langerhans cell histiocytosis (LCH) and one case of histiocytosis that did not fulfil all the criteria for true LCH. All five cases showed cytogenetic abnormalities, including the first report of an abnormal clone in LCH. The clone showed a t(7;12)(q11.2;p13) translocation and was detected in only a small percentage of cells. This case and a further three also contained non-clonal abnormalities and an increase in chromosome breakage. The fifth case, the only one in which no acquired abnormalities were seen, had a constitutional paracentric inversion of chromosome 13q.

Recurrent mediastinal mass in a child with Hodgkin's disease following successful therapy: a diagnostic challenge.

The case of an 11-year-old girl with mediastinal stage III B-E Hodgkin's disease is described. She achieved complete remission with combined chemoradiotherapy according to the Swiss Pediatric Oncology Group-HD Protocol 1985. Six months after all therapy was stopped, a slowly growing retrosternal mass was detected. Computed tomography (CT) and gallium-67 single-photon emission CT (SPECT) could not elucidate the true origin of the tumor, nor did ultrasound-guided transthoracic fine-needle puncture. Open biopsy with histologic examination of the lesion has successfully identified the mass as thymic hyperplasia, a rebound immunologic reaction after chemoradiotherapy that mimicked tumor regrowth.

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.

Increased thrombin generation during fibrinogen and platelet recovery as an explanation for hypercoagulability in children with L-asparaginase therapy for ALL or NHL: a preliminary report.

Three out of 21 patients treated at the Children's Hospital of Eastern Switzerland for ALL or NHL with the respective BFM-90 protocols experienced thrombotic complications during Erwinia L-asparaginase therapy. We therefore investigated the development of the haemostatic imbalance in six children during the induction phase of both protocols. In the average, elevated thrombin generation was found simultaneously to an increase in fibrinogen, cross-linked fibrin degradation products and platelet counts between protocol days 28 to 35. This period thus seems to harbour an increased potential of hypercoagulability which could explain the accumulation of thrombotic complications described by Sutor et al. Moreover, day to day investigations just before and one day after L-asparaginase administration did not show any relevant change in the above named parameters, thus rather indicating a cumulative than a single dose effect of Erwinia L-asparaginase therapy on the coagulation system. These findings lead to the question if the prophylactic use of anticoagulants might reduce the hypercoagulability seen during L-asparaginase therapy, which is currently under investigation in our institutions.

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.

Coincidence of familial platelet glycoprotein Ib/IX deficiency (Bernard-Soulier syndrome), idiopathic autoantibody against platelet glycoprotein Ib/IX, familial appearance of antiphospholipid antibodies, and familial factor XII deficiency.

The case of an 8-year-old boy with apparently homozygous Bernard-Soulier syndrome (platelet GP Ib/IX complex deficiency) and a transient idiopathic autoantibody against GP Ib/IX is described. He had been diagnosed with chronic autoimmune thrombocytopenia (due to the detection of antiplatelet autoantibodies) before Bernard-Soulier syndrome was proven. Both parents and his brother displayed intermediate deficiency of GP Ib/IX, thus indicating a heterozygote state for Bernard-Soulier syndrome. Alloimmunization as an explanation for the appearance of GP Ib/IX antiplatelet antibodies in the propositus can be excluded. A so-called pseudo Bernard-Soulier syndrome due to selective antibodies was also excluded. Flow cytometric analysis revealed residual expression of 2% GP Ib and 13% GP IX on the propositus' platelets. It seems that the propositus showed an idiopathic autoantibody against a platelet glycoprotein in which he is genetically deficient (but which is not completely lacking). Thus, in patients with untypical behavior upon therapy of "autoimmune thrombocytopenia", other differential diagnoses should also be considered even if antiplatelet antibodies are detected. In addition, all family members displayed elevated concentrations of antiphospholipid antibodies. These findings raise the question of a genetic predisposition for the development of autoantibodies. Moreover, an F. XII deficiency was found in all family members except the mother.

Prevention of delayed ischaemic deficits after aneurysmal subarachnoid haemorrhage by intrathecal bolus injection of tissue plasminogen activator (rTPA). A prospective study.

Among a series of 224 patients with aneurysmal subarachnoid haemorrhage (SAH) admitted over a period of three years, 52 patients were prospectively treated with intrathecal tissue plasminogen activator (rTPA). All of these patients were admitted and operated on within 72 h after SAH. SAH was confirmed by CT scan and the volume of blood accumulated in the basal cisterns was graded according to Fisher's scale. All patients had a SAH according to Fisher's grade III, as a prerequisite for inclusion into the study. In 21 patients additional intraventricular bleeding was detectable on CT scan. The diagnosis of a single intracerebral aneurysm as the bleeding source was established by pan-angiography, which also excluded additional cerebro-vascular malformations. The control group consisted of 68 patients, which were also treated within 72 h after SAH. Age and sex distribution as well as the clinical patterns were comparable to the rTPA group. In all patients the aneurysm was clipped using standard microsurgical techniques. After the aneurysm had been excluded from the parent vessel, 10 mg of rTPA, dissolved in 10 ml of its solution fluid, were slowly instilled into the basal cisterns in the treatment group. In patients with additional severe intraventricular bleeding, 5-10 mg of rTPA were injected into the ventricles via an intraventricular catheter at the end of the operation. Apart from the intrathecal application of the thrombolytic substance, the surgical protocol was identical in the patients of the control group. During the postoperative period, the patients in both groups were examined neurologically and by transcranial Doppler on a daily basis.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of relapsing acute lymphoblastic leukemia in childhood. III. Experiences with 54 first bone marrow, nine isolated testicular, and eight isolated central nervous system relapses observed 1985-1989.

Of 54 children with acute lymphoblastic leukemia (ALL) and first hematological recurrence observed between 1985 and 1989, 31 relapsed while still on treatment and 23 after cessation of therapy. Of the former, only one survived. Of the latter, 11 children survived after a minimum follow-up of 25 months. During the same period, a first isolated testicular relapse was observed in nine boys, of whom six survived, and an isolated CNS relapse in eight patients, of whom three survived. As a rule, survivors of a bone marrow or testicular relapse were doing well while those surviving a CNS relapse had considerable neuropsychological sequelae. These results, compared with those of two preceding studies, suggest that with intensification of front-line treatments, it becomes more difficult to rescue children who relapse, particularly those with a bone marrow relapse while on therapy.

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.

[Localization of frontobasal traumatic cerebrospinal fluid fistulas. Comparison of radiologic and surgical findings]. / Lokalisation von frontobasalen traumatischen Liquorfisteln. Ein Vergleich von radiologischem Befund und Operationsbefund.

Computed tomographic and surgical findings were compared in 30 patients with traumatic frontobasal cerebrospinal fluid fistula. Radiological signs were extension of fractures of the rhinobasis, localized opacification of paranasal sinuses, and localized intracranial air collections. Exact localization of dural tears was only possible in about half of all patients (16 of 30). In conclusion there must be surgical inspection of all fractures of the skull base, and only isolated injuries could be treated by selective surgery.

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.

Spontaneous intracerebral hemorrhage.

We report on 146 patients with spontaneous intracerebral hemorrhage treated in the period between 1984 and 1988. The aim of this retrospective study was to point out factors for operative respectively conservative treatment. Looking for etiology, age, unconsciousness, localization and extension of hematoma as well as bleeding into the ventricles our results showed that patients over 70 years of age and/or in coma III and IV (Brussels Coma Scale) have a bad prognosis as well as patients with intraventricular bleeding. Patients seem to benefit from operation if hematoma is located in the hemisphere or cerebellar and the extension ranges from 3 to 5 cm.