Molecular analysis and genotype-phenotype correlation of Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) features hypoplastic anemia and congenital malformations, largely caused by mutations in various ribosomal proteins. The aim of this study was to characterize the spectrum of genetic lesions causing DBA and identify genotypes that correlate with phenotypes of clinical significance. Seventy-four patients with DBA from across Canada were included. Nucleotide-level mutations or large deletions were identified in 10 ribosomal genes in 45 cases. The RPS19 mutation group was associated with higher requirement for chronic treatment for anemia than other DBA groups. Patients with RPS19 mutations, however, were more likely to maintain long-term corticosteroid response without requirement for further chronic transfusions. Conversely, patients with RPL11 mutations were less likely to need chronic treatment. Birth defects, including cardiac, skeletal, hand, cleft lip or palate and genitourinary malformations, also varied among the various genetic groups. Patients with RPS19 mutations had the fewest number of defects, while patients with RPL5 had the greatest number of birth defects. This is the first study to show differences between DBA genetic groups with regards to treatment. Previously unreported differences in the rate and types of birth defects were also identified. These data allow better patient counseling, a more personalized monitoring plan, and may also suggest differential functions of DBA genes on ribosome and extra-ribosomal functions.

Image based feasibility of renal sparing surgery for very low risk unilateral Wilms tumors: a report from the Children's Oncology Group.

PURPOSE: Nephrectomy with lymph node sampling is the recommended treatment for children with unilateral Wilms tumor under the Children's Oncology Group protocols. Using radiological assessment, we determined the feasibility of performing partial nephrectomy in a select group of patients with very low risk unilateral Wilms tumor. MATERIALS AND METHODS: We reviewed imaging studies of 60 patients with a mean age of less than 2 years with very low risk unilateral Wilms tumor (mean weight less than 550 gm) to assess the feasibility of partial nephrectomy. We evaluated percentage of salvageable parenchyma, tumor location and anatomical features preventing a nephron sparing approach. RESULTS: A linear relationship exists between tumor weight and computerized tomography estimated tumor volume. Mean tumor weight in the study population was 315 gm. Partial nephrectomy was deemed feasible in only 5 of 60 patients (8%). CONCLUSIONS: When considering a select population with very low risk unilateral Wilms tumor (lower volume tumor), only a small percentage of nonpretreated patients are candidates for nephron sparing surgery.

The development of bone mineral lateralization in the arms.

UNLABELLED: Bone mineral content (BMC) is known to be greater in the dominant arm after the age of 8 years. We studied a group of children and found that BMC sidedness gradually increased up to the age of 6 years and then remained stable into late adolescence. INTRODUCTION: Bone mineral content (BMC) exhibits sidedness in the arms after the age of 8 years, but it is not known whether BMC is greater in the dominant arm from birth or whether lateralization develops in early childhood. To address this, we examined bone mineral status in relation to handedness and age. METHODS: Subjects (N = 158) were children recently initiating glucocorticoids for underlying disease (leukemia 43 %, rheumatic conditions 39 %, nephrotic syndrome 18 %). Handedness was determined by questionnaire and BMC by dual-energy X-ray absorptiometry. RESULTS: Median age was 7.2 years (range, 1.5 to 17.0 years), 49 % was male, and the spine BMD Z-score was -0.9 (SD, 1.3). By linear regression, BMC sidedness in the arms was significantly related to age (r = 0.294, p = 0.0005). Breakpoint analysis revealed two lines with a knot at 6.0 years (95 % CI, 4.5-7.5 years). The formula for the first line was: dominant:nondominant arm BMC ratio = 0.029 × age [in years] + 0.850 (r = 0.323, p = 0.017). The slope of the second line was not different from 0 (p = 0.332), while the slopes for the two lines were significantly different (p = 0.027). CONCLUSIONS: These results show that arm BMC sidedness in this patient group develops up to age 6 years and then remains stable into late adolescence. This temporal profile is consistent with mechanical stimulation of the skeleton in response to asymmetrical muscle use as handedness becomes manifest.

The use of ultrasound in endemic Burkitt lymphoma in Cameroon.

BACKGROUND: As ultrasound (US) has become more widely available in sub-Saharan Africa, emerging evidence suggests that the prevalence of abdominal disease in endemic Burkitt lymphoma (eBL) is higher than previous estimates. This retrospective chart review was designed to assess: (1) abdominal US utilisation, (2) the incidence of abdominal disease at diagnosis, (3) correlation of extent of disease at diagnosis with overall and event-free survival (EFS). PROCEDURE: The charts of 95 consecutive children with eBL diagnosed between April 2006 and 2008 and treated according to the Malawi 2002/03 protocol at the Banso Baptist Hospital in Cameroon were examined for demographics, clinical presentation, diagnostic workup and outcome. Analysis was performed using descriptive statistics, Z-tests and Student's t-tests. RESULTS: Fifty of 95 presumptive eBL patients (52.7%) had fine needle aspirate (FNA) confirmation of their tumours. Ninety-four of 95 had an US at diagnosis. US was superior to clinical exam in demonstrating abdominal disease (P < 0.001). There was no significant difference between the rates of jaw (73%) and abdominal disease (82%) identified by US at diagnosis. EFS among patients whose disease was upgraded by US (64%) was better that of the patients with clinically diagnosed stage 3 disease. CONCLUSIONS: We demonstrate that US provides more accurate staging of eBL than clinical examination. Abdominal involvement is more common than previously reported and appears to be as frequent as disease of the jaw at presentation. Further study should determine if more accurate staging with US is useful in risk-stratifying treatment.

Genetic analysis of inherited bone marrow failure syndromes from one prospective, comprehensive and population-based cohort and identification of novel mutations.

INTRODUCTION: Inherited bone marrow failure syndromes (IBMFSs) often have substantial phenotypic overlap, thus genotyping is often critical for establishing a diagnosis. OBJECTIVES AND METHODS: To determine the genetic characteristics and mutation profiles of IBMFSs, a comprehensive population-based study that prospectively enrols all typical and atypical cases without bias is required. The Canadian Inherited Marrow Failure Study is such a study, and was used to extract clinical and genetic information for patients enrolled up to May 2010. RESULTS: Among the 259 primary patients with IBMFS enrolled in the study, the most prevalent categories were Diamond-Blackfan anaemia (44 patients), Fanconi anaemia (39) and Shwachman-Diamond syndrome (35). The estimated incidence of the primary IBMFSs was 64.5 per 10(6) births, with Fanconi anaemia having the highest incidence (11.4 cases per 10(6) births). A large number of patients (70) had haematological and non-haematological features that did not fulfil the diagnostic criteria of any specific IBMFS category. Disease-causing mutations were identified in 53.5% of the 142 patients tested, and in 16 different genes. Ten novel mutations in SBDS, RPL5, FANCA, FANCG, MPL and G6PT were identified. The most common mutations were nonsense (31 alleles) and splice site (28). Genetic heterogeneity of most IBMFSs was evident; however, the most commonly mutated gene was SBDS, followed by FANCA and RPS19. CONCLUSION: From this the largest published comprehensive cohort of IBMFSs, it can be concluded that recent advances have led to successful genotyping of about half of the patients. Establishing a genetic diagnosis is still challenging and there is a critical need to develop novel diagnostic tools.

Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation.

Our knowledge of the phenotypes of inherited bone marrow failure syndromes (IBMFSs) derives from case reports or case series in which only one IBMFS was studied. However, the substantial phenotypic overlap necessitates comparative analysis between the IBMFSs. Shwachman-Diamond syndrome (SDS) is an IBMFS that the appreciation of what comprises its clinical phenotype is still evolving. In this analysis we used data on 125 patients from the Canadian Inherited Marrow Failure Study (CIMFS), which is a prospective multicenter population-based study. Thirty-four cases of SDS patients were analyzed and compared to other patients with the four most common IBMFSs on the CIMFS: Diamond Blackfan anemia, Fanconi anemia (FA), Kostmann/severe congenital neutropenia and dyskeratosis congenita (DC). The diagnosis of SDS, FA and DC was often delayed relative to symptoms onset; indicating a major need for improving tools to establish a rapid diagnosis. We identified multiple phenotypic differences between SDS and other IBMFSs, including several novel differences. SBDS biallelic mutations were less frequent than in previous reports (81%). Importantly, compared to patients with biallelic mutations, patients with wild type SBDS had more severe hematological disease but milder pancreatic disease. In conclusion, comprehensive study of the IBMFSs can provide useful comparative data between the disorders. SBDS-negative SDS patients may have more severe hematological failure and milder pancreatic disease.

Failure to report and provide commentary on research ethics board approval and informed consent in medical journals.

BACKGROUND: The Declaration of Helsinki prohibits the publication of articles that do not meet defined ethical standards for reporting of research ethics board (REB) approval and informed consent. Despite this prohibition and a call to highlight the deficiency for the reader, articles with potential ethical shortcomings continue to be published. OBJECTIVE: To determine what proportion of articles in major medical journals lack statements confirming REB approval and informed consent, and whether accompanying commentary alerts readers to this deficiency. DESIGN: Retrospective, observational study. SETTING: Online review of five major medical journals. POPULATION: All clinical research articles published online between 1 January 2005 and 31 December 2006 in the BMJ, Lancet, Annals of Internal Medicine, JAMA and the New England Journal of Medicine. MEASUREMENTS: Statement of REB approval and informed consent. RESULTS: Of 1780 articles reviewed, 1133 (63.7%) met inclusion criteria (manuscripts reporting human subjects, human tissue or identifiable personal data research), 36 (3.2%) articles lacked a statement of REB approval, 62 (5.5%) lacked disclosure of informed consent and 15 (1.3%) articles lacked both. Articles that did not state REB approval were associated with not stating informed consent (p<0.001). There were no editorial comments to alert readers to the lack of either REB approval or informed consent statements associated with any of the deficient articles. CONCLUSIONS: Articles that lack explicit statements of REB approval and informed consent are infrequent but continue to be published in major medical journals without editorial statements to alert the reader to this deficiency.

The return of research results to participants: pilot questionnaire of adolescents and parents of children with cancer.

PURPOSE: The offer to return research results to participants is increasingly recognized as an ethical obligation, although few researchers routinely return results. We examined the needs and attitudes of parents of children with cancer and of adolescents with cancer to the return of research results. METHODS: Seven experts in research ethics scored content validity on parent and adolescent questionnaires previously developed through focus group and phone interviews. The questionnaires were revised and provided to 30 parents and 10 adolescents in a tertiary care oncology setting. RESULTS: The content validity index for individual questions and the overall questionnaires scored as 0.86 for both questionnaires. All 30 parents and 10 adolescents who agreed to participate returned questionnaires. The majority (>95%) indicated that they had a strong or very strong right to receive results. Letter or e-mail was a satisfactory means to return results described as good or neutral (66% parents, 100% adolescents) but more participants wished face-to-face disclosure of results with negative implications (50% parents, 60% adolescents). Very few wanted results disseminated through a Web site. The majority acknowledged the need for peer-review before disclosure (60% of adolescents and parents) but did not want "to be the last to know." CONCLUSIONS: Our data suggest that pediatric oncology patients and parents of children with cancer strongly feel that they have a right to research results, and that they wish to receive these in a timely manner.

Safety and pharmacokinetics of temozolomide using a dose-escalation, metronomic schedule in recurrent paediatric brain tumours.

The aims of this study were to determine the maximum tolerated dose (MTD), toxicity and pharmacokinetics of oral temozolomide administered over 42 d in children with recurrent/refractory brain tumours. Cohorts of 3-6 patients were treated for 42 d, followed by a 7-d rest period for a maximum of 6 cycles. Patients were stratified as heavily pre-treated (HPT) and non-heavily pre-treated (NHPT). Starting doses were 50 mg/m2 (HPT) or 75 mg/m2 (NHPT). Out of 28 patients enrolled, 20 were evaluable for toxicity and 19 for pharmacokinetics. Three patients in the NHPT group developed grade 3/4 haematological toxicity, 2 experienced dose-limiting toxicity (thrombocytopenia) at 100 mg/m2, and 9/20 developed grade 3 lymphopenia. MTD in both strata was 85 mg/m2. Responses were observed in 4 patients: 2 complete responses (CR) in medulloblastoma and supratentorial primitive neuroectodermal tumours (PNET), and 2 partial responses (PR) in high-grade glioma, respectively. Overall cumulative exposure was at least 1.5 times higher than in the 5-d administration schedule. In conclusion, the recommended dose of temozolomide is 85 mg/m2 x 42 d. Dose-limiting toxicities are thrombocytopenia and lymphopenia. The observed response rate warrants phase II studies.

Disease progression in recently diagnosed patients with inherited marrow failure syndromes: a Canadian Inherited Marrow Failure Registry (CIMFR) report.

BACKGROUND: Inherited bone marrow failure syndromes (IMFSs) are genetic disorders characterized by defective single-lineage or multi-lineage hematopoiesis. IMFS patients are at risk for severe cytopenias, development of marrow cytogenetic abnormalities (MCA), myelodysplasia (MDS), and malignancy. The rate of disease progression and proportion of patients at risk for these complications is currently unclear. We examined recently diagnosed IMFS patients to determine distribution of diagnoses, disease progression and development of significant outcomes. METHODS: The CIMFR is a prospective multi-center study established in 2001 to register all IMFS patients in Canada. Analysis was restricted to patients diagnosed after November 30, 1997. Summary statistics were used to depict the study population while survival was described using the Kaplan-Meier method. RESULTS: 74 CIMFR patients were considered recently diagnosed. Median age at diagnosis was 2.7 years (range, birth to 40.6). Annual follow-up data were available for 53 (72%) patients. The five most prevalent diagnoses were Fanconi anemia (FA), Shwachman-Diamond syndrome (SDS), Diamond-Blackfan anemia (DBA), dyskeratosis congenita (DKC), and Kostmann's neutropenia (KS). Eighteen (24%) patients were unclassifiable. Twenty-eight (53%) follow-up patients had disease progression as indicated by new or worsening cytopenias, new marrow changes, or initiation of transfusion support and/or medical therapy. Fourteen (19%) fulfilled minimal diagnostic criteria for myelodysplasia. Eleven patients had hematopoietic stem cell transplantation (HSCT) by first follow-up. Five patients have died. Survival at 36 months is 89.8 +/- 5.7%. CONCLUSIONS: IMFS patients are often diagnosed at a young age. The relative distribution of diagnoses is similar to previous reviews of published cases; however, 25% of patients are currently unclassifiable. Disease progression has occurred in approximately 50% of follow-up patients. Early mortality is noted. Continued prospective observation of these patients is warranted.

Informing research participants of research results: analysis of Canadian university based research ethics board policies.

BACKGROUND: Despite potential benefits of the return of research results to research participants, the TriCouncil Policy Statement (TCPS), which reflects Canadian regulatory ethical requirements, does not require this. The policies of Canadian research ethics boards (REBs) are unknown. OBJECTIVES: To examine the policies of Canadian university based REBs regarding returning results to research participants, and to ascertain if the presence/absence of a policy may be influenced by REB member composition. DESIGN: Email survey of the coordinators of Canadian university based REBs to determine the presence/absence of a policy on return of research results to research participants both during an ongoing study and at conclusion. REB coordinators were asked to return a copy of the policy or guidelines and to describe the member composition of their REB. FINDINGS: Of 50 REBs that were contacted 34 (68%) responded and 22 (64.7%) met the inclusion criteria. Two (9.1%) had a policy that governed the return of research results while on a study, and seven (31.8%) following the completion of a study. Presence of an ethicist or a lawyer on the REB did not influence the presence/absence of such policies. No REBs had specific guidelines describing how participants should be informed of results. CONCLUSIONS: Most REBs did not require researchers to disclose study results to research participants either during or following a study. Thus this study identifies an ethical shortcoming in the conduct of human research in Canada. It has also demonstrated that there are no clear recommendations by REBs to facilitate the return of results to participants following research projects.

Sentinel lymph node mapping and biopsy: a potentially valuable tool in the management of childhood extremity rhabdomyosarcoma.

Multimodal therapy, involving surgery, chemotherapy and radiation, now dominates the management of rhabdomyosarcoma (RMS) in childhood. Yet, despite improvements in these practices, extremity tumors continue to fare relatively poorly. Several investigators have identified prognostic factors that can be used to direct therapy and predict outcome. These factors include histology and metastatic disease, the latter requiring accurate staging to identify. The presence of lymph node metastases has been shown to be of prognostic significance and is incorporated into pre-treatment staging schemes. Up to 50% of all surgically evaluated nodes and 17% of clinically negative nodes in extremity RMS may harbor tumor, underscoring the increased risk of understaging the disease if accurate lymph node dissection is not undertaken. Despite its importance, there appears to be no standard format by which regional nodal status is evaluated in extremity RMS. Sentinel lymph node mapping and biopsy are a minimally invasive technique, currently used in the staging of adult breast cancer and melanoma. In adults, the technique is associated with optimum nodal yield and low morbidity. We describe a case in which sentinel node mapping and dissection were used to easily and accurately stage a distal upper extremity alveolar RMS in a child with clinically and radiologically negative regional lymph nodes. The procedure yielded no positive nodes, was associated with no morbidity and spared the child more extensive radiotherapy. We propose the further evaluation of this simple and innovative technique in the overall management of this childhood malignancy.

Detection of a novel t(6;15)(q21;q21) in a pediatric Wilms tumor.

We report a novel cytogenetic finding in a favorable histology Wilms tumor occurring in a 4-month-old boy. Karyotypic analysis demonstrated a t(6;15)(q21;q21) in all tumor cells examined. This was confirmed using fluorescence in situ hybridization analysis. Molecular analysis of this rearrangement may provide clues to understanding the pathobiology of Wilms tumor.

Concurrent acute lymphoblastic leukemia and juvenile pilocytic astrocytoma in a pediatric patient.

The concurrence of acute lymphoblastic leukemia (ALL) and an asymptomatic juvenile pilocytic astrocytoma is described. A 6-year-old boy without clinical evidence of neurofibromatosis had a juvenile pilocytic astrocytoma diagnosed on radiologic examination and before treatment of acute pre-B cell lymphoblastic leukemia. The patient has had a partial resection of the astrocytoma and is 9 months into treatment of his ALL, which is in complete remission. p53 gene mutation was not identified in this patient. The concurrent diagnosis before treatment of ALL and juvenile pilocytic astrocytoma, the latter normally an indolent tumor, suggests that some cases of astrocytoma previously ascribed to radiotherapy or other treatment may in fact be caused by other factors.

Intrathecal vincristine: an analysis of reasons for recurrent fatal chemotherapeutic error with recommendations for prevention.

PURPOSE: Accidental intrathecal vincristine instillation is usually a fatal error. The authors report an analysis of a patient and suggest means with which to reduce such errors. PATIENTS AND METHODS: A 7-year-old girl with recurrent acute lymphoblastic leukemia was inadvertently injected intrathecally with 1.5 mg vincristine. A detailed analysis of the events leading to this error and a review of all reported cases in the English literature were undertaken. RESULTS: Reasons for errors reported by us and other institutions included mistaking vincristine for an intended intrathecal drug, assuming vincristine was an additional drug to be injected, not checking physician orders, mistaken route of administration, and mislabeling of syringes. CONCLUSION: Intrathecal injection of vincristine may be the end-result of a series of systems errors. Protocol recommendations to reduce the likelihood of this error are presented.

Alternative and complementary therapy use in pediatric oncology patients in British Columbia: prevalence and reasons for use and nonuse.

PURPOSE: Alternative and complementary therapies are infrequently studied in pediatric populations. We performed a population-based survey to aid health care workers in identifying and counseling parents who may use these remedies. PATIENTS AND METHODS: We retrospectively surveyed the parents of 583 pediatric patients diagnosed with cancer in British Columbia between 1989 and 1995. Prevalence and factors that influence the use and nonuse of alternative and complementary therapies were estimated. RESULTS: Alternative and complementary therapies were used by 42% of 366 respondents. Herbal teas, plant extracts, and therapeutic vitamins were the most commonly used alternative therapies. Relaxation/imagery strategies, massage, and therapeutic touch were the most commonly used complementary techniques. Factors that influenced the use of alternative/complementary therapies were prior use (chi2 = 60.0, P < .0001), prior positive attitude towards these remedies (chi2 = 41.6, P < .0001), soliciting information from family and friends (chi2 = 70.5, P < .0001) or from alternative care givers (chi2 = 58.7, P < .0001), high risk of death at diagnosis (chi2 = 9.6, P < .002), and advanced education of the father (chi2 = 7.4, P < .006) or mother (chi2 = 8.6, P < .003). Parents who used alternative/complementary therapies did so in conjunction with conventional medicine (98%). Lack of knowledge and fear of interference with conventional therapies were the most common reasons cited for nonuse. No parent believed that the quality of life of their child deteriorated due to the use of alternative/complementary therapies. CONCLUSION: Alternative and complementary therapy use in pediatric oncology patients is common. Factors have been identified that may be associated with undertaking their use.

Pain management in Canadian level 3 neonatal intensive care units.

OBJECTIVE: To determine current practices in neonatal intensive care units (NICUs) of managing postoperative pain, pain associated with nonsurgical procedures and disease-related pain. DESIGN: Retrospective, self-administered descriptive mail survey. SETTING: Level 3 NICUs in Canada. PARTICIPANTS: The head nurses of the 30 Canadian level 3 NICUs in February 1992; 26 (87%) responded. MAIN OUTCOME MEASURES: Five-point Likert scale of Always (in 100% of cases), Often (in 75% to 99%), Usually (in 25% to 74%), Rarely (in 1% to 24%) and Never (in 0%). Selected items were validated through a chart review. RESULTS: Opioids were used postoperatively always or often in 93% (13/14), 88% (15/17) and 65% (11/17) of the NICUs that cared for neonates having undergone cardiac, major and minor surgery respectively. Most of the NICUs did not use paralysis or sedation alone for postoperative pain management. Local anesthesia was used always or often for emergent chest tube placement in 16% (4/25) of the NICUs, for elective chest tube placement in 48% (12/25) and for lumbar puncture in 12% (3/24). An analgesic was rarely or never used for insertion of a tracheal tube in emergent situations in 88% (23/26) of the NICUs and in elective situations in 84% (21/25); the corresponding figures for sedative use were 85% (22/26) and 73% (19/26). Only 22% (5/23) used opioids regularly in cases of nonsurgically managed necrotizing enterocolitis. Physicians alone determined the rate of opioid weaning in 54% (13/24) of the NICUs. Opioids were usually described as being weaned as tolerated. CONCLUSIONS: Analgesic use for the management of postoperative pain in neonates having undergone cardiac and major surgery is frequent but continues to be infrequent in the postoperative care of patients having undergone minor surgery in some NICUs. Procedural and disease-related pain is frequently untreated or undertreated. Guidelines for establishing a protocol to manage pain in NICUs are given.