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Alveolar rhabdomyosarcoma (ARMS) is a highly aggressive subtype of childhood cancer for which efficacious treatments are needed. Immunotherapy represents a new therapeutic opportunity to pursue, but it requires the identification of worthwhile tumor antigens. Herein, we exploited the capacity of ARMS autoantibodies to recognize tumor self-antigens, probing human protein microarrays with plasma from ARMS patients and healthy subjects. We assessed the autoantibody response in ARMS, validated data with independent techniques, and estimated autoantibodies diagnostic and prognostic significance by receiver-operator characteristic curves (ROC), uni- and multivariate analysis. Of the 48 tumor antigens identified, General Transcription Factor II–I (GTF2i) and Protocadherin Gamma Subfamily C5 (PCDHGC5) were selected as candidate targets to validate tumor-restricted antigen expression and autoantibody reactivity through an independent technique and wider cohort of cases. GTF2i and PCDHGC5 overexpression was observed in tumor tissues compared to normal counterparts, and anti-GTF2i and -PCDHGC5 autoantibodies were found able to distinguish ARMS patients from healthy subjects as well as cases with different histology. Moreover, low levels of PCDHGC5 autoantibodies characterized patients with worse event-free survival and proved to be an independent negative prognostic factor. This approach provided the first comprehensive autoantibody profile of ARMS, gave novel insights into the immune response of this malignancy and paved the way toward novel potential antibody-based therapeutic applications suitable to improve the survival of ARMS patients.

Insulin-like growth factor-binding protein 2 (IGFBP2) is a tumor-associated protein measurable in patients&rsquo, biopsies and blood samples. Increased IGFBP2 expression correlates with tumor severity in rhabdomyosarcoma (RMS). Thus, we examined the plasmatic IGFBP2 levels in 114 RMS patients and 15 healthy controls by ELISA assay in order to evaluate its value as a plasma biomarker for RMS. Additionally, we looked for the presence of a humoral response against IGBFP2 protein measurable by the production of anti-IGFBP2 autoantibodies. We demonstrated that both circulating IGFBP2 protein and autoantibodies were significantly higher in RMS patients with respect to controls and their combination showed a better discriminative capacity. IGFBP2 protein identified metastatic patients with worse event-free survival, whereas both IGFBP2 and anti-IGFBP2 antibodies negatively correlated with overall survival. Our study suggests that IGFBP2 and anti-IGFBP2 antibodies are useful for diagnostic and prognostic purposes, mainly as independent negative prognostic markers in metastatic patients. This is the first study that reports a specific humoral response in RMS plasma samples and proves the value of blood-based biomarkers in improving risk assessment and outcome of metastatic RMS patients.

Introduction: Rhabdomyosarcoma is a soft tissue malignant musculoskeletal tumor frequent in children. Biliary duct localization is extremely rare, but it is the most common cause of malignant obstructive jaundice in pediatric patients. Methods: This report describes a series of 10 patients under 18 years of age with biliary tract rhabdomyosarcoma who were enrolled, from 1979 to 2004, in 3 consecutive Italian pediatric cooperative protocols that had been drawn up by the Soft Tissue Sarcoma Committee of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP). Results: Considering initial and delayed surgery, tumor resection was achieved in 7 cases, 3 complete with free margins (2 liver transplants) and 4 with microscopic residual disease. Chemotherapy was given to all patients and radiotherapy to 3. At present, 5 patients survive in complete remission 90-200 months after diagnosis while 4 died of disease progression or relapse and 1 of liver transplant-related complications. Conclusions: Better outcomes in this series were associated with the feasibility of conservative surgery due to the favorable location of the tumor, in particular in the common bile duct. Chemotherapy and radiotherapy might obviate the need for demolitive surgery or liver transplant, which were linked to worse outcomes in our series.

Background Rhabdomyosarcoma (RMS) occurring at nonparameningeal head and neck (NPM-HN) sites carries a better prognosis than parameningeal RMS and some other sites. We analyzed the treatments administered and results obtained in patients with localized NPM-HN RMS, included in the protocols coordinated by the Italian Soft Tissue Sarcoma Committee (STSC), in an effort to identify prognostic factors that could facilitate the tailoring of treatment. Methods Sixty-six patients up to 18 years of age with previously untreated, localized NPM-HN RMS were prospectively registered in three consecutive protocols: RMS79, RMS88, and RMS96. Primary surgery was recommended when complete tumor resection was deemed feasible without mutilations. In other cases, only a biopsy was performed, followed by chemotherapy and delayed surgery and/or radiotherapy (RT). Results NPM-HN RMS showed favorable characteristics: 72.7% were

Introduction: From 2002 to 2011, the Italian Soft Tissue Sarcoma Committee explored a combination of topotecan and carboplatin as a second-line strategy for children with resistant or relapsing rhabdomyosarcoma. Methods: Patients received two blocks of topotecan 2 mg/m2 on days 1, 2, and 3, and carboplatin 250 mg/m2 on days 4 and 5, followed by alternating blocks of topotecan–cyclophosphamide and carboplatin–etoposide for a total of six courses with 3-week intervals. Tumor response was assessed after two cycles, and local control was implemented when feasible. Results: A total of 38 patients were included in this study: 18/38 had alveolar rhabdomyosarcoma (RMS), 10/38 had metastatic disease at diagnosis, 8/38 had tumor progression during first-line chemotherapy, 21/38 had locoregional relapses, and 9/38 had distant relapses. Thirty-two patients could be assessed for tumor response to topotecan–carboplatin, and 9 (28%) showed a complete or partial response. Twenty-four patients experienced grade IV hematologic toxicity, while transient grade 1 tubulopathy, grade 3 mucositis, transient grade 2 nephrotoxicity, and a grade 2 decline in cardiac function occurred in one patient each. The 5-year overall and progression-free survival rates were 17% and 14%, respectively. Conclusion: the prognosis for children with resistant or relapsing RMS remains unsatisfactory. The topotecan–carboplatin regimen was well-tolerated. Though in case of late relapse the response rate was similar to those reported for other regimes, the result achieved remains unsatisfactory. New approaches, possibly including target agents, seem more attractive for future studies.

Background Pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) may rarely occur in visceral tissues, and little is known about their clinical history. The present study retrospectively analyzed a group of patients prospectively registered in Italian pediatric protocols conducted between 1979 and 2004. Methods Inclusion criteria for the study were as follows: a pathological diagnosis of “adult-type NRSTS,” arising at visceral sites (lung-pleurae, liver, kidney, and mesentery-bowel); age under 18 years; no previous treatment except for primary surgery; available clinical data; and written consent. Results Thirty cases with visceral NRSTS were collected and analyzed. Sites of origin were as follows: mesentery-bowel in 12 cases, lung-pleurae in 11, liver in 5, and kidney in 2. According to the Intergroup Rhabdomyosarcoma Study (IRS) surgical grouping system, patients were classified as follows: nine IRS group I, three group II, 12 group III, and six group IV. Patients were treated with a multimodal approach including surgery, radiotherapy, and/or chemotherapy, according to their characteristics. For the series as a whole, the 5-year event-free and overall survival rates were 33.3% and 40.0%, respectively. The IRS group (reflecting the feasibility of initial complete resection) emerged as the main prognostic factor. Survival rates also correlated with tumor size and local invasiveness, histological subtype, and tumor sites (the worst outcome was seen for tumors arising in the lung and pleurae). Conclusions This study confirmed that visceral NRSTS are aggressive tumors carrying a worse prognosis than pediatric NRSTS arising in soft tissues of the extremities. Local treatment remains the main challenge for these tumors.

Summary Background Prognostic factors have been studied in patients with rhabdomyosarcoma in general, but little is known about prognostic factors in the subgroup of patients with bladder/prostate rhabdomyosarcoma (BP-RMS) requiring salvage surgery after failure of chemotherapy ± radiotherapy to achieve local control. We reviewed the 28-year Italian experience with BP-RMS requiring salvage surgery after failure of nonsurgical management indicated by evidence of disease persistence after chemotherapy ± radiotherapy. Our hypothesis was that the same variables identified as prognostic factors in the general population with RMS could have prognostic value in this subgroup. Method Between 1986 and 2014, 108 patients with a histological diagnosis of BP-RMS were registered into three consecutive protocols. Patients undergoing salvage surgery after failure of chemotherapy ± radiotherapy and follow-up >5 years were considered for study. Variables related to the patient, to treatment, and to the surgical specimen were compared using the log-rank test in patients who achieved and failed to achieve 5-year progression-free survival (5-yr PFS). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for significant variables. Results Of the 108 patients enrolled in the protocols, 33 (30.6%) underwent salvage surgery and 26 matched study criteria. Seventeen patients were disease-free after a median follow-up of 125 months (range 65.5–311.7 months), 5-yr PFS 65.4%. Nine events were registered after a median follow-up of 5.4 months (range 1.9–27.5 months). Among the variables assessed (Table), only an undifferentiated histology proved to be significantly associated with a poorer 5-yr PFS, whereas a tumor size above 5 cm in the removed specimen approached significance. The OR (95% CI) for failure of 5-yr PFS was 28 (2.4–326.8) and 8.3 (1.03–67.1), respectively. Conclusion 5-yr PFS proved unrelated to excision margins of the surgical specimen, that is on whether there was evidence of microscopic residues left behind during surgery. These data suggest that the outcome is more influenced by the biological properties of the tumor. If small foci of differentiated cells are left behind, these probably do not compromise final prognosis. In our patients requiring salvage bladder-prostate surgery after failure of chemotherapy ± radiotherapy, long-term progression-free survival seemed unrelated to patient/tumor characteristics at presentation and preoperative management. Regarding the characteristics of the removed specimen, instead, an undifferentiated tumor histology and a diameter of the removed tumor >5 cm negatively influenced prognosis, whereas the presence of positive excision margins did not. PFS >5 years n/N (%) p Variables at diagnosis Age at diagnosis 14/20 (70) 0.4 >5 years 3/6 (50) Gender Male 12/20 (60) 0.3 Female 5/6 (83) Histology on initial biopsy Embryonal 9/16 (56) 0.1 Botryoid 8/9 (89) Tumor location Prostate 4/7 (57) 0.6 Bladder 11/15 (73) Bladder-prostate 2/4 (50) Tumor size 5/7 (71) 0.7 >5 cm 12/19 (63) T-stage T1 7/10 (70) 0.7 T2 10/16 (62.5) Treatment variables Treatment protocol RMS 88 5/7 (71.5) 0.5 RMS 96 4/8 (50) RMS 2005 6/8 (75) Tumor response at 9 weeks Complete response (CR) 0/1 (0) 0.4 Partial response (PR) > 2/3 9/13 (69) Minor response (MR) > 1/3 but 4/7 (57) No response or stable disease (SD) 4/4 (100) Preoperative radiotherapy No 8/12 (67) 1 Yes 9/14 (64) Pathology variables Tumor location on surgical specimen Prostate 5/8 (62.5) 0.1 Bladder 11/14 (78.5) Bladder-prostate 1/4 (25) Surgical margins Negative 7/12 (58) 0.1 Positive 7/8 (87.5) Diameter of tumor at the surgical specimen 10/12 (83) 0.06 >5 cm 3/8 (37) Histological differentiation Differentiated 11/13 (84.5) 0.002 Undifferentiated 1/7 (14) Myxoid 3/4 (75)

BACKGROUND. The purpose of the current study was to analyze the influence of the initial surgical approach (biopsy vs resection with macroscopic residual tumors) on the outcome of patients with localized Intergroup Rhabdomyosarcoma Study (IRS) Group III rhabdomyosarcoma (RMS) enrolled in the Italian studies between 1979 and 2003. METHODS. Among the 394 patients evaluated, 323 underwent biopsy, as recommended by the protocols, and 71 patients underwent surgical resection with macroscopic residual tumors (debulking operation [DO]), although this procedure was discouraged. All these patients were classified at the same risk group and received the same treatment. The different characteristics (patient age, tumor site, T classification and size, histology) and outcome in the 2 groups were considered. RESULTS. The estimated 5-year overall survival (OS) rates were 68.4% and 72.6%, respectively, after biopsy and DO(P = .38), and the rates of progression-free survival (PFS) were 56.5% and 61.7%, respectively, after biopsy and DO (P = .41). The outcome did not differ significantly when considering other variables such as tumor site, size, and histology. Age > 10 years appeared to have little benefit in patients with DO; the OS was 62% after biopsy and 83.1% after DO (P = .06); the PFS was 49.7% and 72.8%, respectively after biopsy and DO (P = .04). No surgical complications due to the 2 procedures were reported, but in 2 cases the initial DO resulted in a mutilation. CONCLUSIONS. No significant advantages of DO versus biopsy were detected with regard to patient outcome. Biopsy, which is less aggressive, appears to be thebest option for patients with IRS Group III RMS. Cancer 2007. © 2007 American Cancer Society.

Purpose This analysis evaluates whether adjuvant chemotherapy can be recommended for high-risk, surgically-resected, adult-type non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) within the new European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) protocol. The Italian and German Cooperative Groups reviewed their data-bases, analyzing patients classified as group I–II, with high-grade tumor (G3) larger than 5 cm in size. Methods The analysis included 36 patients, and compared the clinical features and outcome of the group of 21 patients who received chemotherapy versus the group of 15 patients treated with local therapies only. Results For the series as a whole, 5-year event-free survival (EFS), metastasis-free survival (MFS), and overall survival (OS) were 26.2%, 34.0%, and 37.5%, respectively. In patients treated with chemotherapy, MFS and OS were 49.5% and 41.5% (median time to relapse: 13 months). In patients who did not receive chemotherapy, MFS and OS were 0% and 23.8% (median time to relapse: 3 months). Conclusion The role of adjuvant chemotherapy in NRSTS is still uncertain, however, the current retrospective analysis showed that: (1) despite the globally good prognosis of grossly-resected cases, patients with G3 and large-size have a high-risk of metastatic spread, and (2) MFS appears to be better in patients who had chemotherapy. Based in part on these results, and in accordance with recent suggestions coming from the literature on adult sarcomas, the EpSSG NRSTS protocol will recommend adjuvant chemotherapy in high-risk surgically-resected patients. Pediatr Blood Cancer © 2005 Wiley-Liss, Inc.

BACKGROUND The role of doxorubicin (Doxo) as part of multidrug regimens used to treat children with soft tissue sarcoma (STS) is controversial. To evaluate the feasibility of combining Doxo with the well established ifosfamide, vincristine, and actinomycin D (IVA) regimen, the Italian STS Committee performed a pilot study on a series of children with metastatic STS. METHODS Between July 2002 and February 2004, 29 evaluable patients were enrolled in this study; 19 patients had rhabdomyosarcoma, 5 patients had peripheral neuroectodermal tumor, and 5 patients had other types of STS. The IVA-Doxo (IVADo) regimen included ifosfamide 3 g/m2 on Days 1 and 2, vincristine 1.5 mg/m2 on Day 1, actinomycin D 1.5 mg/m2 on Day 1, and Doxo 30 mg/m2 on Days 1 and 2. Three courses of IVADo were to be administered in the initial part of treatment and analyzed for toxicity and tumor response. RESULTS Overall, 92 cycles were delivered. Major regimen-related toxicity was myelosuppression, with Grade 4 neutropenia in 67% of cycles and fever and neutropenia in 37% of cycles. Nonhematologic toxicity included Grade 3–4 mucositis (6.5% of cycles), constipation (9.7%), and peripheral neuropathy (6.5%). Other manifestations of major toxicity were venoocclusive disease and seizures, which occurred in one patient each. All but 1 patient with a malignant schwannoma showed some degree of tumor volume reduction; however, considering only complete and partial remissions, the response rate was 76% (± 7.9%). CONCLUSIONS The intensive IVADo regimen was effective against pediatric STS with acceptable toxicity. This combination will be investigated in high-risk patients with rhabdomyosarcoma in a randomized trial launched by the European pediatric Soft tissue sarcoma Study Group. Cancer 2005. © 2005 American Cancer Society.