Prolonged 14-day continuous infusion of high-dose ifosfamide for patients with relapsed and refractory high-grade osteosarcoma: a retrospective multicentre cohort study.

BACKGROUND: The prognosis of patients with Relapsed/Refractory Osteosarcoma (R/R OS) remains dismal without an agreement on systemic therapy. The use of High-Dose Ifosfamide (14 g/sqm) with an external pump in outpatient setting (14-IFO) in R/R OS patients is limited. This study represents the first retrospective cohort analysis focused on evaluating the activity and toxicity of 14-IFO in this setting. PATIENTS AND METHODS: The study investigated 14-IFO activity, in terms of tumour response according to RECIST 1.1 criteria, as well as survival rates and toxicity, according to CTCAE v.5. RESULTS: The trial enrolled 26 patients with R/R OS. The Overall Response Rate (ORR) and Disease Control Rate (DCR) obtained was 23% and 57.5%, respectively. Patients with relapsed OS showed a higher ORR (45%) and DCR (82%) compared to refractory patients, irrespective of the number of prior treatment lines received. The achievement of disease control with 14-IFO administration enabled 27% of patients to undergo new local treatment. Four-month Progression-Free Survival (PFS) was 54% for all patients and 82% for the relapsed OS sub-group. Median Overall Survival (OSurv) was 13.7 months, with 1-year OSurv of 51% for all patients and 71% for relapsed patients. Age over 18 years and the presence of refractory disease were identified as negative prognostic factors for this patient cohort. A total of 101 cycles were evaluated for toxic assessment, demonstrating a tolerable profile without grade 3-4 non-haematological toxicities. CONCLUSIONS: 14-IFO should be considered a viable treatment option for R/R OS, particularly due to its well tolerated toxicity profile and the potential for home-administration, which can improve patient quality of life without compromising efficacy.

Phase 2 study for nonmetastatic extremity high-grade osteosarcoma in pediatric and adolescent and young adult patients with a risk-adapted strategy based on ABCB1/P-glycoprotein expression: An Italian Sarcoma Group trial (ISG/OS-2).

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.

Cardio-Oncology in Childhood: State of the Art.

PURPOSE OF REVIEW: Cardio-oncology is an increasingly important field of cardiology that focuses on the detection, monitoring, and treatment of cardiovascular disease (CVD) occurring during and after oncological treatments. The survival rate for childhood cancer patients has dramatically increased thanks to new treatment protocols and cardiovascular (CV) sequelae represent the third most frequent cause of mortality in surviving patients. This study aims to provide a complete and updated review of all the main aspects of cardio-oncology in childhood and to highlight the critical issues. RECENT FINDINGS: The problem of CV complications in childhood cancer survivors raises the need to make an early diagnosis of cardiotoxicity by the new imaging and laboratory techniques in order to intervene promptly and to implement pharmacological strategies and lifestyle changes to reduce or even to prevent cardiac injury. Furthermore, a stratification of CV risk, also including new predisposing factors such as the presence of some genetic mutations, is of paramount importance before undertaking oncological treatments. Besides, a systematic and personalized planning of long-term follow-up is fundamental to ensure a transition from pediatric to adult hospital and to avoid missed or late diagnosis of cardiomyopathy. We reviewed the main risk factors for cardiotoxicity in children, both traditional and emerging ones: the mechanisms of toxicity of both old and new antineoplastic therapies, the techniques for detecting cardiac damage, and the current evidence regarding pharmacological cardioprotection. At the end, we focused our attention on the existing guidelines and strategies about the long-term follow-up of childhood cancer survivors.

Role of centers with different patient volumes in the management of rhabdomyosarcoma. An analysis by the Italian Pediatric Soft Tissue Sarcoma Committee.

PROCEDURE: The survival of children with rhabdomyosarcoma (RMS) has gradually improved as a result of the adoption of multidisciplinary treatments. Dedicated skills and facilities are indispensable and more readily available at reference centers. In this study, we examined the role of centers' experience (based on the number of patients treated) in their management of patients with RMS. METHODS: We analyzed 342 patients with localized RMS enrolled in the European RMS 2005 protocol from October 2005 to December 2016 at 31 Italian centers that are part of the Soft Tissue Sarcoma Committee (STSC). We grouped the centers by the number of patients each one enrolled (Group 1: >40; Group 2: <40 and >10; and Group 3: <10), and compared a number of indicators to assess the appropriateness of patients' diagnostic workup and treatment and their survival. RESULTS: Overall, 74.6% of patients were treated at 10 centers, and only three of them classifiable as high-volume centers. Only minor differences emerged between the three patient groups in terms of diagnostic investigations and treatment modalities. Survival was similar in the three groups. Approximately, one in four children treated at the centers in Groups 2 and 3 traveled to another center for surgery or radiotherapy. CONCLUSION: Patients treated at STSC centers with different amounts of experience had similar results in terms of survival. This is attributable to all centers in the network adhering to protocol recommendations and receiving the STSC's support on diagnostics and multidisciplinary treatments for RMS.

Pediatric Malignant Mandibular Tumors: Personal Experience and Literature Options Discussion.

INTRODUCTION: Mandibular defects reconstruction could result challenging in childhood, due to facial and mandibular growth patterns. For these reasons, the choice of the most suitable reconstructive option in pediatric patients, affected by mandibular malignancies, still objects of debate. OBJECTIVE: The aim of our study was to compare our reconstructive schedules to the existing literature in order to give a personal contribute to the present panorama. METHODS: We performed, in October 2019, a retrospective evaluation of pediatric patients treated for biopsy-proven mandibular malignancies at our Institute between January 2013 and December 2016. All of them received multimodal therapy in accordance with standard guidelines and their demographic, clinical, treatment, and outcome parameters were collected and analyzed. RESULTS: We observed a shorter duration of surgery, a faster tracheostomy tube and feeding-tube removal, and a minor hospitalization in patients who received grafts transfer compared to those who underwent microsurgical mandibular reconstruction. After a 36-month period of follow-up, osteochondral grafts showed a pattern of growth similar to the mandibular epiphysis (condilylion-gonion linear and vertical ratio ranging to 0.96-1.03 and 1-1.02 at orthopantomogram, respectively). No bone consolidation delays and functional impairment were recorded. CONCLUSIONS: Free flaps mandibular reconstruction in children needs to be better assessed and proximal fibular epiphyseal free flap indication might deserve further studies. Osteochondral grafts find indication for lateral defects, 50-55 mm in maximum length and located in the mandibular ramus, without massive teeth or soft tissue defect. Condyle involvement does not represent an absolute contraindication to rib graft use.

Ewing family tumors of the appendicular skeleton: a retrospective analysis of prognostic factors.

PURPOSE: Authors retrospectively analyzed possible prognostic factors in a series of patients affected by Ewing sarcoma of extremities (eEWS) and treated over a 20-year period at a single institution. METHODS: Between 1997 and 2017, 88 bone eEWS were treated at our institution. Staging, age, gender, tumoral volume, local treatment, surgical margins, post-ChT necrosis were investigated for prognostic correlation with overall survival (OS) and event-free survival (EFS). Median follow-up was 74 months (1-236). RESULTS: Staging of disease correlated with OS (81% vs 59%, p = 0.01) and not with EFS (68% vs 57%, p = 0.28) in localized vs metastatic eEWS at presentation. Age ≥ 14 years (p = 0.002) and volume ≥ 100 cm3 (p = 0.04) were significant negative prognostic factors. No difference was found in local treatment: OS was 76% vs 63% (p = 0.33), while EFS was 68% vs 49% (p = 0.06) after surgery alone or surgery + radiotherapy, respectively. Regarding surgical margins, OS was 76% vs 38% (p = 0.14), and EFS was 65% vs 33% (p = 0.14) in adequate vs not adequate, respectively. OS was 86% and 68% in good and poor responders, respectively (p = 0.13). CONCLUSION: In eEWS, metastatic disease at presentation, age > 14 years and tumoral volume > 100 cm3 are negative prognostic factors. Intensified adjuvant ChT can improve prognosis in poor responders and metastatic patients.

Latissimus dorsi rotational flap combined with a custom-made scapular prosthesis after oncological surgical resection: a report of two patients.

BACKGROUND: Sarcomas that arise from the scapula or periscapular soft tissues often require a total scapulectomy. This often implies a large complex tissue defect that needs adequate reconstruction of both bone and soft tissue. Although various methods have been developed, no optimal procedure has emerged. Postoperative complications are common and functional recovery is not always satisfactory. This study aims to present a new surgical technique that combines a custom-made scapular prosthesis with a functional latissimus dorsi flap. CASE PRESENTATION: Two patients diagnosed with malignant tumour of the scapular region were surgically treated after proper multidisciplinary evaluation. The first patient underwent the procedure as a first surgery, the second as revision surgery. The new technique comprises three surgical stages: excisional surgery with soft tissue resection and scapulectomy, bone reconstruction with custom-made prosthesis, and soft tissue reconstruction using a latissimus dorsi rotational flap overturned on the prosthesis. The goal is to set up a new functional unit combining an anatomically shaped implant (manufactured using latest three-dimensional printing technology) and a muscular flap, and to maintain the neurovascular supply. The patients were followed up to evaluate functional outcome and complications. Both patients were alive with no evidence of disease. Functional results were satisfactory and the Musculoskeletal Tumor Society scores were 87% and 63%, respectively. No surgical complications such as implant breakage, joint collapse, wound dehiscence, or infection were observed. CONCLUSIONS: This new technique upgrades the role of the latissimus dorsi flap to a functional tool in combination with an anatomical, three-dimensionally printed, custom-made prosthesis, and provides adequate well-vascularized and healthy tissue to maximize the likelihood of successful limb salvage.

Inflammatory Myofibroblastic Tumor of the Tongue. Report of a Pediatric Case and Review of the Literature.

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) is an uncommon mesenchymal lesion composed of myofibroblastic and fibroblastic spindle cells, accompanied by inflammatory infiltration. IMT may occur in the tongue. Five cases have been previously reported at this site. CASE REPORT: An inflammatory myofibroblastic tumor arose in the tongue of a 10 month old infant, confirmed by anaplastic lymphoma kinase (ALK) immunohistochemical staining and the clinical response to the tyrosine kinase inhibitor. CONCLUSIONS: IMT can occur in the tongue. This report highlights the differential diagnosis of IMT. ALK staining is both a helpful diagnostic marker and a predictive marker for targeted therapy in this tumor type.

Successful Propranolol Treatment of a Kaposiform Hemangioendothelioma Apparently Resistant to Propranolol.

A newborn with unresectable kaposiform hemangioendothelioma associated with Kasabach Merritt phenomenon, unresponsive to vincristine and prednisone, received second-line treatment with propranolol at a dose of 2 mg/kg/day, starting at 2 months of life and continued for 13 months. There was only slight reduction in tumor mass, but measurement of propranolol levels showed extremely low plasma concentrations. The propranolol dose was progressively increased to 3.5 mg/kg/day, leading to a substantial increase in plasma levels associated with clinically relevant tumor reduction. This case highlights the importance of relating propranolol dose to its plasma concentration before considering the treatment ineffective for this vascular tumor.

Hereditary Multiple Exostoses: a review of clinical appearance and metabolic pattern.

Hereditary multiple exostoses (HME) is an inherited genetic condition characterized by the presence of multiple exostoses (osteochondromas). MHE is a relatively rare autosomal dominant disorder, mainly caused by loss of function mutations in two genes: exostosin-1 (EXT1) and exostosin-2 (EXT2). These genes are linked to heparan sulfate (HS) synthesis, but the specific molecular mechanism leading to the disruption of the cartilage structure and the consequent exostoses formation is still not resolved. The aim of this paper is to encounter the main aspects of HME reviewing the literature, in order to improve clinical features and evolution, and the metabolic-pathogenetic mechanisms underlying. Although MHE may be asymptomatic, a wide spectrum of clinical manifestations is found in paediatric patients with this disorder. Pain is experienced by the majority of patients, even restricted motion of the joint is often encountered. Sometimes exostoses can interfere with normal development of the growth plate, giving rise to limb deformities, low stature and scoliosis. Other many neurovascular and associated disorders can lead to surgery. The most feared complication is the malignant transformation of an existing osteochondroma into a secondary peripheral chondrosarcoma, during adulthood. The therapeutic approach to HME is substantially surgical, whereas the medical one is still at an experimental level. In conclusion, HME is a complex disease where the paediatrician, the geneticist and the orthopaedic surgeon play an interchangeable role in diagnosis, research and therapy. We are waiting for new studies able to explain better the role of HS in signal transduction, because it plays a role in other bone and cartilage diseases (in particular malignant degeneration) as well as in skeletal embryology.

Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial.

BACKGROUND: Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. METHODS: We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. FINDINGS: We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. INTERPRETATION: Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater. FUNDING: Italian Sarcoma Group.

Post-relapse survival in patients with Ewing sarcoma.

BACKGROUND: Post-relapse survival (PRS) was evaluated in patients with Ewing sarcoma (EWS) enrolled in chemotherapy protocols based on the use of high-dose chemotherapy with busulfan and melfalan (HDT) as a first-line consolidation treatment in high-risk patients. PROCEDURE: EWS patients enrolled in ISG/SSG III and IV trials who relapsed after complete remission were included in the analysis. At recurrence, chemotherapy based on high-dose ifosfamide was foreseen, and patients who responded but had not received HDT underwent consolidation therapy with HDT. RESULTS: Data from 107 EWS patients were included in the analysis. Median time to recurrence (RFI) was 18 months, and 45 (42%) patients had multiple sites of recurrence. Patients who had previously been treated with HDT had a significantly (P = 0.02) shorter RFI and were less likely to achieve a second complete remission (CR2). CR2 status was achieved by 42 (39%) patients. Fifty patients received high-dose IFO (20 went to consolidation HDT). The 5-year PRS was 19% (95% CI 11 to 27%). With CR2, the 5-year PRS was 48% (95% CI 31 to 64%). Without CR2, median time to death was six months (range 1-45 months). According to the multivariate analysis, patients younger than 15 years, recurrence to the lung only, and RFI longer than 24 months significantly influenced the probability of PRS. CONCLUSIONS: Age, pattern of recurrence, RFI, and response to second-line chemotherapy influence post-relapse survival in patients with recurrent Ewing sarcoma. No survival advantage was observed from chemotherapy consolidation with HDT.

Neuroblastoma with symptomatic epidural compression in the infant: the AIEOP experience.

BACKGROUND: Symptoms of epidural compression (SEC) in children with neuroblastoma (particularly infants) may be misinterpreted, leading to delay in diagnosis. PATIENTS AND METHODS: Clinical, imaging and follow-up data of 34 infants with neuroblastoma and SEC diagnosed between 2000 and 2011 at Italian AIEOP centers were retrieved and reviewed. RESULTS: Median age at initial SEC was 104 days (IQR 47-234). Main symptoms included motor deficit (85.3%), pain (38.2%), bladder and bowel dysfunctions (20.6% each). In the symptom-diagnosis interval (S-DI) (median, 12 days; IQR 7-34), the frequency of grade 3 motor deficit increased from 11.8% to 44.1% and that of bladder dysfunction from 20.6% to 32.4%. S-DI was significantly longer (P = 0.011) for patients developing grade 3 motor deficit. First treatment of SEC was neurosurgery in 14 patients, and chemotherapy in 20. SEC regressed in 11 patients (32.3%), improved in 9 (26.5%), and remained stable in 14 (41.2%), without treatment-related differences. Median follow-up was 82 months. At last visit, 11 patients (32.3%) were sequelae-free while 23 (67.7%) had sequelae, including motor deficit (55.9%), bladder (50.0%) and bowel dysfunctions (28.4%), and spinal abnormalities (38.2%). Sequelae were rated severe in 50% of patients. Severe sequelae scores were more frequent in patients presenting with spinal canal invasion >66% (P = 0.039) and grade 3 motor deficit (P = 0.084). CONCLUSIONS: Both neurosurgery and chemotherapy provide unsatisfactory results once paraplegia has been established. Sequelae developed in the majority of study patients and were severe in a half of them. Greater awareness by parents and physicians regarding SEC is warranted.

High-dose chemotherapy with autologous stem cell rescue for treatment of retinoblastoma: report of five cases.

RB is a primarily pediatric cancer arising from the retina, initiated by biallelic loss of the RB1 gene. We report five children with bilateral RB (n = 3), extra-ocular disseminated RB, or disseminated relapsed RB, who were treated with tandem high-dose chemotherapy and autologous stem cell rescue. All patients received at least 2.2 × 10(6) /kg CD34(+) (median, 3.9 × 10(6) /kg) cells. The preparative regimen for course 1 was carboplatin, thiotepa, etoposide, and for course 2, CM and melphalan. ANC of at least 0.5 × 10(9) /L occurred at a median of 11 days (range, 10-12) and 15 days (range, 12-16) after the first and second procedure, respectively. Platelet engraftment occurred at a median of 13 days (range, 12-17) and 15 days (range, 14-22) after the first and second procedure, respectively. All of the five patients treated remain alive and disease free at the last follow-up time, ranging between 21 and 44 months after completion of autologous transplant. Additional therapy was required in one patient, in whom enucleation had to be performed because of early disease relapse, refractory to local therapy. Intensification of chemotherapy with repeated high-dose chemotherapy and autologous rescue appears an acceptable choice in selected cases with bilateral or extra-ocular disease, either recurrent or refractory.

Primary Chest Wall Ewing Sarcoma: Treatment and Long-Term Results.

OBJECTIVE: The aim of the study is to evaluate early and long-term results of chest wall primary Ewing's sarcoma patients treated in the time period February 2000-February 2023 by a multidisciplinary approach. METHODS: We retrospectively reviewed the medical records of patients who underwent chest wall resection for a primary tumor. Treatment approach, extent of resection, 30-day mortality, overall survival (OS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS) were analyzed. RESULTS: Overall, n = 15 consecutive patients were treated for chest wall primary Ewing's sarcoma. A median of n = 3 ribs was resected with a median of n = 2 ribs adjacent to the lesion. Resections were extended to the adjacent structures in n = 5 patients (33.3%). In all cases, we performed a prosthetic reconstruction, associated with muscle flap (n = 10, 66.6%) or with rigid titanium bars and muscle flap (n = 6, 40%). A radical resection was accomplished in n = 13 patients (84.6%). The median surgical time was 310 ± 120 min; median hospitalization was 7.8 ± 1.9 days. Post-operative mortality was zero. We recorded n = 4 (30.7%) post-operative complication. The median follow-up (FU) was 26 months. Moreover, 5-year overall and event-free survival were 52% and 48%, respectively. CONCLUSIONS: This case series confirms the benefit of the multidisciplinary approach for Ewing sarcomas in early and long-term results.

Joint-Sparing Resection around the Knee for Osteosarcoma: Long-Term Outcomes of Biologic Reconstruction with Vascularized Fibula Graft Combined with Massive Allograft.

(1) Background: We aim to address the following questions. What was the complication rate of vascularized fibula graft (VFG) combined with massive allograft in patients treated with joint-sparing resection around the knee for a high-grade osteosarcoma? What was the long-term survivorship of VFG free from revision and graft removal? What were the functional results as assessed by the Musculoskeletal Tumor Society (MSTS) score? (2) Methods: 39 patients treated in our unit for osteosarcoma around the knee with intercalary resection and reconstruction with VFG combined with massive allograft were included; 26 patients underwent intercalary tibial resection, while 13 underwent intercalary femoral resection. (3) Results: Mean Follow-Up was 205 months (28 to 424). Complications that required surgery were assessed in requiring surgical revision in 19 patients (49%) after a mean of 31 months (0 to 107), while VFG removal was necessary in three patients (8%). The revision-free survival of the reconstructions was 59% at 5 years and 50% at 10 to 30 years. The overall survival of the reconstructions was 95% at 5 to 15 years and 89% at 20 to 30 years. The mean MSTS score was 29.3 (23 to 30). (4) Conclusions: VFG represents an effective reconstructive option after joint-sparing intercalary resection around the knee for osteosarcoma.

Blockade of IL-10 Signaling Ensures Mifamurtide Efficacy in Metastatic Osteosarcoma.

Osteosarcoma (OS) is the most common primary malignancy of the bone, highly aggressive and metastasizing, and it mainly affects children and adolescents. The current standard of care for OS is a combination of surgery and chemotherapy. However, these treatment options are not always successful, especially in cases of metastatic or recurrent osteosarcomas. For this reason, research into new therapeutic strategies is currently underway, and immunotherapies have received considerable attention. Mifamurtide stands out among the most studied immunostimulant drugs; nevertheless, there are very conflicting opinions on its therapeutic efficacy. Here, we aimed to investigate mifamurtide efficacy through in vitro and in vivo experiments. Our results led us to identify a new possible target useful to improve mifamurtide effectiveness on metastatic OS: the cytokine interleukin-10 (IL-10). We provide experimental evidence that the synergic use of an anti-IL-10 antibody in combination with mifamurtide causes a significantly increased mortality rate in highest-grade OS cells and lower metastasis in an in vivo model compared with mifamurtide alone. Overall, our data suggest that mifamurtide in combination with an anti-IL-10 antibody could be proposed as a new treatment protocol to be studied to improve the outcomes of OS patients.

Late effects of chemotherapy and radiotherapy in osteosarcoma and Ewing sarcoma patients: the Italian Sarcoma Group Experience (1983-2006).

BACKGROUND: Patients with osteosarcoma and Ewing sarcoma have achieved longer survival over the past decades, but late side effects of chemotherapy and radiotherapy have become important concerns. METHODS: The authors reviewed all patients with localized osteosarcoma or Ewing sarcoma who had been enrolled in the Italian Sarcoma Group neoadjuvant protocols from 1983 through 2006. Data were updated in December 2010 to determine 3 endpoints: the incidence of a secondary primary cancer (designated as "second malignant neoplasm" [SMN]), infertility, and cardiotoxicity. RESULTS: Data were available on 883 patients with osteosarcoma and 543 patients with Ewing sarcoma. In the osteosarcoma group, there were 39 SMNs (4.4%) in 36 patients; in the Ewing sarcoma group, 15 patients (2.8%) experienced a single SMN each. The cumulative 10-year and 20-year incidence of an SMN (±standard error) was 4.9% ± 0.9% and 6.1% ± 1.2%, respectively, in the osteosarcoma group and 3.4% ± 0.9% and 4.7% ± 1.6%, respectively, in the Ewing sarcoma group. The most common SMN in the osteosarcoma group was breast cancer (n = 11), and the most common SMN in the Ewing sarcoma group was radiotherapy-induced osteosarcoma (n = 6). After 20 years, the risk of developing an SMN increased, whereas the risk of a recurrence of the primary tumor decreased. Permanent sterility was more common in males than in females. Doxorubicin cardiotoxicity occurred in 18 patients with osteosarcoma (2%) and in 7 patients with Ewing sarcoma (1.3%). CONCLUSIONS: The awareness of late side effects in long-term survivors of primary bone cancers should encourage longer follow-up.

Urinary endothelin-1-like immunoreactivity excretion in Wilms' tumor survivors.

BACKGROUND: We evaluated urinary endothelin (ET)-1-like Immunoreactivity (uET-1 L) excretion in Wilms tumor (WT) survivors and investigated its relationships with glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Glomerular hemodynamics were also assessed by Gomez formulae. METHODS: Seventeen WT survivors underwent renal sequential scintigraphy for residual kidney function determination including ERPF and GFR. Forty-five healthy individuals were selected as the control group. uET-1 L was measured by radioimmunoassay from the 24-h urine collection. RESULTS: In WT survivors, uET-1 L excretion was significantly higher than in controls. Significant correlations were found between uET-1 L and ERPF and GFR. Cluster analysis, applied on uET-1 L, identified two different patient groups. Between them, GFR and ERPF were significantly different. No significant difference existed between the two clusters for age and sex, elapsed time from nephrectomy, treatment, or nephrectomy side. Applying Gomez formulae, significant difference was found for afferent and total renal resistance. CONCLUSIONS: According to our results, uET-1 L seems to be a marker of glomerular injury in patients with renal mass loss revealing renal overload condition. The uET-1 L role in renal damage progression and hemodynamic glomerular worsening in nephrectomized patients should be proven by prospective long-term follow-up studies, even for potential ET-1 receptor antagonist therapeutic use.

A Unique Case of Primary Cutaneous Adenoid Cystic Carcinoma Associated with Aplasia Cutis Congenita in a Four-Year-Old Female: A Case Report.

INTRODUCTION: Primary cutaneous adenoid-cystic carcinoma (PCACC) is a rare malignant tumour reported in only about 450 cases in the literature, with only two adolescent cases reported. PCACC seems to occur between the fifth and seventh decade of life, and the most frequent regions involved are head and neck (46%). Aplasia cutis congenita (ACC) has an incidence of 1:10,000, and it seems to be rarely associated with neoplastic lesions. Interestingly, the association between PCACC and ACC has, so far, never been described. METHODS: We report a case of PCACC in the scalp associated with ACC in a four-year-old patient. DISCUSSION: The patient was under follow-up at the dermatology unit, but suddenly a red lesion appeared within the ACC. This red, ulcerated area increased rapidly over six months, so it was surgically removed, and the pathological examination results were suggestive for cribriform PCACC. According to the guidelines for skin tumours, the patient underwent widening resection, and an advancement-sliding skin flap was performed to recreate the scalp. After one year of follow-up, the patient has no local or widespread recurrence of the PCACC, and the surgical scar appears to have healed well. CONCLUSIONS: This clinical case is the first known patient with PCACC associated with ACC. A skin excision biopsy should be performed with wide margins to avoid a second widening resection of skin in a similar scenario. Genetic studies may help to identify the origin of this rare association.