Richard J. Cohn

Novel mutations target distinct subgroups of medulloblastoma

Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.

A systematic review of psychological interventions for adolescents and young adults living with chronic illness.

OBJECTIVE There is increasing recognition that adolescents and young adults (AYAs) with chronic illnesses experience common psychological challenges. This article reviewed published psychological interventions for AYAs with cancer, diabetes, juvenile idiopathic arthritis, sickle cell disease, and asthma. Common, efficacious intervention components were examined to generate clearer recommendations for future age-appropriate, evidence-based intervention development. METHODS Five databases including MEDLINE, MEDLINE In Process & Non-Indexed Citations, PsycINFO, EMBASE, and CINAHL, were searched for studies involving AYAs aged 10-30 years, using quantitative two-group methods, published from 1979-2010. Of 1,233 abstracts, 87 were extracted for further analysis and a final 25 studies were eligible for inclusion. Thirteen of these studies included AYAs with diabetes, 7 studies involved AYAs with cancer, and 5 included AYAs with other illnesses. RESULTS Educational interventions showed some significant positive results, particularly when targeted knowledge outcomes were measured. Several skills-based programs, some including parents, showed positive results, with moderate effect sizes. Interventions which taught communication skills, incorporated practical components (e.g., role-plays, homework), involved ≥6 sessions, and spanned at least 3 months in length, appeared more likely to achieve positive outcomes. CONCLUSIONS Skills-based interventions delivered over multiple sessions may yield the most positive results in AYAs with chronic illness. Given the few peer-support groups eligible for review, their efficacy remains unclear. This review points to the need for intervention development that teaches adaptive coping skills, is grounded in theoretical frameworks, and adheres to strict randomization and independent assessments to evaluate efficacy in assisting AYAs adjust to chronic illness.

Hidden financial costs in treatment for childhood cancer: An Australian study of lifestyle implications for families absorbing out-of-pocket expenses

Purpose The impact of out-of-pocket expenses on five domains of family lifestyle were explored: social, assets, credit, utilities, and charity. Methods Using a cross-sectional survey, 100 parents of pediatric cancer patients reported on the types of out-of-pocket expenses incurred and the perceived lifestyle impact of meeting those expenses. Results Eighty percent of the sample reported a minimum of five different out-of-pocket expenses (total mean value = AUS

Neurocognitive outcome 12 months following cerebellar mutism syndrome in pediatric patients with medulloblastoma

19,064; approximately US

Granulocytic sarcoma in children with acute myeloblastic leukemia and t(8;21)

9,723). The majority reflected travel, accommodation, and communication costs, use of work-related entitlements, and changes in paid employment. In lifestyle terms, the area of greatest impact was found for the social domain, such as cancelling vacations and giving up recreational pleasures and social expenditure. Those families living furthest from the major cancer treatment center reported the greatest range of out-of-pocket expenses and subsequent lifestyle impact. While there were few differences as a function of cancer type, results suggested that families most vulnerable to financial distress tended to be those whose child had spent relatively longer on treatment. Conclusions In meeting out-of-pocket expenses, parents primarily seek ways to “trim the fat” off existing family expenditure. While all families may incur extra expenses, parents of patients located a significant distance from the cancer treatment center remain especially vulnerable (despite increased government allowances). Creative solutions for addressing some expenses may include applications of telemedicine to augment outreach services.

Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss

The aim is to prospectively assess early neurocognitive outcome of children who developed cerebellar mutism syndrome (CMS) following surgical resection of a posterior fossa embryonal tumor, compared with carefully matched control patients. Children who were enrolled on an ongoing IRB-approved protocol for treatment of embryonal tumors, were diagnosed with postoperative CMS, and had completed prospectively planned neuropsychological evaluation at 12 months postdiagnosis were considered eligible. The cognitive outcomes of these patients were examined in comparison to patients without CMS from the same treatment protocol and matched with regard to primary diagnosis, age at diagnosis, and risk/corresponding treatment (n = 22 pairs). Seventeen were also matched according to gender, and 14 were also matched according to race. High-risk patients received 36-39.6 Gy CSI and 3D conformal boost to the primary site to 55.8-59.4 Gy. Average-risk patients received 23.4 Gy CSI and 3D conformal boost to the primary site to 55.8 Gy. Significant group differences were found on multiple cognitive outcomes. While the matched control patients exhibited performance in the average range, patients who developed CMS postsurgery were found to have significantly lower performance in processing speed, attention, working memory, executive processes, cognitive efficiency, reading, spelling, and math. Patients treated for medulloblastoma who experience postoperative CMS show an increased risk for neurocognitive impairment, evident as early as 12 months following diagnosis. This study highlights the need for careful follow-up with neuropsychological evaluation and for obtaining critical support for patients and their families.

Family information needs at childhood cancer treatment completion

BACKGROUND Granulocytic sarcomas (GS) have been associated with t(8;21). The prognosis of patients with GS is generally regarded as being less favorable than of patients with acute myeloblastic leukemia (AML). GS occurs relatively commonly in Africa and has been reported to affect 10-25% of black children presenting with AML. We sought to establish the incidence of GS in our pediatric population, to determine whether an association with t(8;21) existed, and to report on the outcome of these cases in a single series. PROCEDURE The records of consecutive pediatric patients treated for de novo AML in Johannesburg between January 1985-December 1995 were reviewed. Fifteen cases of GS among a total of 88 cases of AML presented to the Paediatric Haematology/Oncology Clinics of the Johannesburg and Baragwanath Hospitals. Fourteen (93%) of these patients were black male children. RESULTS All 9 cases of orbital GS (60%) and almost all cases with concurrent AML M2 had t(8;21). This translocation was present in only 4 n(8.5%) of the remaining 47 AML cases without GS for which cytogenetic data were available. One case presented with a complex chromosomal translocation not previously associated with GS. The median disease-free survival of the GS patients, using conventional chemotherapy treatment protocols, was significantly better than for the patients with AML and no GS (P = 0.0004). CONCLUSIONS Our data support a strong association between orbital GS, t(8;21), and AML M2 in the pediatric population. This entity occurred virtually exclusively in black male children at presentation. One third of these children who presented with AML had a GS. The favorable prognosis noted in our GS patients on standard induction and intensification therapy without local irradiation conflicts with some previous reports but is consistent with the favorable outcome documented in AML with t(8;21).Background Granulocytic sarcomas (GS) have been associated with t(8;21). The prognosis of patients with GS is generally regarded as being less favorable than of patients with acute myeloblastic leukemia (AML). GS occurs relatively commonly in Africa and has been reported to affect 10–25% of black children presenting with AML. We sought to establish the incidence of GS in our pediatric population, to determine whether an association with t(8;21) existed, and to report on the outcome of these cases in a single series. Procedure. The records of consecutive pediatric patients treated for de novo AML in Johannesburg between January 1985–December 1995 were reviewed. Fifteen cases of GS among a total of 88 cases of AML presented to the Paediatric Haematology/Oncology Clinics of the Johannesburg and Baragwanath Hospitals. Fourteen (93%) of these patients were black male children. Results. All 9 cases of orbital GS (60%) and almost all cases with concurrent AML M2 had t(8;21). This translocation was present in only 4 (8.5%)of the remaining 47 AML cases without GS for which cytogenetic data were available. One case presented with a complex chromosomal translocation not previously associated with GS. The median disease-free survival of the GS patients, using conventional chemotherapy treatment protocols, was significantly better than for the patients with AML and no GS (P= 0.0004). Conclusions. Our data support a strong association between orbital GS, t(8;21), and AML M2 in the pediatric population. This entity occurred virtually exclusively in black male children at presentation. One third of these children who presented with AML had a GS. The favorable prognosis noted in our GS patients on standard induction and intensification therapy without local irradiation conflicts with some previous reports but is consistent with the favorable outcome documented in AML with t(8;21). Med. Pediatr. Oncol. 31: 144–149, 1998.

Novel mutations and polymorphisms in the Fanconi anemia group C gene

Taking a genome-wide association study approach, we identified inherited genetic variations in ACYP2 associated with cisplatin-related ototoxicity (rs1872328: P = 3.9 × 10−8, hazard ratio = 4.5) in 238 children with newly diagnosed brain tumors, with independent replication in 68 similarly treated children. The ACYP2 risk variant strongly predisposed these patients to precipitous hearing loss and was related to ototoxicity severity. These results point to new biology underlying the ototoxic effects of platinum agents.

Dietary intake after treatment in child cancer survivors

Despite the recognized importance of information provision across the cancer trajectory, little research has investigated family information needs recently after childhood cancer. This mixed‐methods, multiperspective, study explored the information needs of families of childhood cancer survivors in the first year post‐treatment.

Online group-based cognitive-behavioural therapy for adolescents and young adults after cancer treatment: a multicenter randomised controlled trial of Recapture Life-AYA.

Fanconi anemia (FA) is an autosomal recessive disorder associated with hypersensitivity to DNA cross‐linking agents and bone marrow failure. At least four complementation groups have been defined, and the FA group C gene (FAC) has been cloned. We have screened 76 unrelated FA patients of diverse ethnic and geographic origins and from unknown complementation groups for mutations in the FAC gene either by chemical cleavage mismatch analysis or by single‐strand conformational polymorphism (SSCP). Five mutations were detected in four patients (5.3%), including two novel mutations (W22X and L496R). Nine polymorphisms were detected, seven of which have not been described previously (663A → G, L190F, IVS6 + 30C → T, 1312V, V449M, Q465R, and 1974G → A). Six of the nine polymorphisms occurred in patients or controls from the Tswana or Sotho chiefdoms of South Africa and were not found in 50 unrelated European controls. Restriction site assays were established for all 8 pathogenic mutations identified in the FAC gene to date and used to screen a total of 94 unrelated FA patients. This identified only one other group C patient, who was homozygous for the mutation IVS4 + 4A → T. This study indicates that the proportion of FA patients from complementation group C is generally likely to be less than 10%. Guidelines for the selection of FA patients for FAC mutation screening are proposed.