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Background: According to retrospective osteosarcoma series, ABCB1/P-glycoprotein (Pgp) overexpression predicts for poor outcomes. A prospective trial to assess a risk-adapted treatment strategy using mifamurtide in Pgp+ patients was performed. Methods: This was a phase 2, multicenter, uncontrolled trial including patients 40 years old or younger with nonmetastatic extremity high-grade osteosarcoma stratified according to Pgp expression. All patients received high-dose methotrexate, doxorubicin, and cisplatin (MAP) preoperatively. In Pgp+ patients, mifamurtide was added postoperatively and combined with MAP for a good histologic response (necrosis ≥ 90%; good responders [GRs]) or with high-dose ifosfamide (HDIFO) at 3 g/m2/d on days 1 to 5 for a histologic response < 90% (poor responders [PRs]). Pgp– patients received MAP postoperatively. After an amendment, the cumulative dose of methotrexate was increased from 60 to 120 g/m2 (from 5 to 10 courses). The primary end point was event-free survival (EFS). A postamendment analysis was performed. Results: In all, 279 patients were recruited, and 194 were included in the postamendment analysis: 70 (36%) were Pgp–, and 124 (64%) were Pgp+. The median follow-up was 51 months. For Pgp+ patients, 5-year EFS after definitive surgery (null hypothesis, 40%) was 69.8% (90% confidence interval [CI], 62.2%-76.2%): 59.8% in PRs and 83.7% in GRs. For Pgp– patients, the 5-year EFS rate was 66.4% (90% CI, 55.6%-75.1%). Conclusions: This study showed that adjuvant mifamurtide, combined with HDIFO for a poor response to induction chemotherapy, could improve EFS in Pgp+ patients. Overall, the outcomes compared favorably with previous series. Mifamurtide and HDIFO as salvage chemotherapy are worth further study.

Cerebral cavernous malformations (CCMs) represent a common autosomal dominant disorder that predisposes patients to hemorrhagic strokes and focal neurological signs. Mutations in three genes (KRIT1, MGC4607, and PDCD10) have been associated with CCMs. We investigated the role of two new mutations in the KRIT1 gene in two Italian families affected by CCMs. Whole blood DNA was extracted and the mutations were detected after polymerase chain reaction (PCR), denaturing high-performance liquid chromatography screening, and sequencing of the coding regions of the three CCMs-associated genes. Total RNA was extracted, and the KRIT1 cDNA was sequenced and subsequently subjected to real-time quantitative PCR in order to examine the translational outcome of each genomic mutation. A novel splicing acceptor site deletion of the exon 14 in one family and an intronic nucleotide change close to the exon 19 in the other one were identified, both in the KRIT1 gene. These mutations were proven to alter the correct splicing mechanism, resulting, respectively, in a truncated protein of 432 amino acids and in a protein lacking an internal segment. We report two novel cases of splicing affecting genomic variants, suggesting a careful reanalysis of previously identified splice site variations in KRIT1 to look for their possible causative roles of similar missplicing events and their consequent involvement in the pathogenesis of CCMs. Moreover, our genotype-phenotype functional correlation suggests that the C-terminal portion of the KRIT1 protein is likely to contain a short, previously unrecognized segment necessary for its activity.

BACKGROUND In 1991, the Italian Association for Pediatric Hematology-Oncology and the National Council of Research (CNR) initiated an Italian Cooperative Study (SE 91-CNR Protocol) with the main objective of improving the overall survival (SUR) and the event free survival (EFS) of children and young adults with localized Ewing sarcoma and primitive neuroectodermal tumors of bone compared with a previous study (IOR/Ew2 Protocol). METHODS Between November 1991 and November 1997, 165 patients were enrolled in this study, 160 of whom were evaluable. The patients were treated with a multimodal approach characterized by intensified chemotherapy, hyperfractionated and accelerated radiation therapy, and the addition of ifosfamide and etoposide to standard chemotherapy with vincristine, actinomycin-D, doxorubicin, and cyclophosphamide. RESULTS After a median follow-up of 37 months, 126 of the 160 evaluable patients remained free of disease recurrence. Thirty-one patients developed a disease recurrence (20 with disseminated disease). CONCLUSIONS The 3-year SUR and EFS rates found in the current study (83.6% and 77.8%, respectively) may be considered satisfactory. Only age at diagnosis ≤14 years and a good histologic response appeared to affect the outcome of patients with localized Ewing sarcoma positively. These results appear to demonstrate the efficacy of the addition of ifosfamide in induction chemotherapy to four-drug standard combination chemotherapy, as confirmed by the improved outcome in terms of 3-year EFS reported in the SE 91-CNR Protocol compared with the IOR/Ew2 Protocol (77.8% vs. 60.7%). In addition, the better outcome also could be explained by the change in treatment strategy with a trend toward the use of more surgery than radiation therapy compared with the authors' previous protocol. Cancer 1999;86:421–8. © 1999 American Cancer Society.