Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia.

Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1's critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias.

IBZM SPECT imaging of striatal dopamine-2 receptors in psychotic patients treated with the novel antipsychotic substance quetiapine in comparison to clozapine and haloperidol.

We investigated the striatal dopamine-2 (D2) receptor occupancy caused by different antipsychotic substances in 18 psychotic patients (16 with schizophrenic and two with schizoaffective disorder according to DSM-IV) with single photon emission computed tomography (SPECT) using 123I-iodobenzamide (IBZM) as tracer substance. Four patients were treated with the novel antipsychotic compound quetiapine (300-700 mg/day), six with clozapine (300-600 mg/ day) and eight with haloperidol (10-20 mg/day). They were compared with eight healthy controls. Measurement of S/F ratios and consecutive calculation of D2 receptor occupancy revealed a significantly lower striatal D2 occupancy rate with quetiapine and clozapine in comparison to haloperidol. In correspondence with the low striatal D2 receptor occupancy rates and again in contrast to the haloperidol treatment group, there were no extrapyramidal motor side-effects (EPS) in the quetiapine and clozapine treatment groups. Therefore, the reported data support the position that quetiapine can be considered to be an atypical antipsychotic substance due to its relatively weak striatal D2 receptor blocking property and therefore its low propensity to induce EPS.

Remission of severe tardive dyskinesia in a schizophrenic patient treated with the atypical antipsychotic substance quetiapine.

In a single inpatient case study, a schizophrenic patient with tardive dyskinesia after prolonged treatment with typical neuroleptics was treated with the new atypical neuroleptic quetiapine, a dibenzothiazepin-derivative. Within 2 weeks of treatment with quetiapine, symptoms of tardive dyskinesia improved; 10 weeks after starting treatment tardive dyskinesia stopped completely. Over the same period, dopamine D2 receptor occupancy decreased substantially, as measured by IBZM-SPECT after 14 and 77 days of treatment.

Striatal dopamine-2 receptor occupancy in psychotic patients treated with risperidone.

Seventeen psychiatric patients (11 with schizophrenia, 5 with other psychotic disorders, and 1 with obsessive-compulsive disorder) were examined by single photon emission computed tomography with 123I-iodobenzamide (IBZM) as tracer. Patients were treated with risperidone in two different dosage groups (3 mg and 8 mg) and haloperidol (10-20 mg) and compared with eight healthy control subjects. There was a statistically significant difference in basal ganglia/frontal cortex ratios of IBZM binding between controls and all treatment groups. A statistically significant difference was also found concerning these ratios and percentage of dopamine D2 receptor occupancy rates between the treatment groups with lowest ratios and highest percentage of D2 receptor occupancy in the group of patients treated with haloperidol, followed by the group treated with 8 mg of risperidone and the group treated with 3 mg of risperidone.

Pediatric patient-controlled analgesia: enhancing the self-care construct.

A review and research critique of nine medical and nursing studies indicates the successful use of pediatric patient-controlled analgesia (PCA). Orem's Self-Care Construct theoretically provides a nursing framework for analysis of these studies. Additionally, parental involvement in their child's pain control experience is examined, implying a new arena for nursing research.

IHS criteria for migraine and tension-type headache in children and adolescents.

We investigated the influence of age on the IHS criteria for migraine and tension-type headache in 437 consecutive children and adolescents and found the following age-associated statistically significant differences: migraine duration, occurrence of migraine aura, and bilateral location of tension-type headache were more often fulfilled by adolescents, whereas aggravation of headache by physical activity (in migrainous disorder) and photophobia (in migraine with aura) were more often fulfilled by children. Accordingly, there are only a few differences concerning the fulfillment of the IHS criteria for migraine and tension-type headache in children and adolescents. Independent of age, the intensity of headache and the presence or absence of nausea are most important for differentiating the two major types of idiopathic headache. The sensitivity of the IHS criteria for migraine could be increased by reducing the minimum duration of migraine and by allowing the diagnosis of migraine when severe headache is associated with nausea, even though the criteria of location, quality, and aggravation by physical activity are not fulfilled.

Magnetic resonance imaging for recurrent headache in childhood and adolescence.

We investigated 429 consecutive patients, aged 5 to 18 (mean: 11.0 +/- 3.1) years, diagnosed with migraine or tension-type headache. The patients underwent either MRI or exclusively clinical follow-up examinations. Magnetic resonance imaging revealed normal findings in 82.3% and structural changes in 17.7%. However, the vast majority of these changes had minimal or no pathological relevance, and a causal relationship to the patient's headache could not be proven in any case. In the non-MRI group, clinical follow-up examinations confirmed the initial diagnosis in all patients and MRI was not required in any of these subjects. In conclusion, our study shows a poor relation between recurrent headache fulfilling the criteria of migraine and tension-type headache and structural changes incidentally detected by MRI. In addition, it suggests that clinical follow-up examinations are reliable. Accordingly, MRI is not required for routine examination of recurrent headache in children and adolescents, but it should be performed in patients with abnormal neurological findings, atypical headache pattern, or significant change of preexisting headache.

Psychosocial factors in children and adolescents with migraine and tension-type headache: a controlled study and review of the literature.

We investigated 341 children and adolescents to evaluate the relevance of psychosocial factors in idiopathic headache. According to the criteria of the International Headache Society, 151 subjects had migraine and 94 had tension-type headache (TTH). Ninety-six subjects were headache-free controls. Psychosocial factors covered family and housing conditions, school problems, relations in the peer group, and several other items. We found that migraine patients did not differ from headache-free controls. Patients with TTH more often had divorced parents than the headache-free controls, and they had fewer peer relations than migraineurs and controls. In addition, migraine patients were significantly more often absent from school due to headache. All other psychosocial factors failed to discriminate between the three study groups. In conclusion, this controlled study in children and adolescents suggests that migraine is not related to family and housing conditions, school situation, or peer relations, whereas TTH is associated with a higher rate of divorced parents and fewer peer relations.

IHS criteria and gender: a study on migraine and tension-type headache in children and adolescents.

The aim of this study was to investigate whether the IHS criteria for migraine and tension-type headache depend on gender. Among 409 children and adolescents with recurrent idiopathic headache seen at a university outpatient clinic, girls had significantly more often migraine with aura. Also, there was a trend towards a higher frequency of tension-type headache in girls. In migraine, aggravation of headache by physical activity and occurrence of aura symptoms were more common in females, whereas vomiting and phonophobia occurred more often in males. In tension-type headache, females more often reported mild intensity of headache. All other criteria were similar in both sexes. Age influenced the expression of some of the accompanying symptoms in the various types of migraine, but had only minimal influence on other diagnostic criteria of migraine and tension-type headache in females as well as in males. Our study suggests that the frequency of migraine (except that of migraine with aura) is similar among girls and boys, that tension-type headache may occur more often in girls, and that gender has some influence on the IHS criteria for migraine, but almost no influence on those of tension-type headache.

Diagnosis of headache in childhood and adolescence: a study in 437 patients.

We investigated whether the criteria for idiopathic headache published by the International Headache Society (IHS) are useful in childhood and adolescence and compared the diagnoses according to this classification with those of Vahlquist. We used a semi-structured questionnaire to examine a total of 437 children and adolescents referred consecutively to a headache outpatient clinic. Twenty-eight of 437 patients were excluded because of symptomatic or unclassifiable headache. Of 409 patients with idiopathic headache, 70.4% had definite migraine or tension-type headache (IHS 1.1, 1.2, 2.1, 2.2), 20.5% had a migrainous disorder (IHS 1.7) and 9.1% had headache of the tension-type not fulfilling the criteria (IHS 2.3). In the differential diagnosis of migraine and tension-type headache the intensity of pain, aggravation of headache by physical activity, nausea and vomiting were the most important features. The quality of pain, photo- and phonophobia were less helpful and location least important. The duration of migraine attacks was less than 2 h in 19.0% of the migraine patients. In general, the diagnostic criteria of migraine were highly specific but less sensitive, and those of tension-type headache highly sensitive but less specific. The agreement between IHS criteria and those of Vahlquist was marked (kappa = 0.57). We conclude that the IHS criteria are useful for classifying headache in children and adolescents referred to a headache outpatient clinic. A forthcoming modification of the IHS criteria should consider a reduction of the minimum duration of migraine attacks from 2 h to 1 h and should try to increase the sensitivity of the criteria for migraine and the specificity of the criteria for tension-type headache.