Johannes H. M. Merks

Prevalence and patterns of morphological abnormalities in patients with childhood cancer.

CONTEXTnConstitutional gene defects predispose to cancer in children. Such tumor predisposition syndromes can be recognized by specific patterns of morphological abnormalities.nnnOBJECTIVESnTo assess the prevalence of morphological abnormalities in a large cohort of patients with childhood cancer and to identify new tumor predisposition syndromes.nnnDESIGN, SETTING, AND PARTICIPANTSnPatients were recruited from Emma Childrens Hospital, Academic Medical Center, Amsterdam, the Netherlands, between January 2000 and March 2003. A total of 1073 patients underwent a physical examination directed at 683 morphological abnormalities. The patient cohort consisted of 898 long-term survivors of childhood cancer and 175 newly diagnosed pediatric patients with cancer. The control group consisted of 1007 schoolchildren examined in an identical way. Mean ages of patients and controls were 21.2 and 10.4 years, respectively.nnnMAIN OUTCOME MEASURESnPrevalence and patterns of morphological abnormalities in patients compared with controls. To prevent age bias, only age-independent abnormalities were used for overall prevalence analysis. Patients younger than 9 years were excluded from the pattern analysis. The sample was restricted to white patients to prevent ethnicity bias.nnnRESULTSnMorphological abnormalities were significantly more prevalent in pediatric patients with cancer. Major abnormalities were present in 26.8% of patients vs 15.5% of controls (P < .001) and minor anomalies in 65.1% of patients vs 56.2% of controls (P < .001). Three or more minor anomalies were detected in 15.2% of patients vs 8.3% in controls (P < .001). Forty-two patients were diagnosed with an established tumor predisposition syndrome. Multivariate analyses showed 14 morphological abnormalities to occur significantly more often in the patient group. For 2 of these (blepharophimosis and asymmetric lower limbs), we identified statistically significant patterns of co-occurring morphological abnormalities suggestive of new tumor predisposition syndromes. Thirty-four patients fit 1 of the 2 novel tumor predisposition patterns.nnnCONCLUSIONSnPediatric patients with cancer show a significantly higher prevalence of morphological abnormalities compared with controls. Specific patterns of morphological abnormalities indicate possible unrecognized tumor predisposition syndromes, but validation in an independent sample is needed.

A novel local treatment strategy for advanced stage head and neck rhabdomyosarcomas in children: results of the AMORE protocol

The AMORE protocol is a local treatment regimen for head and neck rhabdomyosarcomas (HNRMS), consisting of Ablative surgery, Moulage technique brachytherapy and surgical Reconstruction. The aim of AMORE is to intensify local treatment for children with HNRMS and to avoid external beam radiation therapy (EBRT) and its long-term sequelae. All children with primary irresectable, non-orbital HNRMS in whom EBRT was indicated, were evaluated for the feasibility of AMORE. In 20 children, AMORE was performed (15 with parameningeal disease and five with non-parameningeal disease). Complete remission was achieved in all 20 patients. Local complications were limited. 5 patients experienced a local relapse and 1 patient developed distant metastases. Estimated 5-year OS and EFS were 67.5 and 64.1% for the entire group, and 64.2 and 60.0% for the parameningeal subgroup. We conclude that the AMORE protocol is a feasible strategy, with a good local control rate. Long-term sequelae of EBRT might be avoided although, to date, the follow-up is too short for definitive conclusions regarding these sequelae.

Phenotype, Cancer Risk, and Surveillance in Beckwith-Wiedemann Syndrome Depending on Molecular Genetic Subgroups

Patients with Beckwith–Wiedemann syndrome (BWS) have an increased risk to develop cancer in childhood, especially Wilms tumor and hepatoblastoma. The risk varies depending on the cause of BWS. We obtained clinical and molecular data in our cohort of children with BWS, including tumor occurrences, and correlated phenotype and genotype. We obtained similar data from larger cohorts reported in the literature. Phenotype, genotype and tumor occurrence were available in 229 of our own patients. Minor differences in phenotype existed depending on genotype/epigenotype, similar to earlier studies. By adding patients from the literature, we obtained data on genotype and tumor occurrence of in total 1,971 BWS patients. Tumor risks were highest in the IC1 (H19/IGF2:IG‐DMR) hypermethylation subgroup (28%) and pUPD subgroup (16%) and were lower in the KCNQ1OT1:TSS‐DMR (IC2) subgroup (2.6%), CDKN1C (6.9%) subgroup, and the group in whom no molecular defect was detectable (6.7%). Wilms tumors (median age 24 months) were frequent in the IC1 (24%) and pUPD (7.9%) subgroups. Hepatoblastoma occurred mostly in the pUPD (3.5%) and IC2 (0.7%) subgroups, never in the IC1 and CDKN1C subgroups, and always before 30 months of age. In the CDKN1C subgroup 2.8% of patients developed neuroblastoma. We conclude tumor risks in BWS differ markedly depending on molecular background. We propose a differentiated surveillance protocol, based on tumor risks in the various molecular subgroups causing BWS.

Synovial sarcoma in children and adolescents: the European pediatric Soft tissue sarcoma Study Group prospective trial (EpSSG NRSTS 2005)

BACKGROUNDnTo report the results of the first European prospective nonrandomized trial dedicated to pediatric synovial sarcoma.nnnPATIENTS AND METHODSnFrom August 2005 to August 2012, 138 patients <21 years old with nonmetastatic synovial sarcoma were registered in 9 different countries (and 60 centers). Patients were treated with a multimodal therapy including ifosfamide-doxorubicin chemotherapy and radiotherapy, according to a risk stratification based on surgical stage, tumor size and site, and nodal involvement.nnnRESULTSnWith a median follow-up of 52.1 months (range 13.8-104.4 months), event-free survival (EFS) was 81.9% and 80.7%, and overall survival (OS) was 97.2% and 90.7%, at 3 and 5 years, respectively. The only significant prognostic variable at univariate analysis was the risk group: 3-year EFS was 91.7% for low-risk, 91.2% for intermediate-risk, and 74.4% for high-risk cases. In 24 low-risk patients (completely resected tumor ≤5 cm in size) treated with surgery alone, there were two local relapses and no metastatic recurrences. Among 67 high-risk patients (unresected, or axial tumor or nodal involvement), 66 underwent surgery after neoadjuvant chemotherapy. Response to chemotherapy was 55.2%, including 22.4% cases with complete or major partial remissions, and 32.8% with minor partial remissions.nnnCONCLUSIONnThis study demonstrates that collaborative prospective studies on rare pediatric sarcomas are feasible even on a European scale, with excellent treatment compliance. The overall results of treatment were satisfactory, with higher survival rates than those previously published by pediatric groups. Nonetheless, larger, international projects are needed, based on a cooperative effort of pediatric and adult oncologists.nnnCLINICAL TRIALS NUMBERnEuropean Union Drug Regulating Authorities Clinical Trials No. 2005-001139-31.

Management of tumors of the chest wall in childhood: a review.

Chest wall tumors in childhood are major challenges with respect to diagnostic workup and treatment. Incidence rate is less than 1 per 1,000,000 and various benign and malignant diseases are noted. From the malignant diseases, Ewing tumors and rhabdomyosarcoma tumors are most often seen. Depending on diagnosis, staging, and age, therapy has to be tailored for each patient, which should be discussed in a multidisciplinary team setting. Radical resection is in most cases the major component of treatment. Use of chemotherapy depends on the diagnosis. In soft-tissue tumors, previously considered to be chemotherapy insensitive, favorable results are currently reported. The role of radiotherapy is debated owing to its pronounced late sequelae in children, but should be added when adequate margins cannot be achieved by surgery.

The AMORE Protocol for Advanced-Stage and Recurrent Nonorbital Rhabdomyosarcoma in the Head-and-Neck Region of Children: A Radiation Oncology View

PURPOSEnA multidisciplinary approach, consisting of consecutive Ablative Surgery, MOld technique with afterloading brachytherapy and immediate surgical REconstruction (AMORE) applied after chemotherapy, was designed for children with rhabdomyosarcoma in the head-and-neck region. Analysis of the first 42 patients was performed.nnnMETHODS AND MATERIALSnAfter macroscopically radical tumor resection, molds were constructed for each individual to fit into the surgical defect. The molds, made of 5-mm-thick layers of thermoplastic rubber, consisted of different parts. Flexible catheters were positioned between layers. After brachytherapy, the molds were removed. Surgical reconstruction was performed during the same procedure.nnnRESULTSnDose to the clinical target volume varied from 40 to 50 Gy for the primary treatment (31 patients) and salvage treatment groups (11 patients). There were 18 females and 24 males treated from 1993 until 2007. Twenty-nine tumors were located in the parameningeal region, and 13 were located in the nonparameningeal region. Patient age at the time of AMORE was 1.2-16.9 years (average, 6.5 years). Follow-up was 0.2-14.5 years (average, >5.5 years). Eleven patients died, 3 with local recurrence only, 6 with local and distant disease, 1 died of distant metastases only, and 1 patient died of a second primary tumor. Overall 5-year survival rates were 70% for the primary treatment group and 82% for the salvage group. Treatment was well tolerated, and acute and late toxicity were mild.nnnCONCLUSIONSnThe AMORE protocol yields good local control and overall survival rates, and side effects are acceptable.

The face in congenital melanocytic nevus syndrome

Congenital melanocytic nevi (CMN) are known to be associated with neurological abnormalities and melanoma, but have not been considered to be part of a developmental syndrome. The objective of this study was to test our clinical observation that children with CMN show more facial similarities than might be expected by coincidence. We selected facial photographs of 95 white Caucasian children with CMN from our database only on the basis of good neutral views, allowing careful evaluation of facial morphology. These were scored independently by two clinical geneticists using standardized categories and definitions for facial morphology. Prevalence of age‐independent features was compared to established norms in a large population, and associations with cutaneous phenotype were investigated. CMN were found to be associated with characteristic facies, and 74% of children in this series had at least three typical features. The characteristic features were: wide or prominent forehead, apparent hypertelorism, eyebrow variants, periorbital fullness, small/short nose, narrow nasal ridge, broad nasal tip, broad or round face, full cheeks, prominent pre‐maxilla, prominent/long philtrum, and everted lower lip. No association was found with the severity of cutaneous phenotype. We conclude that children with CMN often have a characteristic face. We propose the term “congenital melanocytic nevus syndrome” to describe this association.

Brachytherapy as Part of the Multidisciplinary Treatment of Childhood Rhabdomyosarcomas of the Orbit

INTRODUCTIONnRhabdomyosarcomas in the orbit form a major challenge in terms of cure without severe side effects in childhood cancer. Our specifically developed approach consists of applying brachytherapy to the tumor area using a mold. Analysis of its results for 20 patients was performed.nnnMETHODS AND MATERIALSnThirteen patients were referred for brachytherapy if complete remission was not reached after chemotherapy (Group I) and 7 in case of relapse (Group II). In total, 20 patients were treated between 1991 and 2007. Four were female and 16 male; their ages varied from 1.1 to 16.5 years, with an average of 8.5 years. After macroscopically radical tumor resection, molds with holes drilled to hold flexible catheters were placed into the orbit. The dose to the clinical target volume was 40-50 Gy.nnnRESULTSnThree patients of Group I and 1 patient of Group II developed local recurrence and underwent exenteration. The progression-free survival in Group I is 71.9% (95% CI 0.44-1.0), in Group II 85.7% (95% CI 0.60-1.0), the overall 5-year survival rate of the entire group is 92% (95% CI 0.76-1.0). During treatment, no serious side effects were observed. The late complications encountered in this series were cataract in 2 patients, 1 of whom also developed mild retinopathy. Two patients with ptosis needed surgical correction. No facial asymmetries or bone growth anomalies were observed.nnnCONCLUSIONSnThis entire procedure of brachytherapy with a mold offers a tailor-made treatment for orbital rhabdomyosarcomas with only few signs of late toxicity.

Parameningeal rhabdomyosarcoma in pediatric age: results of a pooled analysis from North American and European cooperative groups

BACKGROUNDnParameningeal (PM) site is a well-known adverse prognostic factor in children with localized rhabdomyosarcoma (RMS). To identify risk factors associated with outcome at this site, we pooled data from 1105 patients treated in 10 studies conducted by European and North American cooperative groups between 1984 and 2004.nnnPATIENTS AND METHODSnClinical factors including age, histology, size, invasiveness, nodal involvement, Intergroup Rhabdomyosarcoma Study (IRS) clinical group, site, risk factors for meningeal involvement (MI), study group, and application of radiotherapy (RT) were studied for their impact on event-free and overall survival (EFS and OS).nnnRESULTSnTen-year EFS and OS were 62.6 and 66.1% for the whole group. Patients without initial RT showed worse survival (10-year OS 40.8% versus 68.5% for RT treated patients). Multivariate analysis focusing on 862 patients who received RT as part of their initial treatment revealed four unfavorable prognostic factors: age <3 or >10 years, signs of MI, unfavorable site, and tumor size. Utilizing these prognostic factors, patients could be classified into different risk groups with 10-year OS ranging between 51.1 and 80.9%.nnnCONCLUSIONSnWhile, in general, PM localization is regarded as an adverse prognostic factor, the current analysis differentiates those with good prognosis (36% patients with 0-1 risk factor: 10-year OS 80.9%) from high-risk PM patients (28% with 3-4 factors: 10-year OS 51.1%). Furthermore, this analysis reinforces the necessity for RT in PM RMS.

Conservative strategy in infantile fibrosarcoma is possible: The European paediatric Soft tissue sarcoma Study Group experience

BACKGROUNDnInfantile fibrosarcoma (IFS) is a very rare disease occurring in young infants characterised by a high local aggressiveness but overall with a favourable survival. To try to reduce the total burden of therapy, the European pediatric Soft tissue sarcoma Study Group has developed conservative therapeutic recommendations according to initial resectability.nnnMATERIAL AND METHODSnBetween 2005 and 2012, children with localised IFS were prospectively registered. Initial surgery was suggested only if possible without mutilation. Patients with initial complete (IRS-group I/R0) or microscopic incomplete (group II/R1) resection had no further therapy. Patients with initial inoperable tumour (group III/R2) received first-line vincristine-actinomycin-D chemotherapy (VA). Delayed conservative surgery was planned after tumour reduction. Aggressive local therapy (mutilating surgery or external radiotherapy) was discouraged.nnnRESULTSnA total of 50 infants (median age 1.4 months), were included in the study. ETV6-NTRK3 transcript was present in 87.2% of patients where investigation was performed. According to initial surgery, 11 patients were classified as group I, 8 as group II and 31 as group III. VA chemotherapy was first delivered to 25 children with IRS-III/R2 and one with IRS-II/R1 disease. Response rate to VA was 68.0%. Mutilating surgery was only performed in three cases. After a median follow-up of 4.7 years (range 1.9-9.0), 3-year event-free survival and overall survival were respectively 84.0% (95% confidence interval [CI] 70.5-91.7) and 94.0% (95% CI 82.5-98.0).nnnCONCLUSIONSnConservative therapy is possible in IFS as only three children required mutilating surgery, and alkylating or anthracycline based chemotherapy was avoided in 71.0% of patients needing chemotherapy. VA regimen should be first line therapy in order to reduce long term effects.