Principles of Wilms' tumor biology

The last few years have provided dramatic breakthroughs in understanding the genetic factors involved in Wilms' tumorigenesis and normal kidney development. The implications of these findings for the clinical management of children with Wilms' tumor are only now becoming apparent. Over 80% of patients with Wilms' tumor can be cured using contemporary multimodality therapy. As a consequence, the current NWTSG is attempting to intensify treatment for patients with poor prognostic features while decreasing therapy, and thereby adverse late effects, for patients with favorable prognosticators.     

In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia

Recent reports have established the prenatal origin of leukemia translocations and resultant fusion genes in some patients, including MLL-AF4 translocations in infants and TEL-AML1 translocations in children. We now report evidence for the prenatal origin of a translocation in childhood acute myeloid leukemia (AML). The t(8;21) AML1-ETO translocations were sequenced at the genomic level in 10 diagnostic leukemia samples from children with available neonatal Guthrie blood spots. Clonotypic genomic AML1-ETO sequences were detected in the Guthrie spots for 5 individuals, providing unambiguous evidence of prenatal origin in these cases. Two of these patients were older than 10 years of age at diagnosis, indicative of a protracted postnatal latency. Three of the patients were assessed for the persistence of genomic fusion sequences in complete clinical remission samples and were found to be positive. These data indicate that t(8;21) in childhood AML can arise in utero, possibly as an initiating event in childhood AML, and may establish a long-lived or stable parental clone that requires additional secondary genetic alterations to cause leukemia.     

Evidence for susceptibility genes to familial Wilms tumour in addition to WT1, FWT1 and FWT2

Three loci have been implicated in familial Wilms tumour: WT1 located on chromosome 11p13, FWT1 on 17q12-q21, and FWT2 on 19q13. Two out of 19 Wilms tumour families evaluated showed strong evidence against linkage at all three loci. Both of these families contained at least three cases of Wilms tumour indicating that they were highly likely to be due to genetic susceptibility and therefore that one or more additional familial Wilms tumour susceptibility genes remain to be found.     

Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome?

Rhabdomyosarcoma has 2 major histological subtypes, embryonal and alveolar. Alveolar histology is associated with the fusion genes PAX3-FKHR and PAX7-FKHR. Definition of alveolar has been complicated by changes in terminology and subjectivity. It is currently unclear whether adverse clinical behaviour is better predicted by the presence of these fusion genes or by alveolar histology. We have determined the presence of the PAX3/7-FKHR fusion genes in 91 primary rhabdomyosarcoma tumours using a combination of classical cytogenetics, FISH and RT-PCR, with a view to determining the clinical characteristics of tumours with and without the characteristic translocations. There were 37 patients with t(2;13)/PAX3-FKHR, 8 with t(1;13) PAX7-FKHR and 46 with neither translocation. One or other of the characteristic translocations was found in 31/38 (82%) of alveolar cases. Univariate survival analysis revealed the presence of the translocation t(2;13)/PAX3-FKHR to be an adverse prognostic factor. With the difficulties in morphological diagnosis of alveolar rhabdomyosarcoma on increasingly used small needle biopsy specimens, these data suggest that molecular analysis for PAX3-FKHR will be a clinically useful tool in treatment stratification in the future. This hypothesis requires testing in a prospective study. Variant t(1;13)/PAX7-FKHR appears biologically different, occurring in younger patients with more localised disease.     

1 Versus 2-cm Excision Margins for pT2-pT4 Primary Cutaneous Melanoma (MelMarT): A Feasibility Study

Background

There is a lack of consensus regarding optimal surgical excision margins for primary cutaneous melanoma?>?1 mm in Breslow thickness (BT). A narrower surgical margin is expected to be associated with lower morbidity, improved quality of life (QoL), and reduced cost. We report the results of a pilot international study (MelMarT) comparing a 1 versus 2-cm surgical margin for patients with primary melanoma?>?1 mm in BT.

Methods

This phase III, multicentre trial [NCT02385214] administered by the Australia & New Zealand Medical Trials Group (ANZMTG 03.12) randomised patients with a primary cutaneous melanoma?>?1 mm in BT to a 1 versus 2-cm wide excision margin to be performed with sentinel lymph node biopsy. Surgical closure technique was at the discretion of the treating surgeon. Patients’ QoL was measured (FACT-M questionnaire) at baseline, 3, 6, and 12 months after randomisation.

Results

Between January 2015 and June 2016, 400 patients were randomised from 17 centres in 5 countries. A total of 377 patients were available for analysis. Primary melanomas were located on the trunk (56.9%), extremities (35.6%), and head and neck (7.4%). More patients in the 2-cm margin group required reconstruction (34.9 vs. 13.6%; p?<?0.0001). There was an increased wound necrosis rate in the 2-cm arm (0.5 vs. 3.6%; p?=?0.036). After 12 months’ follow-up, no differences were noted in QoL between groups.

Discussion

This pilot study demonstrates the feasibility of a large international RCT to provide a definitive answer to the optimal excision margin for patients with intermediate- to high-risk primary cutaneous melanoma.

     

Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations

Background A 13-year-old girl presented with rectal bleeding and was found to have two colonic carcinomas (stage Dukes' C) and multiple colonic polyps. At the age of 7 years she had widespread hyperpigmented and hypopigmented skin lesions, and had developed medulloblastoma, which was treated with chemotherapy and craniospinal irradiation. At the age of 10 years she had developed acute myelocytic leukemia, M5. She was treated with chemotherapy including sibling bone marrow transplant with busulfan/cyclophosphamide conditioning. A three-generation family history identified no relatives with colonic carcinomas or polyposis. Investigations Immunohistochemical analysis was performed on a sample of colonic adenoma. Staining for MLH1 and MSH2 was normal but was absent for MSH6. Direct sequencing of MSH6 was performed in the proband and both parents. Diagnosis Constitutional biallelic mutations in the mismatch repair gene MSH6 were identified in the proband. Both parents are carriers of one mutation. This is the first individual with biallelic MSH6 mutations reported with either medulloblastoma or acute myelocytic leukemia. Management Cascade genetic testing and colonoscopic screening for colorectal carcinoma has been offered to relatives carrying one mutation. The proband underwent panproctocolectomy and received adjuvant capecitabine. Identification of constitutional biallelic mismatch repair gene mutations allows the avoidance of chemotherapeutic agents likely to be ineffective and mutagenic in the context of the underlying mismatch repair deficiency. It is important to consider this diagnosis in children presenting with malignancy and abnormal skin pigmentation, even in the absence of a strong family history of tumors.