Daniel Orbach

Fusion Gene–Negative Alveolar Rhabdomyosarcoma Is Clinically and Molecularly Indistinguishable From Embryonal Rhabdomyosarcoma

PURPOSE To determine whether the clinical and molecular biologic characteristics of the alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) subtypes have relevance independent of the presence or absence of the PAX/FOXO1 fusion gene. PATIENTS AND METHODS The fusion gene status of 210 histopathologically reviewed, clinically annotated rhabdomyosarcoma samples was determined by reverse transcriptase polymerase chain reaction. Kaplan-Meier analysis was used to assess event-free survival and overall survival in fusion gene-negative ARMS (ARMSn; n = 39), fusion gene-positive ARMS (ARMSp; n = 94), and ERMS (n = 77). A total of 101 RMS samples were also profiled for whole-genome expression, and 128 were profiled for genomic copy number imbalances. Profiling data were analyzed by supervised and unsupervised methods to compare features related to histopathology and fusion gene status. Results were also projected by meta-analysis techniques across three separate publically available data sets. RESULTS Overall and event-free survival, frequency of metastases, and distribution of site at initial presentation were not significantly different between ARMSn and ERMS. Consistent with this, analysis of gene expression signatures could not reproducibly distinguish ARMSn from ERMS whereas fusion gene-positive cases were distinct. ARMSn and ERMS frequently show whole-chromosome copy number changes, notably gain of chromosome 8 with associated high levels of expression of genes from this chromosome. CONCLUSION The clinical behavior and molecular characteristics of alveolar cases without a fusion gene are indistinguishable from embryonal cases and significantly different from fusion-positive alveolar cases. This implies that fusion gene status irrespective of histology is a critical factor in risk stratification of RMS.

Infantile Fibrosarcoma: Management Based on the European Experience

PURPOSE To retrospectively analyze the clinical features and results of treatment in 56 infants with fibrosarcoma enrolled onto cooperative European protocols between 1979 and 2005 and treated with a combination of surgery and chemotherapy. PATIENTS AND METHODS We performed a retrospective case review of infants under the age of 2 years with fibrosarcoma treated between 1979 and 2005 in six European studies. Patients were staged according to the Intergroup Rhabdomyosarcoma Staging System international classification as a function of the type of initial surgery and the extent of disease and were treated with surgery and chemotherapy. Survival was calculated using the Kaplan-Meier method. RESULTS Primary tumor site was the limbs in 66% of patients; median tumor diameter was more than 5 cm in 63% of patients; and postoperative staging was as follows: group I, 22%; group II, 27%; group III, 47%; and group IV, 4%. Response rate to chemotherapy was 75%, and the specific response rate to vincristine-dactinomycin was 71%. Local control was obtained in 84% of patients. At the end of follow-up, 45% of survivors had been treated by surgery alone, 6% by chemotherapy alone, 46% by surgery and chemotherapy, and 2% by surgery, chemotherapy, and radiotherapy. The 5-year overall survival (OS) rate was 89%. The 5-year OS and event-free survival rates for localized patients were 89% and 81%, respectively. CONCLUSION Although complete resection is rarely feasible at diagnosis, conservative surgery remains the mainstay treatment for infantile fibrosarcoma. An alkylating agent-free and anthracycline-free regimen is usually effective and should be chosen as first-line chemotherapy for inoperable tumors. Overall prognosis is good, but progression or relapse, mainly local, remains possible.

Ribosomal Protein SA Haploinsufficiency in Humans with Isolated Congenital Asplenia

Spleen Knockout Explained Isolated congenital asplenia (ICA) is a rare disorder where patients are born without a spleen and are at increased risk of bacterial infection but have no other developmental abnormalities. Through sequence analysis of familial and sporadic cases, Bolze et al. (p. 976, published online 11 April) found that ICA patients carry mutations in the gene encoding ribosomal protein SA and as a result express about half the normal amount of this protein. The mechanism by which reduced expression of a housekeeping protein causes an organ-specific defect remains unclear. A rare human disorder, characterized by the absence of a spleen at birth, is associated with mutations in a ribosomal protein. Isolated congenital asplenia (ICA) is characterized by the absence of a spleen at birth in individuals with no other developmental defects. The patients are prone to life-threatening bacterial infections. The unbiased analysis of exomes revealed heterozygous mutations in RPSA in 18 patients from eight kindreds, corresponding to more than half the patients and over one-third of the kindreds studied. The clinical penetrance in these kindreds is complete. Expression studies indicated that the mutations carried by the patients—a nonsense mutation, a frameshift duplication, and five different missense mutations—cause autosomal dominant ICA by haploinsufficiency. RPSA encodes ribosomal protein SA, a component of the small subunit of the ribosome. This discovery establishes an essential role for RPSA in human spleen development.

Chromosome Instability Accounts for Reverse Metastatic Outcomes of Pediatric and Adult Synovial Sarcomas

PURPOSE Synovial sarcoma (SS) occurs in both children and adults, although metastatic events are much more common in adults. Whereas the importance of the t(X;18) translocation in SS oncogenesis is well established, the genetic basis of SS metastasis is still poorly understood. We recently reported expression (CINSARC; Complexity Index in Sarcoma) and Genomic Index prognostic signatures related to chromosome integrity in sarcomas and GI stromal tumors. Here we investigate whether these signatures can also predict outcomes in SS. PATIENTS AND METHODS One hundred patients who had primary untreated SS tumors were selected for expression and genomic profiling in a training/validation approach. RESULTS CINSARC and Genomic Index have strong independent and validated prognostic values (P < .001). By comparing expression profiles of tumors with or without metastasis, 14 genes that are common to the CINSARC signature were identified, and the two top-ranked genes, KIF14 and CDCA2, were validated as prognostic markers in an independent cohort. Comparing genomic profiles of adult versus pediatric SS, we show that metastasis is associated with genome complexity in both situations and that the adult genome is more frequently rearranged. Accordingly, pediatric patients with an even genomic profile do not develop metastasis. CONCLUSION Metastasis development in SS is strongly associated with chromosome complexity, and CINSARC and Genomic Index are validated independent prognostic factors. The differences in metastasis frequency between adults and children are associated with genome instability, which is much more frequent in adults. Genomic Index is potentially the best overall biomarker and clearly the most clinically relevant, considering that genome profiling from formalin-fixed samples is already used in pathology.

Non-metastatic unresected paediatric non-rhabdomyosarcoma soft tissue sarcomas: Results of a pooled analysis from United States and European groups

BACKGROUND Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with initially unresected tumours represent a particular subset of patients with a poor outcome. Various international research groups pooled their data in a joint study in order to investigate prognostic variables and treatment modalities. METHODS The study population consisted of 304 patients <21 years old treated between 1980 and 2005 using a multimodality therapeutic strategy. RESULTS Synovial sarcoma and malignant peripheral nerve sheath tumour (MPNST) were the most frequent histotypes. Most patients received initial chemotherapy: major responses were recorded in 41% and minor in 16% of cases. Overall survival (OS) was 60.0% and 51.5% at 5 and 10 years, respectively, and it was significantly associated with patients age, histological subtype, tumour site and size, quality of delayed surgical resection, radiotherapy administration and response to induction chemotherapy. MPNST associated to neurofibromatosis type 1 was the tumour type with the worst rate of response to chemotherapy and the worst outcome. CONCLUSIONS In unresected NRSTS patients, radiotherapy and delayed surgery are of crucial importance. Patients who respond to chemotherapy have better chance of survival. However, given the relatively poor prognosis, research on intensive multimodal treatment approaches and novel strategies is warranted.

Long-Term Evaluation of Ifosfamide-Related Nephrotoxicity in Children

PURPOSE Ifosfamide is widely used in pediatric oncology but its nephrotoxicity may become a significant issue in survivors. This study is aimed at evaluating the incidence of late renal toxicity of ifosfamide and its risk factors. PATIENTS AND METHODS Of the 183 patients prospectively investigated for renal function, 77 treated for rhabdomyosarcoma, 39 for other soft tissue sarcoma, 39 for Ewings sarcoma, and 28 for osteosarcoma were investigated at least 5 years after treatment. No patients had received cisplatin and/or carboplatin. Glomerular and tubular functions were graded according to the Skinner system. RESULTS The median dose of ifosfamide was 54 g/m(2) (range, 18 to 117 g/m(2)). After a median follow-up of 10 years, 89.5% of patients had normal tubular function, and 78.5% had normal glomerular function rate (GFR). Serum bicarbonate and calcium were normal in all patients. Hypomagnesemia was observed in 1.2% and hypophosphatemia in 1%. The tubular threshold for phosphate was reduced in 24% of the patients (grade 1 in 15%, grade 2 in 8%, and grade 3 in 0.5%). Glycosuria was detected in 37% of the patients but was more than 0.5 g/24 hours in only 5%. Proteinuria was observed in 12%. Ifosfamide dose and interval from therapy to investigations were predictors of tubulopathy in univariate and multivariate analysis. In a multivariate analysis, an older age at diagnosis and the length of interval since treatment had independent impacts on the risk of abnormal GFR. CONCLUSION Renal toxicity is moderate with a moderate dose of ifosfamide. However, since it can be permanent and can get worse with time, repeated long-term evaluations are important, and this risk should be balanced against efficacy.

Extra‐renal non‐cerebral rhabdoid tumours

Rhabdoid tumours (RTs) are aggressive malignancies of childhood, mainly occurring in the kidney and brain. We describe a national multi‐centre retrospective analysis of extra‐renal non‐cranial RTs (ERRTs).

Hypercalcemia and Childhood Cancer: A 7-year Experience

Hypercalcemia is a rare but potentially fatal complication during the management of childhood cancer. The treatment of severe hypercalcemia in children has not been clearly defined. The authors present a retrospective series of 16 children (11 boys and 5 girls) with severe hypercalcemia (≥2.9 mmol/L) treated between 1997 and 2004 for malignancy. Median serum calcium level was 3.14 mmol/L. Hypercalcemia was present at the initial diagnosis of cancer (eight patients) or occurred during treatment (five patients) or during relapse (three patients). Three children had several episodes of hypercalcemia. All children were treated by hydration for a median of 7 days (range 2-12 days). Eight patients received intravenous pamidronate. The other treatments were adapted to the mechanism of hypercalcemia. Serum calcium levels were lowered to below 3 mmol/L after a median of 2 days and to below 2.7 mmol/L after a median of 4 days after starting treatment. Pamidronate was well tolerated apart from one case of multifactorial renal failure. Intravenous pamidronate is a safe and effective treatment for severe cancer-related hypercalcemia in children. Specific therapy must be initiated as soon as possible. Serum calcium levels must be monitored for a fortnight after administration of pamidronate due to the risk of hypocalcemia.

Testicular function of survivors of childhood cancer: a comparative study between ifosfamide- and cyclophosphamide-based regimens.

PURPOSE This study aimed at comparing gonadal toxicity of ifosfamide versus cyclophosphamide received during childhood. METHODS The evaluation was based on basal FSH measurement. LH and testosterone were also measured in most of the patients. One hundred patients had received ifosfamide and 59 had received cyclophosphamide. RESULTS Median age at treatment was 11.2 years. The median interval since treatment was 10.7 years (range 4.1-20.2) and median age at evaluation was 21.4 years (17.5-36.1). The median dose of ifosfamide and of cyclophosphamide was 54 g/m(2) (18-114) and 8.3 g/m(2) (4.6-22), respectively. All but two males had normal testosterone levels. FSH was abnormal in 28/59 patients (47.5%) after receiving cyclophosphamide and was within the normal range in 94/100 patients (94%) after receiving ifosfamide. CONCLUSIONS These results show that ifosfamide is associated with a lower risk of gonadal damage than cyclophosphamide. The risk of abnormal FSH increased with the cumulative dose of cyclophosphamide.

Pancreatoblastoma: A report from the European cooperative study group for paediatric rare tumours (EXPeRT)

BACKGROUND Pancreatoblastoma is a very rare malignant tumour typically occurring in the early years of life. Due to its rarity, standardised diagnostic and therapeutic guidelines are not available for pancreatoblastoma. METHODS The newborn cooperative group denominated EXPeRT - European cooperative study group for paediatric rare tumours - combined in a joint analysis of all cases registered between 2000 and 2009 by the national groups of Italy, France, United Kingdom, Poland and Germany. RESULTS Twenty patients <18years old (median age 4years) were analysed: nine had distant metastases at diagnosis. Seventeen patients had tumour resection, at initial or delayed surgery. Eighteen received chemotherapy (response rate 73%), seven received radiotherapy. For the whole series, 5-year event-free survival and overall survival were 58.8% and 79.4%, respectively. Outcome did not correlate with tumour site and size, but was strongly influenced by the feasibility of tumour complete resection. CONCLUSIONS This international study confirms the rarity of the disease, the critical role of surgical resection both as therapy and as a prognostic variable, and the potential efficacy of chemotherapy. The adoption of an intensive multidisciplinary approach is required, as well as the referral to highly experienced centres. Further international cooperation is needed to collect larger series and stimulate biological studies to improve our understanding of the biology and the natural history of PBL.