Purpose
Research indicates complementary and alternative medicine (CAM) use among children with cancer is common and widespread. CAM use, particularly traditional Chinese medicine (TCM), is prevalent ...in the country of origin of Chinese immigrant families, yet little is known about its use after immigrating to Canada. This paper describes 25 Chinese immigrant parents’ perception about the use of CAM in their child with cancer in Canada.
Methods
This qualitative grounded theory study is part of a larger study of the caregiving experiences of first generation Chinese and South Asian parents of children with cancer. Chinese parents of children at least 6 months post-diagnosis were recruited from four Canadian pediatric oncology centers. Interviews were conducted in English, Cantonese, or Mandarin and transcribed into English. Analysis involved coding and the use of the constant comparison method to identify important themes.
Results
In discussing their caregiving experiences, CAM emerged as an important theme. The following sub-themes were identified: (1) trust in conventional medicine to cure cancer; (2) use of dietary modifications and restrictions; (3) extent of communication with healthcare providers about TCM use; and (4) limited availability of culturally relevant information.
Conclusions
While Chinese immigrant parents in this study placed their trust in conventional medicine to treat their child, the use of food as therapy is part of their daily cultural practice. To ensure safe cancer treatment and more culturally sensitive care, it is essential for health providers to offer reliable information and encourage open discussions about CAM use with Chinese immigrant parents.
Rothia spp. (previously termed Stomatococcus) are normal flora that can cause invasive infections in immunocompromised hosts. The objective of this study was to describe infection characteristics and ...outcomes of Rothia spp. infections in a large cohort of children with newly diagnosed acute myeloid leukemia (AML). This retrospective chart review is a subanalysis of a larger study in which the aim was to identify factors associated with infection in pediatric patients with AML. Only sterile site infections occurring during chemotherapy were included. Among 578 children with AML, 17 (2.9%) children with at least 1 Rothia spp. infection were identified. All children were neutropenic at the time of infection. Eight (47%) had antecedent colitis or mucositis. Of the 17 infections, 16 were bacteremia and 1 was meningitis. Sepsis occurred in 4 patients, and 1 patient died due to infection. Rothia spp. infections are rare in pediatric AML but can cause significant morbidity and mortality. Future studies should describe trends in incidence and resistance patterns over time.
FLT3 is a highly expressed cell surface receptor in a majority of acute leukemias with near universal expression in acute myeloid leukemia (AML). High FLT3 expression level in conjunction with ...11q23/MLL-rearrangement has been associated with poor prognosis in pre-B acute lymphoblastic leukemia (ALL) and is considered a potential therapeutic target through FLT3 inhibition. In vitro studies have demonstrated enhanced sensitivity of ALL and AML cells with high FLT3 expression to the cytotoxic effects of FLT3 inhibition. Although the clinical impact of high allelic ratio FLT3/ITD has been demonstrated in AML, the significance of FLT3 expression in those without the mutation has not been well studied, and all previous studies have been limited to evaluation of FLT3 transcript levels for correlation with outcome. Here we present the results of a prospective evaluation of FLT3 cell surface protein expression (CD135) on the diagnostic leukemic blast population as determined by multi-dimensional flow cytometry (MDF) in specimens from patients treated on COG AAML0531. Of the 495 patients enrolled after September 25, 2008, 366 patients enrolled on the accompanying biology study and had diagnostic specimens for evaluation of central CD135 expression by MDF. All diagnostic specimens underwent central MDF analysis for CD135 expression. FLT3 mutation data was available on all 366 patients, 57 patients were FLT3/ITD (15.6%), 21 were FLT3/ALM (5.7%) and the remaining 290 were FLT3wild type (FLT3/WT).
There was significant variability of CD135 expression across the population with a mean fluorescence intensity (MFI) ranging from 3-232 (median 18). Median CD135 expression for those with FLT3/ITD, FLT3/ALM, FLT3/WT was 22 vs. 19 vs. 17 respectively (p=NS). Patients were divided into quartiles based on CD135 expression and clinical characteristics and outcome were correlated with CD135 expression across the four quartiles. There was not a significant difference in CD135 expression by age, gender, race, or ethnicity across the four quartiles. Those with high CD135 expression (Q4) had similar median diagnostic WBC counts as those with lower CD135 (Q1-3), although median diagnostic blast % in those in Q4 was significantly elevated (p=0.003). Nearly half of those in Q4 were FAB M5 compared to 13% in Q1-3 (p<0.001) and all those with FAB M7 had low CD135 expression (p=0.004).
Evaluation of the diagnostic cytogenetics and CD135 expression demonstrated significant correlation of CD135 expression with MLL translocations, as 22% of patients in Q4 had MLLtranslocations vs. 11% in Q1-3 (p=0.005). This was primarily driven by patients with t(9;11), p=0.001. There was an inverse correlation between inv(16) and CD135 expression as only 2% of those in Q4 had inv(16) compared to 15% in Q1-3 (p<0.001). CD135 was then correlated with response to induction and post-induction outcome. Complete remission (CR) rate was comparable between those with high or lower CD135 expression (p=0.76). Those with high or lower CD135 expression had similar 3-yr overall survival (OS) from diagnosis of 70% and 66% respectively (p=0.9) and relapse risk from CR of 42% and 36% respectively (p=0.35).
Given the known prognostic and therapeutic significance of FLT3/ITD, we evaluated any prognostic implications of FLT3 expression in patients without FLT3/ITD, most of whom lack other cytogenetic risk features. Similar to the entire cohort, in the FLT3/ITD-negative cohort CD135 expression correlated with FAB M5 (p<0.001), t(9;11), (p<0.001) and inversely correlated with inv(16), p=0.001. 3-yr OS for those in Q4 was 71% vs. 67% in Q1-3 (p=0.955). Given the association of MLL and CD135 expression, we evaluated the association of CD135 expression with outcome in patients with MLLtranslocations (N=73); in these patients the 3-yr event free survival (EFS) was similar between those with high or lower CD135 expression (p=0.621).
In summary, we found that CD135 surface expression did not correlate with FLT3 mutations or clinical outcomes. Although FLT3 expression in FLT3/ITD-negative patients does not appear to offer additional prognostic information with current therapy, it may provide a therapeutic target in a subset of high expressing patients. This study also demonstrates that elevated FLT3 expression is associated with MLL rearrangements and warrants further study in this population with regards to potential prognostic and therapeutic implications.
No relevant conflicts of interest to declare.
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Escalation of treatment intensity for childhood acute myeloid leukemia has improved EFS but with excessive toxicity and toxic mortality (TM), compelling a search for more targeted less toxic ...alternatives.
To determine if the addition of GO to standard chemotherapy improves EFS in pediatric AML.
Patients < 30 years of age were randomly assigned to receive standard therapy alone (noGO) or to receive two doses of GO 3 mg/m2/dose on day 6 of Induction I (IndI) and on day 7 of Intensification II (IntII) in a 5 cycle chemotherapy backbone previously piloted by COG (Cooper et al, Cancer 2012). Use of stem cell transplant (SCT) was stratified by overall risk group assignment (based on cytogenetics, FLT3-ITD high allelic ratio (HAR), and IndI response) in which high risk patients were allocated to best allogeneic donor SCT after Int I, low risk (LR) patients received chemotherapy only, and intermediate risk (IR) were assigned to SCT if there was a matched family donor (MFD).
Between 2006-2010, 1022 of 1070 enrolled non-DS pts were eligible for analysis; characteristics are presented in Table 1. Median follow-up was 3.6 (range 0-6.4) years for those alive.
Protocol therapy was well tolerated with a TM of 2% in induction and 5% overall with no difference by study arm. VOD was observed in 3% (severe in 0.6%) with no difference by study arm. From time of enrollment, GO was significantly associated with better overall EFS (hazard ratio (HzR) 0.83 (95% CI: 0.7-0.99; p=.04) and relapse-free survival (HzR 0.74 (0.6-0.93; p=.01)) whereas OS was not significantly improved (HzR 0.91 (0.74-1.13)). At 3 yr, noGO v GO EFS was 47 v 53%, p=.05 and OS was 65 v 69%, p=.18. In multivariate analyses, GO was significantly associated with improved EFS than standard therapy after adjustment for significant adverse risk factors: age <2yr, initial WBC>100,000x109/L, and black race. GO was not associated with significantly better induction complete remission (CR) when compared to standard therapy (88% v 85%; p=NS). Table 2 illustrates the overall results by randomized arm and by overall risk group from time of CR showing a consistent reduction in relapse risk in all risk groups. Further risk group analysis found several unique results. In the LR group, relapse rates (RR) trended lower in the GO arm but the benefit was reduced by TM during Int 2 & 3 that was significantly worse in the GO arm (3 v 10%, p=.02). In the IR group, EFS, RR, and OS trended towards improvement with GO. However when pts were censored at the time of SCT (as treated), the outcomes were not significantly different between arms (log-rank p=.14 EFS and p=.81 OS). Table 1 shows an imbalance for SCT received in assigned IR pts with fewer actually receiving SCT in the noGO arm. As such, Table 2 shows outcomes by intent-to-treat for IR pts with MFD censored and by as treated for IR pts receiving MFD SCT. Noteworthy in the IR group alone who did receive a SCT, GO arm pts had a significantly better DFS than the noGO arm (intent to treat: p=.022; as treated: p=.044). However, for the IR pts randomized to the noGO arm, SCT failed to provide benefit. For HR pts achieving CR they as well trended towards better survival & RR in the GO arm.
GO improves EFS in children, adolescents and young adults with AML by reducing the risk of relapse among those achieving remission.
No relevant conflicts of interest to declare.
Cooperative group oncology trials have led to dramatic improvements in outcomes for children with cancer, but the current method of reporting adverse events (AEs) is inefficient and potentially ...ineffective. Like all cooperative oncology groups, AEs on Children's Oncology Group (COG) clinical trials are reported by clinical research associates via case report forms using the National Cancer Institute Common Terminology Criteria system. Despite the extensive resources needed for AE reporting, there is evidence that AEs may not be accurately reported. However, there are no data on the sensitivity, specificity and positive and negative predictive values (PPV, NPV) of AE reporting on pediatric or adult cooperative group oncology trials. This study sought to determine these operating characteristics for AE reporting for COG clinical trial AAML0531, the most recently completed clinical trial for de novo acute myeloid leukemia (AML) in children.
Chart abstraction was performed by a single pediatric oncologist on patients enrolled on COG clinical trial AAML0531 at 5 hospitals in the United States. Presence or absence of the following 12 grade III or higher AEs was determined for each hospital day: hypertension, hypotension, hypoxia, adult respiratory distress syndrome (ARDS), anorexia, typhlitis, disseminated intravascular coagulation (DIC), microbiologically proven viridans group streptococcal bacteremia (VGS), microbiologically proven invasive fungal infection (IFI), pain, seizure, and acute renal failure. The definitions for the gold standard of chart abstraction were defined a priori. Using the daily AE assessments based on chart review, the presence or absence of each toxicity was determined for each chemotherapy course. These data were then merged with COG adverse event data that includes grade III or higher toxicities for each patient by chemotherapy course. The percentages of chemotherapy courses with each toxicity were determined for chart abstraction and COG data. Sensitivity, specificity, PPV and NPV for COG AE reporting of the 12 toxicities were determined by comparing to the gold standard of chart abstraction data. Age, gender, race and ethnicity were determined from COG data.
COG clinical trial AAML0531 enrolled 1028 patients between August 14, 2006 and June 15, 2010. Chart abstraction was performed on 99 of these patients (373 courses). Compared to all patients enrolled on AAML0531, the 99 patients were younger (mean age 8.0 vs. 9.3 years, p = 0.04), and a larger percentage was African American (18.2% vs. 11.5%, p = 0.05). No differences were observed in gender (female: 48.5% vs. 50.4%, p = 0.72) or ethnicity (Hispanic: 18.2% vs. 18.4%, p = 0.96). In the COG AE report, the rates of toxicities ranged from 0.3% of courses (seizure) to 18.8% of courses (anorexia). In the chart abstraction data the rates of toxicities ranged from 0% of courses (seizure) to 37.0% of courses (pain). Table 1 shows the sensitivity, specificity, PPV and NPV for the 12 targeted toxicities. For toxicities with 10 or more identified events, the sensitivity of COG data ranged from 18.2% (DIC) to 70.0% (hypotension). Of significant concern, sensitivity was less than or equal to 50% for eight toxicities, including hypertension (38.5%), hypoxia (25.3%), anorexia (49.6%), VGS (49.2%), and pain (21.7%). The PPV ranged from 50% (IFI and ARDS) to 100% (DIC and renal failure).
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In this cohort of 99 patients treated on COG clinical trial AAML0531, the sensitivity of COG adverse event reporting was relatively low for all but one AE and was less than or equal to 50% for eight of the 12 targeted toxicities. Although PPV was high for most toxicities, it was not 100% for many, indicating that false positive results occur for nearly all of the evaluated AEs. This data demonstrates that the current system of AE reporting on cooperative group oncology trials has modest sensitivity and a demonstrable false positive rate. Work is ongoing to further refine these estimates and to develop improved AE reporting methodologies.
No relevant conflicts of interest to declare.
Introduction: Inherited bone marrow failure syndromes (IBMFS) are characterized by single or multi-lineage cytopenias as well as non-hematologic manifestations. Hematopoietic stem cell ...transplantation (HSCT) is the only curative therapy for the hematological abnormalities. However, high rates of mortality and morbidity from this procedure have been reported in patients with IBMFSs.
Objective: The study aim was to investigate the impact of patient, donor and treatment-related variables on the outcome of HSCT in IBMFS patients.
Methods: Data of patients who were prospectively enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR) from 2001 to 2012 and underwent HSCT were analyzed. The CIMFR is a population-based multicenter study, which includes all 16 pediatric tertiary care centers across all provinces in Canada. These centers care for >95% of the eligible pediatric IBMFS population in Canada. Descriptive analyses, as well as univariate and multivariate analyses (using a Cox proportional hazards model) were performed to assess the impact of multiple factors on probability of survival following transplant.
Results: Among 363 patients enrolled in CIMFR, 65 underwent allogeneic HSCT. Thiry-four patients were male and 30 were female (gender unknown for 1 patient). Median age at diagnosis with IBMFS was 3.0 years (range: prenatal diagnosis to 32.0 years) and median age at HSCT was 6.5 years (range: 0.25-20.1 years). Median follow-up time post-HSCT (time to death or last follow-up) was 2.8 years (range 0.01–15.9 years). Indications for transplant included severe cytopenia (n=44), myelodysplastic syndrome (n=18) acute myeloid leukemia (n=2) and unavailable cause (n=1). Cell type were bone marrow (n=40), cord blood (n=17), peripheral blood (n=5), unknown (n=3). Sixty-two percent of patients (n=40) received cells from an unrelated donor. Seventy-four percent (n=47) of patients had a full HLA-matched donor; 19 of those were related and 28 were unrelated donors. The most common conditioning regimen combined high dose cyclophosphamide, fludarabine and anti-thymocyte globulin (n=17). Incidence of graft failure, acute (grade II-IV) graft versus host disease (GVHD) and chronic GVHD was 14%, 30% and 22%, respectively. Five-year probability of survival for HSCT recipients was 73.4% ± 6.1% (SE). Causes of death included infections (CMV, fungal infections and bacterial), GVHD, lymphoproliferative disorder and congestive heart failure, pulmonary fibrosis, bronchiolitis obliterans. In the univariate analysis, factors significantly associated with increased mortality post-HSCT included ≥20 pre-HSCT platelet transfusions, pre-transplant administration of granulocyte colony-stimulating factor, 1 or more HLA mismatches, donor type (divided into four categories: matched related, partially matched related, matched unrelated, partially matched unrelated) and conditioning regimens combining high doses of cyclophosphamide with fludarabine and anti-thymocyte globulin (while comparing this combination against all others). The former 3 variables remained significant in the multivariate analysis.
Conclusion: Number of pre-transplant platelet transfusions, use of granulocyte colony-stimulating factor and one or more donor-recipient HLA mismatches were shown to increase the risk of mortality in patients with IBMFSs undergoing HSCT. Novel strategies are needed to improve outcome in patients with a high risk of HSCT-related complications.
No relevant conflicts of interest to declare.
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Background and Objectives. Phenotypic overlap among the inherited bone marrow failure syndromes (IBMFSs) frequently limits the ability to establish a diagnosis based solely on clinical ...manifestations. Since a large number of IBMFS genes (>70) have been identified, genetic testing is often prolonged and costly. Correct diagnosis, care and counseling often depend on identifying the mutated gene. Thus time-efficient and cost-effective strategies for genetic testing are essential. The aims of this study were to develop and evaluate the application of a next generation sequencing (NGS) IBMFS Gene Panel assay for genetic testing of patients with previously characterized categories of IBMFSs (e.g. Fanconi anemia and Diamond Blackfan anemia) but unknown genotype, as well as patients with unclassified IBMFSs.
Methods. We designed a NGS assay to test a comprehensive panel of 72 known IBMFS genes. Genomic DNA from patients enrolled on the Canadian Inherited Marrow Failure Registry was analyzed using the Haloplex technology and Illumina Seq2000 platform. The average gene coverage was 99.12%. SureCall program was used to align, map, and identify variants. Polyphen, Sift and MutationTaster were used to predict the effect of variants on the protein. Human Splicing Finder program was used to analyze effect of splicing. The assay was validated by detecting all 50 mutations and polymorphic variants that were previously found by Sanger sequencing in 31 patients.
Results. A total of 158 patients with unknown mutations were studied. Among 75 patients with known categories of IBMFSs but unknown genotypes, we found deleterious mutations in 43 patients (57.3%). These categories included Diamond Blackfan anemia, Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, TAR syndrome, familial thrombocytopenia and Kostmann/severe congenital neutropenia. Among 83 patients with unclassified IBMFSs, we found deleterious mutations and established the diagnosis in 16 patients (19.2%). Established diagnoses included dyskeratosis congenita, Diamond-Blackfan anemia, myelokathexis, GATA2-associated familial MDS, WAS-associated severe congenital neutropenia, G6PC3-associated severe congenital neutropenia, MYH9-associated disorder, MASTL-associated disorder and Wiskott-Aldrich syndrome. All identified mutations were validated. The assay allowed identification of mutant genes that had not been previously reported to be associated with the patient phenotypes in two cases. The assay led to amendment of established diagnoses in two other cases. The assay results directed a change in clinical care in multiple cases, including implementation of cancer surveillance program and consideration for prenatal diagnosis. The cost of the NGS was $470/patient compared to $4643/patient among those who underwent genetic testing by Sanger sequencing during the tenure of the study.
Conclusion. Our novel assay is a rapid, accurate, and cost saving strategy for genetic investigation of patients with IBMFSs. It can identify mutations in classified and unclassified IBMFSs with high level of sensitivity and precision.
No relevant conflicts of interest to declare.
The assessment of oral mucositis is important. There is a paucity of validated oral mucositis assessment instruments for use in children. This paper reviews the available mucositis measurement tools ...and their applicability to a paediatric population.
Literature search of PUBMED and bibliography searches identified articles relevant to mucositis measurement tools and the measurement of mucositis in paediatrics.
The relevant issues in the literature could be grouped into three categories: (1) development and evaluation of oral assessment tools, (2) oral assessment in the paediatric population, and (3) challenges to the assessment of oral mucositis in children. There were numerous validated mucositis assessment scales for use in adults. Only three of these scales have received limited evaluation for use in the paediatric population. The unique challenges presented by the paediatric population are excluded from much of the discussion in the literature.
The paper demonstrates the need to consider the issues specific to children. It must be determined whether previously developed tools are ideally suited for children enrolled on mucositis clinical trials.
It has been identified that there is a need for increased palliative care research within the paediatric setting. The assessment of parental views is necessary for this population. However, the ...conduct of research and recruitment of participants is often challenging. While conducting a study that involved parents of children receiving palliative or end-of-life care, the authors found that there were particular challenges to recruiting these parents. This comprehensive review of the literature aims to address the ethical and recruitment issues of involving parents of children that are receiving palliative or end-of-life care. Key elements, that may maximize completion of research and a more representative sample, are also discussed. These elements include obtaining the opinions on study design and interview script from experienced families and maximizing the partnership between health care professionals and the research team. Palliative Medicine 2007; 21
: 435—440
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