Parkinson's disease with camptocormia.

BACKGROUND: Camptocormia is defined as an abnormal flexion of the trunk that appears when standing or walking and disappears in the supine position. The origin of the disorder is unknown, but it is usually attributed either to a primary or a secondary paravertebral muscle myopathy or a motor neurone disorder. Camptocormia is also observed in a minority of patients with parkinsonism. OBJECTIVE: To characterise the clinical and electrophysiological features of camptocormia and parkinsonian symptoms in patients with Parkinson's disease and camptocormia compared with patients with Parkinson's disease without camptocormia. METHODS: Patients with parkinsonism and camptocormia (excluding patients with multiple system atrophy) prospectively underwent a multidisciplinary clinical (neurological, neuropsychological, psychological, rheumatological) and neurophysiological (electromyogram, ocular movement recording) examination and were compared with age-matched patients with Parkinson's disease without camptocormia. RESULTS: The camptocormia developed after 8.5 (SD 5.3) years of parkinsonism, responded poorly to levodopa treatment (20%) and displayed features consistent with axial dystonia. Patients with camptocormia were characterised by prominent levodopa-unresponsive axial symptoms (ie, axial rigidity, gait disorder and postural instability), along with a tendency for greater error in the antisaccade paradigm. CONCLUSION: We suggest that (1) the salient features of parkinsonism observed in patients with camptocormia are likely to represent a specific form of Parkinson's disease and camptocormia is an axial dystonia and (2) both camptocormia and parkinsonism in these patients might result from additional, non-dopaminergic neuronal dysfunction in the basal ganglia.

Neurosurgery in Parkinson's disease: the doctor is happy, the patient less so?

Despite the overall excellent outcome of neurosurgery in patients with Parkinson's disease, there is often a contrast between the improvement in motor disability and the difficulties of patients to reintegrate a normal life. In this study, the personal, familial and professional difficulties experienced by patients two years after bilateral high frequency stimulation of the subthalamic nucleus were carefully analyzed. To avoid such socio-familial maladjustment, we strongly suggest taking into consideration the patients' psychological and social context before the operation and during the post-operative follow-up.

Results of 58872 and 58921 trials in acute myeloblastic leukemia and relative value of chemotherapy vs allogeneic bone marrow transplantation in first complete remission: the EORTC Children Leukemia Group report.

The first EORTC (European Organization of Research and Treatment of Cancer) acute myeloblastic leukemia (AML) pilot study (58872) was conducted between January 1988 and December 1991. Out of 108 patients, 78% achieved complete remission (CR), and event-free survival (EFS) and survival rates (s.e., %) at 7 years were 40 (5) and 51% (6%), respectively. It indicated that mitoxantrone could be substituted for conventional anthracyclines in the treatment of childhood AML without inducing cardiotoxicity. The aim of the next EORTC 58921 trial was to compare the efficacy and toxicity of idarubicin vs mitoxantrone in initial chemotherapy courses, further therapy consisting of allogeneic bone marrow transplantation (alloBMT) in patients with an HLA-compatible sibling donor or chemotherapy in patients without a donor. Out of 177 patients, recruited between October 1992 and December 2002, 81% reached CR. Overall 7-year EFS and survival rates were 49 (4) and 62% (4%), respectively. Out of 145 patients who received the first intensification, 39 had a sibling donor. In patients with or without a donor, the 7-year disease-free survival (DFS) rate was 63 (8) and 57% (5%) and the 7-year survival rate was 78 (7) and 65% (5%), respectively. Patients with favorable, intermediate and unfavorable cytogenetic features had a 5-year EFS rate of 57, 45 and 45% and a 5-year survival rate of 89, 67 and 53%, respectively.

[Ifosfamide induced encephalopathy: 15 observations]. / Encéphalopathie induite par l'ifosfamide: 15 observations.

INTRODUCTION: Ifosfamide is an alkylating agent used in the treatment of germ-cell tumors, sarcomas and lymphomas. One of its main side effects is the encephalopathy of which the incidence may reach 30% in the literature, in adults and children just as well. OBJECTIVES: Based on both our experience and a review of the literature, we propose some recommendations for the management of this complication. PATIENTS AND METHODS: We report 15 encephalopathy cases in non-brain tumor patients, which occurred between January 1987 and March 2002 in children from 2 to 17 years old, treated for solid tumors at the Institut Gustave Roussy. Ifosfamide was administered at a posology between 5.4 and 15 g/m(2)/course, associated with other antimitotics such as actinomycin D, etoposide or vincristine. RESULTS: Six patients experienced a grade III neurological toxicity according to the NCI classification, which developed as excess drowsiness lasting up to 36 hours. Six other patients developed grade IV neurotoxicity, including two comas resolving within 4 days and four short generalized convulsions. Three other children experienced grade II drowsiness. Brain MRIs were normal and EEG showed an aspecific encephalopathy tracing. This early central neurotoxicity appeared right from the first administration, and occurred immediately after the first injection or during the second or third day of treatment. It was most often reversible, usually 3 to 5 days after the last ifosfamide administration. Five patients were administered a treatment with Methylene Blue with a demonstrable efficacy in only one case. No death or neurological sequelae have been noted. Ifosfamide has been renewed after the neurological accident in 7 of those patients. Only 1 of those 7 patients developed grade IV neurotoxicity during the next course of treatment. In 2 of those 7 children, Methylene Blue was used in a prophylactic way. No neurological disorders have been noted during the next courses of treatment. DISCUSSION: In the literature, the following are described as risk factors for ifosfamide encephalopathy: advanced pelvic disease, previous cisplatyl treatment and renal failure. We have not found any of these predisposing factors in our series, but three of the fifteen patients had severe neurotoxicity associated with Vincristin during previous treatments. CONCLUSION: Facing a clinical diagnosis of ifosfamide encephalopathy, it is recommended to discontinue administration of ifosfamide and inject by intravenous route 50 mg Methylene Blue every 4 hours until the symptomatology recedes. The re-challenge of Ifosfamide is not contra-indicated and should be performed under prophylactic treatment with Methylene Blue by intravenous route at the dose of 50 mg every 6 hours.

NB87 induction protocol for stage 4 neuroblastoma in children over 1 year of age: a report from the French Society of Pediatric Oncology.

PURPOSE: NB87 was designed to test the efficacy of a short, non cross-resistant, induction protocol for unselected patients over 1 year of age with stage 4 neuroblastoma. A secondary objective was to compare in a randomized study the toxicity of two modalities of cisplatin administration. PATIENTS AND METHODS: A total of 183 patients received two cycles of alternating sequences: cyclophosphamide 300 mg/m2/d on days 1 to 5, vincristine 1.5 mg/m2/d on days 1 and 5, and doxorubicin 60 mg/m2/d on day 5 (CADO); and cisplatin 40 mg/m2/d and etoposide 100 mg/m2/d on days 1 to 5 (CVP), followed by surgery of the primary tumor (126 patients). Ninety-one were randomized to receive cisplatin either as bolus (BO; n = 48) or continuous infusion (CI; n = 43). International Neuroblastoma Staging System (INSS) and Response Criteria (INRC) were used with emphasis on skeletal evaluation by meta-iodobenzylguanidine (MIBG). RESULTS: Hematotoxicity was predominant, with a higher incidence of neutropenia (P = .01) for CADO and of thrombocytopenia for CVP (P < .001). Severe infections, as well as nonhematologic toxicities, occurred more often after the first sequence. Gastrointestinal complications were predominant during both courses of CVP. The toxic death rate, including surgery, was 3%. Complete remissions (CRs) were less frequent on MIBG (45%) compared with marrow (66%) or other metastases (61%). Combining all metastatic sites resulted in a 39% CR rate. After surgery, the final CR rate was 42%. Nephrotoxicity was minimal in both arms (92% normal clearance for CI v 82% for BO). Hearing loss greater than 40 dB at 6,000 to 8,000 Hz was reported equally in both arms (n = 6 for CI v n = 5 for BO). CONCLUSION: Intensified chemotherapy using CADO/CVP increases CR rates despite a shorter induction duration. However, the rate of MIBG normalization remains unsatisfactory and could be raised through the dose-intensive use of agents such as cyclophosphamide.

Mitoxantrone and high dose Ara-C for the treatment of ANLL in childhood: a pilot study of the EORTC CLCG (EORTC 58 872).

Since January 1988, 91 children with ANLL have been treated with a polychemotherapy regimen containing Mitoxantrone (MTZ), excluding other anthracyclines. Induction consisted of Ara-C, MTZ, and VP 16. Consolidation lasted 6 weeks with Vincristine, MTZ, Ara-C and 6-thioguanine (6TG), and was followed by 2 intensification courses combining High-dose Ara-C with respectively MTZ or VP 16. Maintenance therapy associated 6TG, Ara-C and MTZ up to a cumulative dose of 150 mg/m2. 91 patients are evaluable: 70 (76.9%) achieved complete remission, 59 (64.8%) after induction alone. There were 7 early deaths, 5 deaths in complete remission, and 17 relapses. Major toxic side effects were observed during the consolidation phase, mainly infectious complications, and the median duration of neutropenia was 82 days in this phase, leading to decrease the MTZ dose from 10 to 8 mg/m2. The event-free survival at three years is 38%. Cardiac toxicity is presently absent in children without previous cardiopathy.

Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Children Leukemia Cooperative Group.

We present here the long-term results of three randomized clinical trials conducted on children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1983 and 1998 by the Children Leukemia Cooperative Group (CLCG) from EORTC. In study 58831/32, the overall event-free survival (EFS) rates (+/- s.e.) at 6 and 10 years were 66% +/- 1.8% and 65% +/- 1.8%, respectively, and the risk of isolated central nervous system (CNS) relapse was 6% +/- 1% and 7% +/- 1%, respectively. In patients with a standard risk of relapse the omission of cyclophosphamide had no adverse effect on disease-free survival rates at 10 years (trial 58831). In medium- and high-risk patients the omission of radiotherapy did not increase the risk of CNS or systemic relapse (trial 58832). In study 58881 (1989-1998) the overall EFS rate at 8 years was 68.4% +/- 1.2% and the risk of isolated CNS relapse was 4.2%+/-0.5%. In this trial which adressed three randomized questions, the following results were obtained: the combination of cytarabine at high doses with methotrexate at high doses during interval therapy did not improve prognosis. The addition of 6-mercaptopurine iv during maintenance increased the risk of late relapse. E. coli asparaginase was more toxic and has a higher efficacy than Erwinia asparaginase. Leukocyte counts >100 x 10(9)/l, specific genetic abnormalities, a poor initial response to steroids or a high level of minimal residual disease at early time points were consistently associated with an adverse prognosis in the 58881 trial.

[Evans' syndrome: a retrospective study from the ship (French Society of Pediatric Hematology and Immunology) (36 cases)]. / Syndrome d'Evans: étude rétrospective de la société d'hématologie et d'immunologie pédiatrique (36 cas).

UNLABELLED: Evans' Syndrome (ES) is defined as the combination of immune thrombocytopenia (ITP) and autoimmune haemolytic anemia (AIHA), in the absence of any known underlying etiology. Pathophysiology, epidemiology and outcome remain unclear. POPULATION: Thirty-six children (20 male, 16 female), who were diagnosed in the SHIP french centres (Société d'hématologie et d'immunologie pédiatrique) between 1990 and 2002 with ES, were included in this retrospective study. RESULTS: Median age at diagnosis was 4 years. In 21 children, ES occurred in the setting of consanguinity, family history of autoimmune/inflammatory disease, associated autoimmune disorder or immunoregulatory abnormalities (serum imunoglobulins, peripheral blood lymphocytes subsets, low level of the C3-C4 complement components, nuclear antibodies). Several successive treatments were used in this serie (median: 3, range: 0-10) including corticosteroid therapy (35/36), intravenous immunoglobulins (32/36), immunosuppressive agents (14/36), splenectomy (9/36) and anti CD 20 monoclonal antibodies (6/36). Patients with a low level of serum immunoglobulins were more often non-responders to corticosteroidtherapy/intravenous immunoglobulins and required more frequently further therapy (P=0.03). Three patients died (intracranial bleeding, N=2, Guillain-Barre syndrome; N=1). CONCLUSION: ES was a severe, life-threatening disease, requiring aggressive immunosuppressive therapy in as many as half the patients. Our forthcoming study aims to (i) describe homogeneously-studied and prospectively-analysed cohort of childhood ES, (ii) separate ES from specific immune deficiency (especially fas gene mutations), generalised autoimmune/inflammatory disorders and genetic diseases, (iii) identify well-defined ES subsets, (iv) establish prognostic factors and optimal treatment within these subsets.

CSF drug levels for children with acute lymphoblastic leukemia treated by 5 g/m2 methotrexate. A study from the EORTC Children's Leukemia Cooperative Group.

A multicenter EORTC study was conducted in children with acute lymphocytic leukemia to determine whether 5 g/m2 of methotrexate (MTX) (24 h i.v. infusion, four cycles) is an appropriate dosage for obtaining CSF drug concentrations approaching the critical cytotoxic level of 10(-6) M. A total of 193 cycles were analyzed for 58 patients. At the end of the 24 h infusion, the mean MTX serum level was 65.27 +/- 33.11 microM; the mean CSF MTX level was 1.47 +/- 1.1 microM; no significant difference in CSF MTX levels was observed between patients with (n = 20) and those without i.v. Ara-C (n = 38). The mean CSF MTX/serum MTX ratio was 0.029 +/- 0.027. CSF drug concentrations greater than or equal to 10(-6) M were achieved in 81% of the courses. The highest level was 8.4 X 10(-6) M. Only 5% of patients failed to achieve this drug concentration in at least one cycle. No significant correlation was observed between blood and CSF MTX levels. Mean CSF MTX levels were comparable from one cycle to another.

The Children Leukemia Group: 30 years of research and achievements.

The EORTC Children Leukemia Group (CLG) is part of the offspring of the EORTC Hemopathies Working Party which in 1978 split into a paediatric and to an 'adult' branch. At that time, the Berlin-Frankfurt-Munster (BFM) designed by H. Riehm for acute lymphoblastic leukaemia (ALL) appeared much more efficacious than all others and the CLG decided to adapt that treatment strategy for its own clinical trials. The main results of these may be summarised as follows:for standard risk patients, the deletion of cyclophosphamide from consolidation and reconsolidation courses does not jeopardise the patient's outcomefor medium- and high-risk patients receiving high-dose methotrexate (MTX), cranial radiotherapy is superfluouswith the dose scheduling of the BFM regimen, E-Coli L-Asparaginase is more efficacious than Erwinia L-Asparaginasethe addition of monthly intravenous (i.v.) 6-mercaptopurine to conventional maintenance chemotherapy is detrimentalthe assessment by quantitative polymerase chain reaction (PCR) of minimal residual disease at completion of induction is feasible in a cooperative setting and can be used as a powerful and independent prognostic factor. The CLG also conducted clinical studies of acute myeloblastic leukaemia. Since 1989, lymphoblastic non-Hodgkin's lymphomas have been treated within the ALL trials. The CLG collaborates with other Groups within the I-BFM Study Group and participants in the meta-analytic studies conducted by the Oxford team by the Oxford Children ALL Collaborative Group.

Juvenile myelomonocytic leukemia: analyses of treatment results in the EORTC Children's Leukemia Cooperative Group (CLCG).

Forty-six children with juvenile myelomonocytic leukemia (JMML) diagnosed between 1978 and 1993 in 12 centers were retrospectively studied. There is no evidence that any conventional treatment influences the long-term evolution of JMML. Among 28 patients treated without bone marrow transplantation (BMT), 26 died (median survival: 17 months), two are alive, one in complete remission (CR) after intensive chemotherapy. Allogenic BMT is the best treatment: 18 patients underwent BMT, 11 are in CR (at 9, 15, 22, 25, 41, 45, 49, 53, 66, 90 and 108 months). Conditioning regimens using chemotherapy alone may cure some patients (3/6) occasionally despite autologous reconstitution (1/3); if relapse occurs, a second BMT may be curative (2/3). Among the 12 patients conditioned immediately with TBI, six are in CR, one is in relapse, five died (one of them in durable autologus CR from Schwannoma). It is our opinion that splenectomy is of therapeutic value and seems not to have influenced the incidence of infections complications. We found no argument in favor of intensive chemotherapy before conditioning. Results with HLA-matched unrelated donors are satisfactory. One patient relapsed at 4 months after an unrelated BMT and entered a new CR after discontinuation of cyclosporine.

Chromosomal changes in a documented case of malignant histiocytosis: significance of polyploidy.

A case of malignant histiocytosis was studied by cytology, cytochemistry, electron microscopy, and cytogenetics. It was shown that the malignant cells expressed a fully differentiated histiocytic pattern with high macrophagic activity. This correlated with the presence of polyploid metaphases. The significance of polyploid cells in the definition of malignant histiocytosis is discussed.

Chromosomal subclonal evolution in paroxysmal nocturnal hemoglobinuria evolving into acute megakaryoblastic leukemia.

Four cytogenetic studies were performed in the course of a paroxysmal nocturnal hemoglobinuria evolving into acute megakaryoblastic leukemia. The clonal evolution was characterized by a unique structural change (9p) at the time of diagnosis, heralding an accelerated and complex karyotypic alteration including 5q-, 12p-, +21, -5, -7. At the terminal phase, the initial population was replaced within 1 week by a new overgrowing clone with -5, +8, +17. This suggests that the paroxysmal nocturnal hemoglobinuria-associated preleukemia and leukemic states share with acute nonlymphocytic leukemia the same nonrandom chromosomal changes.

Initial chemotherapy including ifosfamide in the management of Ewing's sarcoma: preliminary results. A protocol of the French Pediatric Oncology Society (SFOP).

Phase II studies using ifosfamide both alone and combined with vindesine and cisplatin have shown the effectiveness of this drug in patients with Ewing's sarcoma (ES) who had relapsed during VAC (vincristine, actinomycin, cyclosphosphamide)/VAd (vincristine, Adriamycin) therapy. In November 1984, these results led the SFOP to adopt a protocol consisting of (1) initial chemotherapy with three cycles of IVA (ifosfamide, 3 g/m2 on days 1 and 2; actinomycin D, 750 mg/m2 on days 1-3; vincristine, 1.5 mg/m2 on day 1) alternating every 3 weeks with IVAd (vincristine on day 22; ifosfamide on days 21-23; Adriamycin, 60 mg/m2 on day 22); (2) radical surgery if possible; (3) local radiotherapy (RT); and (4) maintenance chemotherapy with alternating IVA and VAd (vincristine, Adriamycin) for up to 9 months. In May 1987, 87 patients with previously untreated ES entered the study; 61 had localized ES. To date, 54 patients with localized disease and 22 with metastatic disease have finished initial chemotherapy; 40 patients with localized disease have been evaluated. In all, 28 patients (70%) were in complete remission (17 patients) or had a tumor regression of greater than 50% 11 patients) and were considered to be good responders; 12 patients were considered to be poor responders. After local radiotherapy in all but 7 patients and surgical resection in 29, 52 of 54 were considered to be in clinical remission. A total of 13 patients with metastatic disease were good responders at the completion of the initial chemotherapy. These results confirm the efficacy of primary chemotherapy using ifosfamide for the treatment of ES.

A case of an exceptionally high level of urinary-4-hydroxyproline containing polypeptides.

The determination of total urinary-4-hydroxyproline in an adolescent showed a very high excretion of hydroxyproline containing peptides: 26.2 mmol/24 h. Estimation of total urinary 3-hydroxyproline and peptide fractionation on Biogel P 2 demonstrated unusual features. Such cases are of great interest for structural studies of the urinary polypeptides and understanding of collagen catabolism.

Neoadjuvant chemotherapy for extensive unilateral retinoblastoma.

AIM: The role of neoadjuvant chemotherapy was studied when first line enucleation cannot be safely performed in unilateral extensive retinoblastoma (major buphthalmia or radiologically detectable optic nerve involvement). METHODS: Six patients, referred for unilateral retinoblastoma, presented with major buphthalmia (two) or optic nerve invasion (four): they were treated by neoadjuvant chemotherapy using etoposide and carboplatin. RESULTS: Good tumour response was observed in the two patients with buphthalmia and in three of four cases with optic nerve involvement. Meningeal progressive disease was observed in the last patient. The five patients without disease progression were then operated on: anterior enucleation in the patients with buphthalmia and enucleation via a double neurosurgical and ophthalmological approach with prechiasmatic optic nerve section in the other three cases. Postoperative chemotherapy was performed in these five patients. Local radiotherapy to the chiasmatic region and posterior part of the optic canal was necessary in only one patient. The non-operated patient died with disease progression 6 months after the diagnosis. The other five patients are alive with a follow up of 12, 15, 21, 36, and 40 months after stopping treatment. CONCLUSION: Neoadjuvant chemotherapy can be useful in extensive unilateral retinoblastoma with buphthalmia and/or radiological optic nerve invasion at diagnosis.

[Interference of anaesthesia and transfusion on rheological parameters (author's transl)]. / Interférence de l'anesthésie et de la transfusion sur les paramètres rhéologiques.

This study was designed to investigate the rheological and plasmatic parameters from multiple transfused patients and patients undergoing surgery non transfused. Blood filtrability compared with the erythrocyte electrophoretic mobility shows the perturbance resulting from the delay of conservation and the importance of the transfused blood. The 2-3 DPG, ATP and oxygen-hemoglobin affinity suggest the excellent recuperation of the erythrocyte metabolic function in vitro. The rheological parameters seems to be a good mean in the supervision of red massive transfusion blood cell.

[Pitfalls of hematopoietic growth factors on MR images]. / Images pièges induites en IRM par les facteurs de croissance hématopoïétiques.

We report the effects of hematopoietic growth factors on MR signal intensity of bone marrow in 2 children undergoing chemotherapy for musculoskeletal malignancies. The two patients with initially fatty marrow had signal intensity changes: diffuse decreased signal of the distal femoral metaphysis and patchy areas in the diaphysis of both tibia and fibula, simulating metastases. These changes coincided with dramatic increase in neutrophil counts. Technetium 99 skeletal scintigraphy was normal. After a three year follow-up the patients are in good health.

Neurosurgery at an earlier stage of Parkinson disease: a randomized, controlled trial.

BACKGROUND: Stimulation of the subthalamic nucleus is an effective treatment for advanced Parkinson disease (PD) and is currently performed after a mean disease duration of 14 years, when severe motor complications have resulted in marked loss of quality of life. We examined whether surgery at an early stage would maintain quality of life as well as improve motor function. METHODS: Twenty patients with PD of short duration (time elapsed since first symptom +/- SD: 6.8 +/- 1.0 years) with mild to moderate motor signs (Unified Parkinson's Disease Rating Scale III "off" medication: 29 +/- 12) who responded well to levodopa treatment were included in pairs, matched for age, duration and severity of disease, and impairment in socioprofessional functioning. Patients were prospectively randomized to undergo bilateral subthalamic nucleus stimulation (n = 10) or receive optimized medical treatment (n = 10). Parkinsonian motor scores, quality of life, cognition, and psychiatric morbidity were assessed at inclusion and at 6, 12, and 18 months after randomization. RESULTS: Quality of life was improved by 24% in surgical and 0% in nonsurgical patients (p < 0.05). After 18 months, the severity of parkinsonian motor signs "off" medication, levodopa-induced motor complications, and daily levodopa dose were reduced by 69%, 83%, and 57% in operated patients and increased by 29%, 15%, and 12% in the group with medical treatment only (p < 0.001). Adverse events were mild or transient, and overall psychiatric morbidity and anxiety improved in the surgical group. CONCLUSIONS: Subthalamic nucleus stimulation should be considered a therapeutic option early in the course of Parkinson disease.