The American Society of Pediatric Hematology/Oncology workforce assessment: Part 2-Implications for fellowship training.

The American Society of Pediatric Hematology/Oncology (ASPHO) solicited information from division directors and fellowship training program directors to capture pediatric hematology/oncology (PHO) specific workforce data of 6 years (2010-2015), in response to an increase in graduating fellows during that time. Observations included a stable number of physicians and advanced practice providers (APPs) in clinical PHO, an increased proportion of APPs hired compared to physicians, and an increase in training-level first career positions. Rapid changes in the models of PHO care have significant implications to current and future trainees and require continued analysis to understand the evolving discipline of PHO.

Maternal vitamin and iron supplementation and risk of infant leukaemia: a report from the Children's Oncology Group.

BACKGROUND: Prenatal supplementation has been inversely associated with childhood, but not with infant, leukaemia. METHODS: Mothers of 443 cases of infant leukaemia diagnosed during 1996-2006 and 324 frequency-matched controls completed interviews. Associations were evaluated by unconditional logistic regression. RESULTS: We observed no associations between prenatal vitamin (odds ratio (OR)=0.79, 95% confidence interval (CI): 0.44-1.42) or iron supplementation (OR=1.07, 95% CI: 0.75-1.52) and infant leukaemia after adjustment for race/ethnicity and income. Similar results were observed for leukaemia subtypes analysed separately. CONCLUSION: The observed null associations may be attributable to high supplementation rates and/or national fortification programmes.

Compliance with and short-term adverse events from clarithromycin versus placebo in patients with stable coronary heart disease: the CLARICOR trial.

BACKGROUND: The randomized placebo-controlled double-blind CLARICOR trial investigated the influence of clarithromycin versus placebo on cardiovascular events and mortality in patients with chronic coronary artery disease (ClinicalTrials.gov NCT 00121550). The trial randomized 2172 patients to 500 mg of clarithromycin daily versus 2200 patients to matching placebo for 14 days. This paper presents protocol-specified analysis of the patient-reported information regarding their compliance and non-serious adverse events during the 14 days of treatment as well as serious adverse events (mortality and hospitalizations) during the first 30 days after randomization. METHODS: Randomized clinical trial focusing on patient-reported information regarding their compliance and adverse events. RESULTS: Of the randomized patients, 99% reported information regarding their compliance and adverse events. A 100% tablet intake was reported by 90% of the clarithromycin group and by 93.7% of the placebo group. Of the clarithromycin patients, 39.5% reported at least one non-serious adverse event versus 25.1% of the placebo patients (P < 0.001). Gastrointestinal adverse reactions were reported 950 times by 697 patients (32.3%) in the clarithromycin group and 485 times by 390 patients (17.9%) in the placebo group (P < 0.001). No significant differences were seen in other non-serious or serious adverse events during the first month after inclusion. Short-term non-serious adverse events did not explain the previously reported long-term significantly increased mortality associated with clarithromycin. CONCLUSIONS: Gastrointestinal adverse reactions are common during clarithromycin administration, but at least half are also seen with a placebo.

The Osteoporosis Self-Assessment Tool versus alternative tests for selecting postmenopausal women for bone mineral density assessment: a comparative systematic review of accuracy.

SUMMARY: We performed a systematic review of studies comparing the Osteoporosis Self-Assessment Tool (OST) and other tests used to select women for bone mineral density (BMD) assessment. In comparative meta-analyses, we found that the accuracy of OST was similar to other tests that are based on information from the medical history. By contrast, assessment by quantitative ultrasonography at the heel was more accurate than OST in discriminating between women with high and low BMD. The methodological quality of the included studies was generally low. INTRODUCTION: Numerous tests are suggested for triaging postmenopausal women for bone mineral density (BMD) assessment by dual-energy X-ray absorptiometry. Previous studies suggest that OST, based on age and weight only, may be as accurate as more complex triage tests. We systematically compare the accuracy of OST and alternative triage tests in postmenopausal women. METHODS: We searched PubMed, Embase, Web of Science, citation lists, and conference proceedings. Our main measure of accuracy was the diagnostic odds ratio (DOR). We compared summary estimates of DOR (sDOR) for OST and alternative tests in pairwise meta-analyses by using the Moses-Littenberg approach. RESULTS: Summary estimates of DOR for OST and the clinical decision rules Simple Calculated Osteoporosis Risk Estimation (SCORE) and Osteoporosis Risk Assessment Instrument (ORAI) did not differ significantly in white women (relative sDOR: 0.57-1.17, all p >or= 0.11). By contrast, sDOR was higher for Stiffness Index assessed by calcaneal quantitative ultrasonography than for OST (relative sDOR: 1.9, p = 0.005). Studies were few in Asian and black women. Methodological quality, assessed with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist, was generally low. CONCLUSIONS: In white women, the accuracy of OST and alternative clinical decision rules was similar, whereas Stiffness Index was more accurate than OST. Low study quality renders transferability to clinical settings uncertain.

Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials.

BACKGROUND: Randomized trials without reported adequate allocation concealment have been shown to overestimate the benefit of experimental interventions. We investigated the robustness of conclusions drawn from meta-analyses to exclusion of such trials. MATERIAL: Random sample of 38 reviews from The Cochrane Library 2003, issue 2 and 32 other reviews from PubMed accessed in 2002. Eligible reviews presented a binary effect estimate from a meta-analysis of randomized controlled trials as the first statistically significant result that supported a conclusion in favour of one of the interventions. METHODS: We assessed the methods sections of the trials in each included meta-analysis for adequacy of allocation concealment. We replicated each meta-analysis using the authors' methods but included only trials that had adequate allocation concealment. Conclusions were defined as not supported if our result was not statistically significant. RESULTS: Thirty-four of the 70 meta-analyses contained a mixture of trials with unclear or inadequate concealment as well as trials with adequate allocation concealment. Four meta-analyses only contained trials with adequate concealment, and 32, only trials with unclear or inadequate concealment. When only trials with adequate concealment were included, 48 of 70 conclusions (69%; 95% confidence interval: 56-79%) lost support. The loss of support mainly reflected loss of power (the total number of patients was reduced by 49%) but also a shift in the point estimate towards a less beneficial effect. CONCLUSION: Two-thirds of conclusions in favour of one of the interventions were no longer supported if only trials with adequate allocation concealment were included.

CLL family 'Pedigree 14' revisited: 1947-2004.

The notion that inherited predisposition contributes to the development of haematological malignancies is generally thought of as being a relatively new idea. However, Videbaek made a clear enunciation of such a hypothesis in 1947, from a study of tumour incidence in relatives of patients with different leukaemias. To gain further insight into inherited susceptibility to chronic lymphocytic leukaemia (CLL), we followed up the descendants of Videbaek's 'Pedigree 14' series of families. Using the Danish medical and pedigree databases, complete tracing of 222 descendants of the original 57 family members was achieved. To date, 10 family members have been diagnosed with CLL, one with T-cell lymphoma and 17 with nonhaematological cancers, including five with breast cancer. The detailed follow up of this family provides further support for inherited predisposition to CLL and illustrates the value of follow-up studies of previously published family material for genetic analyses.

Heterogeneity in MLL/AF-4 fusion messenger RNA detected by the polymerase chain reaction in t(4;11) acute leukemia.

We have designed a single polymerase chain reaction (PCR) primer pair that detects the MLL/AF-4 fusion mRNA encoded by the derivative 11 chromosome from t(4;11)(q21;q23) leukemia cells using the reverse transcriptase PCR technique. PCR amplification was possible in seven of seven cells studied. Sequencing of the amplified products showed three different breakpoints on 11q23 and three on 4q21, resulting in six unique fusion sequences. All fusion sequences maintained an open reading frame. The areas of the MLL and AF-4 genes that are conserved in all derivative 11 fusion RNAs and therefore likely to contribute to the function of the oncogenic fusion protein are centromeric regions of MLL through exon 6 (retaining the AT hook motif) and telomeric regions of AF-4 beginning at codon 491 (containing nuclear localization and GTP-binding motifs). A single primer pair was able to detect the derivative 11 fusion transcript in seven of seven cases of t(4;11) acute leukemia tested. Given the variability shown in specific fusion sequences, studies correlating differential exon usage with clinical parameters will require different fusion-specific oligonucleotides or PCR primer pairs.

Attitudes and practices among pediatric oncologists regarding end-of-life care: results of the 1998 American Society of Clinical Oncology survey.

PURPOSE: In 1998, the American Society of Clinical Oncology (ASCO) surveyed its membership to assess the attitudes, practices, and challenges associated with end-of-life care of patients with cancer. In this report, we summarize the responses of pediatric oncologists and the implications for care of children dying from cancer. METHODS: The survey consisted of 118 questions, covering eight categories. All ASCO members in the United States, Canada, and the United Kingdom were mailed a survey, which was completed by 228 pediatric oncologists. Predictors of particular attitudes and practices were identified using stepwise logistic regression analysis. Potential predictors were age, sex, religious affiliation, importance of religious beliefs, recent death of a relative, specialty, type of practice (rural or urban, academic or nonacademic), amount of time spent in patient care, number of new patients in the past 6 months, and number of patients who died in the past year. RESULTS: Pediatric oncologists reported a lack of formal courses in pediatric palliative care, a strikingly high reliance on trial and error in learning to care for dying children, and a need for strong role models in this area. The lack of an accessible palliative care team or pain service was often identified as a barrier to good care. Communication difficulties exist between parents and oncologists, especially regarding the shift to end-of-life care and adequate pain control. CONCLUSION: Pediatric oncologists are working to integrate symptom control, psychosocial support, and palliative care into the routine care of the seriously ill child, although barriers exist that make such comprehensive care a challenge.

Cytogenetic studies of infant acute lymphoblastic leukemia: poor prognosis of infants with t(4;11) - a report of the Children's Cancer Group.

Infants less than 1 year of age at diagnosis of acute lymphoblastic leukemia (ALL) have a poor prognosis, which has been attributed primarily to a breakpoint in chromosomal band 11q23 or the MLL gene. Most infants with an 11q23 breakpoint have a t(4;11)(q21 ;q23). We studied the cytogenetics of the leukemia cells of 56 infants on CCG-1883, a single-arm clinical treatment protocol for infant ALL. Twenty-one patients had t(4;11)(q21;q23), seven had other rearrangements with breakpoints in 11q23 (other 11q23), 16 had normal chromosomes, two had t(1;19)(q32;p13), one had >50 chromosomes, and nine had non-recurring structural abnormalities. To determine whether there is a difference in outcome for infants with t(4;11), other 11q23 and the remaining patients, we compared event-free survival (EFS) and other clinical and laboratory features of the above infants. Infants without t(4;11) and those with other 11q23 rearrangements had significantly better EFS than those with t(4;11) (P= 0.007 and P= 0.02, respectively). t(4;11) correlated with age less than 6 months and with CD10 negativity, both of which also were poor prognostic indicators. After adjustment for age, there was still a significant difference in EFS between patients with t(4;11) and those with other 1lq23 rearrangements (P=0.02), and between patients with t(4;11) and those without t(4;11) (P=0.04). Among CD10 negative patients, t(4;11) was associated with a worse EFS (P=0.01). Multivariate analysis showed that after adjusting for a variety of clinical and laboratory features, t(4;11) was the most important prognostic factor for poor outcome, and patients with other 11q23 rearrangements had as good an outcome as the remaining patients without t(4;11).

Familial occurrence of migraine without aura and migraine with aura.

We report a study of 121 probands (patients) with migraine without aura (MO) and 72 probands with migraine with aura (MA), diagnosed according to the operational diagnostic criteria of the International Headache Society and selected from 35 general practices in Denmark. The probands were interviewed about the presence of MO and MA among their first-degree relatives. Compared with the general population, the first-degree relatives of probands with MO had a threefold increase of MO, and only one first-degree relative of one proband with MO had MA. First-degree relatives of probands with MA had a twofold increase of both MA and MO. Compared with the general population, few spouses had MO and MA. This threefold and twofold increase in family risk of MO and MA, combined with the lack of increased risk in spouses, strongly suggests that MO and MA are genetically determined.

DQ beta sequences in HLA-DR4 haplotypes.

A cDNA clone encoding the entire mature DQ beta chain was isolated and sequenced from the DR4-Dw14 homozygous cell line, LS40. The sequence was compared with published DQ beta sequences from cells expressing DR4-DQw3, and found to be identical. The lack of DQ beta sequence polymorphism within this serotype (to date, DQ beta sequences have been derived from five cell lines comprising three Dw subtypes) adds to the data that suggest a recent evolutionary divergence of Dw subtypes within DR4-DQw3.

Comparison of ultrasound, radiography, and clinical examination in the diagnosis of acute maxillary sinusitis: a systematic review.

The objective of this study was to assess the discriminative properties of the methods for diagnosing acute maxillary sinusitis (AMS) in unselected patients. The study design was a systematic review of evaluation studies identified by using Medline, by searching reference lists, by hand searches, and by contacting investigators. Evaluation studies were conducted anywhere in the world. Subjects were adults with suspected AMS. Main outcome measures were: sensitivity, specificity, positive and negative likelihood ratios of the primary studies, weighted means of these parameters in each comparison (clinical examination, radiography, and ultrasound compared to a reference standard in diagnosing AMS), and summary ROC curves and their Q* points where sensitivity equals specificity. For the years from 1962 to present, 49 study reports were found; 11 articles on studies that included a total of 1144 patients were eligible. Compared to sinus puncture, radiography was the most accurate method for diagnosing AMS: the Q* point on the summary ROC curve was 0.82 (95% confidence interval, CI, 0.78-0.85). Ultrasound was slightly less accurate than radiography compared to sinus puncture (Q* 0.80, 95% CI 0.76-0.83). Only two articles reported clinical examination compared to sinus puncture and the Q* for them was 0.75 (95% 0.58-0.86). Clinical examination is a rather unreliable method for diagnosing AMS, even in the hands of experienced specialists. Using radiography or ultrasound improves the accuracy of diagnosis. The diagnosis of AMS is rarely studied in primary care settings. Future comparative trials should preferably combine diagnosis and treatment, evaluating the two aspects of clinical management as unit.

AF4/FEL, a gene involved in infant leukemia: sequence variations, gene structure, and possible homology with a genomic sequence on 5q31.

The most common chromosome abnormality among infants with acute lymphoblastic leukemia is a t(4;11)(q2l;q23) and patients with this 4;11 translocation have a very poor prognosis. This unique genetic rearrangement fuses the MLL/ALL-1/HRX-Htrx gene at 11q23 with the AF4/FEL gene at 4q21. The resulting chimeric mRNAs presumably encode chimeric proteins which contribute to the leukemogenic state. The AF4 gene remains poorly understood with an unknown function. In this report, we describe the cDNA sequence information from human placental tissue where AF4 mRNA is highly expressed. We identified six intron-exon boundaries in the AF4 genomic structure and discussed more than 30 AF4 cDNA sequence variations reported in the literature. In addition, we identified three overlapping genomic sequences in GenBank entitled the "interleukin growth hormone cluster on chromosome 5q31," which, when aligned and translated, had three regions that suggested homology to the predicted AF4 protein sequence (32% amino acid sequence identity over 314 amino acids, 43% over 63 amino acids, and 50% over 40 amino acids). Of interest, this same chromosome 5q31 region has also been implicated in MLL gene rearrangements in human leukemia.

Anal cancer subtype reproducibility study.

For histological subtyping of anal squamous carcinomas the WHO advocates a six-way subdivision, but it has been suspected that the six types cannot be reliably discriminated in practice. We conducted a blinded study involving slides from 103 consecutive cases, each slide being examined by three experts (from Denmark, Australia and UK) on two occasions at least 8 months apart. Agreement on subtypes was low: 72% between rounds within pathologist, 61% between pathologists. Even for the commonest, and most stably diagnosed, type, viz. large-cell keratinising squamous carcinoma, the intra- and interpathologist frequencies of confirmation were only 81% and 71%, respectively. The pathologist marked the picture as typical and his subtype diagnosis as certain 41% of times: even then confirmation frequencies were only 88% and 74%, respectively. Calculations, including kappa analyses, suggest that 26% of the typing variation was noise. The WHO scheme must be even more unreliable in everyday practice. We finally mention a recently demonstrated link between human papilloma virus (HPV) and certain types of anal cancer, which may well provide an additional argument for revising existing subtyping schemes.

The safety of chorionic villus sampling. A synthesis of the literature.

Altogether 10 reports on the safety of chorionic villus sampling, either by the transcervical (TC) or the transabdominal (TA) approach, were reviewed and combined with our own data. After discussion of how unintended fetal loss rates are best estimated, the excess total fetal loss after TC and TA compared with amniocentesis were estimated to be 1.70% (+/- 0.65%) and practically zero (+/- 1.0%), respectively (standard errors in parentheses). The absolute risk of unintended loss after TC is +2.7% (+/- 0.7%) and after TA 1.0% (+/- 1.0%). These estimates are still too uncertain to allow precise weighting of benefits and human costs. A uniform style of reporting studies in this area is proposed.

The MLL (11q23) and AF-4 (4q21) genes disrupted in t(4;11) acute leukemia: molecular and clinical studies.

Recurring chromosomal translocations involving chromosome band 11q23 have been observed in acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML), especially AML with FAB M4 or M5 phenotype. Though numerous partner chromosomes have been documented, the t(4;11) is the translocation seen most commonly in infant ALL. t(4;11) leukemia, associated with hyperleukocytosis, hepatosplenomegaly, and central nervous system (CNS) disease, has a dismal prognosis. Leukemia with 11q23 rearrangement often shows both lymphoid and myeloid characteristics, leading to speculation that the disrupted gene is involved in lymphoid and myeloid differentiation. The genes at 11q23 and 4q21 have been cloned and sequenced; the data is consistent with a role for these genes in transcriptional regulation. Absence of molecular rearrangement of 11q23 identifies a group of infants with a good prognosis.

Molecular analysis of infant acute leukemia.

Infant acute leukemia, known to have a poor outcome with conventional therapy, usually has a molecular rearrangement at chromosome band 11q23. The 11q23 translocation partner is typically at 4q21 in infant ALL, but other 11q23 translocation partners occur in infant ALL and AML. The MLL gene at 11q23, and the AF4 gene at 4q21, have been extensively studied to identify heterogeneity of structural rearrangement and prognostic indicators, to look for clues as to etiology, and to improve therapy.

Comparison of outcome in two series of patients with severe head injuries.

A comparison is made between the outcome distributions of two Dutch series of patients with severe head injuries. Both series are taken from the same study and cover the same period (1974 to 1977). There is a large difference in survival rate between the series: 45% versus 63%. The authors present a possible method for assessing the influence of differences in initial severity of injury on outcome. It is estimated that, of the 18% difference in survival rate, 10.5% is due to differences in severity of injury on admission. The remaining 7.5% difference in survival rate is not explained, but may have been caused by unmeasured variations in the initial determination of severity of injury or by differences in effectiveness of management. The higher survival rate was achieved at the center with the more conservative management regimen. An evaluation of recent literature suggests that reports that do not find aspects of "aggressive" management beneficial are more reliable in comparing series than are those that claim improved outcome after aggressive therapy.

Phase II evaluation of interferon-alpha-2a for progressive or recurrent craniopharyngiomas.

OBJECT: Craniopharyngiomas originate from the same cells as squamous cell skin carcinoma, which can be treated successfully with interferon-alpha (IFNalpha)-2a. The authors evaluated the activity and toxicity of systemic IFN in young patients with craniopharyngiomas. METHODS: Fifteen patients between the ages of 4.2 and 19.8 years who had progressive or recurrent craniopharyngiomas were enrolled in this study. Nine of these patients had never received external-beam radiation therapy. Therapy consisted of 8,000,000 U/m2 IFNalpha-2a administered daily for 16 weeks (induction phase) followed by the same dose three times per week for an additional 32 weeks (maintenance phase). Of the 12 patients who could be evaluated, radiological studies demonstrated a response to treatment in three with predominantly cystic tumors (one minor response, one partial response, and one complete response); one of these patients also showed improvement in visual fields. The size of the cystic component of the tumors often increased temporarily during the first several months of therapy. Three patients met the criteria for progressive disease during therapy. The median time to progression was 25 months. The need for radiation therapy in patients treated with IFN was delayed for 18 to 35 months (median 25 months) in six patients. All patients developed transient flulike symptoms shortly after receiving the first dose of IFN. Other toxicities (predominantly hepatic, neurological, and cutaneous) were seen in nine (60%) of the 15 patients during the first 8 weeks of treatment but resolved after temporary discontinuation and/or dose reduction. CONCLUSIONS: Interferon-alpha-2a is active against some childhood craniopharyngiomas; its toxicity precludes administration of high daily doses, and the optimum dose level and schedule remain to be defined.

Reflexology and bronchial asthma.

Many asthma patients seek alternative or adjunctive therapies. One such modality is reflexology, whereby finger pressure is applied to certain parts of the body. The aim of the study was to examine the popular claim that reflexology treatment benefits bronchial asthma. Ten weeks of active or simulated (placebo) reflexology given by an experienced reflexologist, were compared in an otherwise blind, controlled trial of 20+20 outpatients with asthma. Objective lung function tests (peak flow morning and evening, and weekly spirometry at the clinic) did not change. Subjective scores (describing symptoms, beta2-inhalations and quality of life) and also bronchial sensitivity to histamine improved on both regimens, but no differences were found between groups receiving active or placebo reflexology. However, a trend in favour of reflexology became significant when a supplementary analysis of symptom diaries was carried out. It was accompanied by a significant pattern compatible with subconscious unblinding, in that patients tended to guess which treatment they had been receiving. No evidence was found that reflexology has a specific effect on asthma beyond placebo influence.