Tamas Revesz

Prevention of oral mucositis in children receiving cancer therapy: A systematic review and evidence-based analysis

This systematic review investigated, critically appraised, and rated the evidence on agents used to prevent oral mucositis in children. A comprehensive search of the relevant literature was performed up to December 2011. Articles were included according to the inclusion/exclusion criteria and were critically appraised for validation and quality assessment using a checklist consisting of 18 categories. Each article was then rated for its strength of evidence. 16,471 articles were retrieved from 19 different databases and then reduced to 27 articles that fit the inclusion criteria. Five articles on oral care protocols supported their use to prevent oral mucositis in children. Seven articles on chlorhexidine mouthwash and three on laser therapy had conflicting evidence of its use. The preventative agents that were supported by one or two articles included: benzydamine mouthwash, iseganan mouthwash, granulocyte-macrophage colony-stimulating factor (GM-CSF) mouthwash, oral/enteral glutamine, oral propantheline and cryotherapy, oral cryotherapy, oral sucralfate suspension, prostaglandin E2 tablets, and chewing gum. The reduction in the rates of occurrence of oral mucositis when using agents of fair (B) to good (A) evidence ranged from 22% to 52%. In conclusion, this review suggests the use of oral care protocols to prevent oral mucositis in children because of their strength of evidence (fair to good). The authors suggest avoiding agents with fair to good evidence against their use (oral sucralfate suspension, prostaglandin E2 tablets, and GM-CSF mouthwash). Agents with conflicting evidence (chlorhexidine mouthwash (used solely), laser therapy, and glutamine) should also be avoided until further research confirms their efficacy.

Outcome of central nervous system relapses in childhood acute lymphoblastic leukaemia--prospective open cohort analyses of the ALLR3 trial.

The outcomes of Central Nervous System (CNS) relapses in children with acute lymphoblastic leukaemia (ALL) treated in the ALL R3 trial, between January 2003 and March 2011 were analysed. Patients were risk stratified, to receive a matched donor allogeneic transplant or fractionated cranial irradiation with continued treatment for two years. A randomisation of Idarubicin with Mitoxantrone closed in December 2007 in favour of Mitoxantrone. The estimated 3-year progression free survival for combined and isolated CNS disease were 40.6% (25·1, 55·6) and 38.0% (26.2, 49.7) respectively. Univariate analysis showed a significantly better survival for age <10 years, progenitor-B cell disease, good-risk cytogenetics and those receiving Mitoxantrone. Adjusting for these variables (age, time to relapse, cytogenetics, treatment drug and gender) a multivariate analysis, showed a poorer outcome for those with combined CNS relapse (HR 2·64, 95% CI 1·32, 5·31, pu200a=u200a0·006 for OS). ALL R3 showed an improvement in outcome for CNS relapses treated with Mitoxantrone compared to Idarubicin; a potential benefit for matched donor transplant for those with very early and early isolated-CNS relapses. Trial Registration Controlled-Trials.com ISRCTN45724312

Treatment of metastatic sialoblastoma with chemotherapy and surgery

Tumors of the salivary gland are very uncommon in children. Sialoblastoma is a rare, aggressive, blastomatous, and potentially malignant congenital tumor. Distant metastases are rare. We present a case of sialoblastoma with lung metastases that developed in a 4‐year‐old girl adjacent to a congenital nevus in the left cheek. The tumor was inoperable at diagnosis but the largest of the pulmonary metastases was removed surgically. The patient responded well to chemotherapy and underwent surgical excision of the primary tumor, followed by three more courses of chemotherapy. Pediatr Blood Cancer 2008;50:134–137.

Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia.

Somatic genetic abnormalities are initiators and drivers of disease and have proven clinical utility at initial diagnosis. However, the genetic landscape and its clinical utility at relapse are less well understood and have not been studied comprehensively. We analyzed cytogenetic data from 427 children with relapsed B-cell precursor ALL treated on the international trial, ALLR3. Also we screened 238 patients with a marrow relapse for selected copy number alterations (CNAs) and mutations. Cytogenetic risk groups were predictive of outcome postrelapse and survival rates at 5 years for patients with good, intermediate-, and high-risk cytogenetics were 68%, 47%, and 26%, respectively (P < .001). TP53 alterations and NR3C1/BTG1 deletions were associated with a higher risk of progression: hazard ratio 2.36 (95% confidence interval, 1.51-3.70, P < .001) and 2.15 (1.32-3.48, P = .002). NRAS mutations were associated with an increased risk of progression among standard-risk patients with high hyperdiploidy: 3.17 (1.15-8.71, P = .026). Patients classified clinically as standard and high risk had distinct genetic profiles. The outcome of clinical standard-risk patients with high-risk cytogenetics was equivalent to clinical high-risk patients. Screening patients at relapse for key genetic abnormalities will enable the integration of genetic and clinical risk factors to improve patient stratification and outcome. This study is registered at www.clinicaltrials.org as #ISCRTN45724312.

Psychosocial correlates of paediatric cancer in the United Arab Emirates

To study the psychosocial factors and illness variables associated with childrens and parents perceptions of and ways of coping with cancer, in 38 childhood cancer patients aged 5–15xa0years, coping was studied in relation to sociodemographic variables and self-perception in terms of competence, behaviour and self-worth. Less optimal coping was found to be associated with poor family communications and lack of sharing/expression of emotions (P=0.005), presence of behavioural and emotional problems in the child (P=0.008) and parental lack of hope (P=0.001). No association was found with gender, parental education or occupation, socioeconomic status, or childs self-perception including global estimation of self-worth. Furthermore, none of the illness variables was found to be associated with coping. Awareness about health-related issues was found to be strongly associated with parental education (P=0.000). Our findings suggest that parental hope and both social and family communication are integral to helping patients and families cope with the illness experience.

Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia

Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment‐related mortality of 8%. Leukaemia‐free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre‐HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre‐HSCT (LFS 41%, OS 64%, P < 0·0001) or post‐HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B‐other ALL had more relapses (CIR 50%, LFS 41%) than T‐ALL and the main precursor‐B subtypes including BCR‐ABL1, KMT2A (MLL), ETV6‐RUNX1 (TEL‐AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B‐other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post‐HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post‐HSCT therapy.

Sensitive and specific measurement of minimal residual disease in acute lymphoblastic leukemia

A sensitive and specific quantitative real-time polymerase chain reaction method, involving three rounds of amplification with two allele-specific oligonucleotide primers directed against an rearrangement, was developed to quantify minimal residual disease (MRD) in B-lineage acute lymphoblastic leukemia (ALL). For a single sample containing 10 microg of good quality DNA, MRD was quantifiable down to approximately 10(-6), which is at least 1 log more sensitive than current methods. Nonspecific amplification was rarely observed. The standard deviation of laboratory estimations was 0.32 log units at moderate or high levels of MRD, but increased markedly as the level of MRD and the number of intact marker gene rearrangements in the sample fell. In 23 children with ALL studied after induction therapy, the mean MRD level was 1.6 x 10(-5) and levels ranged from 1.5 x 10(-2) to less than 10(-7). Comparisons with the conventional one-round quantitative polymerase chain reaction method on 29 samples from another 24 children who received treatment resulted in concordant results for 22 samples and discordant results for seven samples. The sensitivity and specificity of the method are due to the use of nested polymerase chain reaction, one segment-specific and two allele-specific oligonucleotide primers, and the use of a large amount of good quality DNA. This method may improve MRD-based decisions on treatment for ALL patients, and the principles should be applicable to DNA-based MRD measurements in other disorders.

Self-perception profile in children with cancer: self vs parent report.

Self-perception about competence, behaviour, and self-worth were examined in 30 children (8 to 14 years) recently diagnosed as having cancer and were compared with that of their parents perception. The poor agreement between parents and childrens ratings on physical appearance and social acceptance is noteworthy in that these two domains are particularly vulnerable in children with cancer, given the effects of chemotherapy on physical appearance and childrens tendency to view themselves as socially undesirable or a burden to others. This finding, if replicated, can have implications for therapeutic intervention since the discrepancy score could be used to challenge childrens negative views in the context of cognitive therapy to improve their self-esteem.

Implementation of a hospital oral care protocol and recording of oral mucositis in children receiving cancer treatment

PurposeThis retrospective/prospective study was carried out to implement a standardized hospital oral care protocol and record the incidence of oral mucositis for inpatients with childhood cancer.MethodsThe implementation process included stages of collaboration, consultation, education, and evaluation. The retrospective part of the study documented the existing hospital oral care protocol and audited medical records of all pediatric patients diagnosed with cancer over a 12-month period. The frequency of recorded oral mucositis and the rate of referral to the pediatric dentistry department were assessed. Following evaluation of the retrospective study, the literature was searched to create a new hospital oral care protocol. Referral to the dental department was standardized and frequent in-service presentations were given to staff. The oral mucositis scale was recorded daily for all inpatients, and compliance rates were assessed.ResultsFifty-nine patients’ medical records were audited during the retrospective study. Oral mucositis prevalence was clearly documented at 34%, while an additional 20% lacked a definitive diagnosis. During the prospective study, 38 patients were followed and had a verified incidence of oral mucositis of 33%. The rate of compliance of implementing the oral mucositis scale improved from 41% during the first 4 months to 87% during last 3 months. Referral rates to the dental department increased from 53% during the retrospective study to 100% during the prospective study.ConclusionsMutual understanding and collaboration between the oncology and dental departments in hospitals is crucial for standardizing patient care and for improving oral care standards.

New cellular markers at diagnosis are associated with isolated central nervous system relapse in paediatric B-cell precursor acute lymphoblastic leukaemia.

In childhood acute lymphoblastic leukaemia (ALL), central nervous system (CNS) involvement is rare at diagnosis (1–4%), but more frequent at relapse (~30%). Because of the significant late sequelae of CNS treatment, early identification of patients at risk of CNS relapse is crucial. Using microarray‐analysis, we discovered multiple differentially expressed genes between B‐cell precursor (BCP) ALL cells in bone marrow (BM) and BCP‐ALL cells in cerebrospinal fluid (CSF) at the time of isolated CNS relapse. After confirmation by real‐time quantitative polymerase chain reaction, selected genes (including SCD and SPP1) were validated at the protein level by flowcytometric analysis of BCP‐ALL cells in CSF. Further flowcytometric validation showed that a subpopulation of BCP‐ALL cells (>1%) with a ‘CNS protein profile’ (SCD positivity and increased SPP1 expression) was present in the BM at diagnosis in patients who later developed an isolated CNS relapse, whereas this subpopulation was <1% or absent in all other patients. These data indicate that the presence of a (small) subpopulation of BCP‐ALL cells with a ‘CNS protein profile’ at diagnosis (particularly SCD‐positivity) is associated with isolated CNS relapse. Such information can be used to design new diagnostic and treatment strategies that aim at prevention of CNS relapse with reduced toxicity.