Purpose: We compared two chemotherapy regimens that included methotrexate (MTX), cisplatin (CDP), and doxorubicin (ADM) with or without ifosfamide (IFO) in patients with nonmetastatic osteosarcoma of the extremity. Patients and Methods: Patients age ≤ 40 years randomly received regimens with the same cumulative doses of drugs (ADM 420 mg/m², MTX 120 g/m², CDP 600 mg/m², and IFO 30 g/m²) but with different durations (arm A, 44 weeks; arm B, 34 weeks). IFO was given postoperatively when pathologic response to MTX-CDP-ADM was poor (arm A) or given in the primary phase of chemotherapy with MTX-CDP-ADM (arm B). End points of the study included pathologic response to preoperative chemotherapy, toxicity, and survival. Given the feasibility of accrual, the statistical plan only permitted detection of a 15% difference in 5-year overall survival (OS). Results: From April 2001 to December 2006, 246 patients were enrolled. Two hundred thirty patients (94%) underwent limb salvage surgery (arm A, 92%; arm B, 96%; P = .5). Chemotherapy-induced necrosis was good in 45% of patients (48% in arm A, 42% in arm B; P = .3). Four patients died of treatment-related toxicity (arm A, n = 1; arm B, n = 3). A significantly higher incidence of hematologic toxicity was reported in arm B. With a median follow-up of 66 months (range, 1 to 104 months), 5-year OS and event-free survival (EFS) rates were not significantly different between arm A and arm B, with OS being 73% (95% CI, 65% to 81%) in arm A and 74% (95% CI, 66% to 82%) in arm B and EFS being 64% (95% CI, 56% to 73%) in arm A and 55% (95% CI, 46% to 64%) in arm B. Conclusion: IFO added to MTX, CDP, and ADM from the preoperative phase does not improve the good responder rate and increases hematologic toxicity. IFO should only be considered in patients who have a poor histologic response to MTX, CDP, and ADM.

Background: Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H + −rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma. Method: MG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre-treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin. Results: Preclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients. Conclusion: This study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy.

Autologous fat tissue grafting (AFTG) has been successfully used in the treatment of different sclerotic conditions, including localized scleroderma. Patients with advanced systemic sclerosis (SSc)-related perioral thickening and mouth opening limitation are candidates for this therapeutic approach. AFTG of the lips was performed to improve mouth opening in patients with SSc. We enrolled in the study 20 female patients with diffuse SSc (median age 35 ± 15 years and 11 ± 10 years of disease duration). Two-milliliter fractions of autologous fat drawn from trochanteric or periumbilical areas were injected in eight different sites around the mouth. Baseline and after-treatment mouth opening changes were assessed by measuring interincisal distance and oral perimeter, while skin hardness was tested by digital durometer. Pre- and posttreatment modifications of microvascular architecture were assessed by counting capillaries in the inferior lip videocapillaroscopy (VC) images and by scoring the microvascular density (MVD) in anti-CD34/CD31 immunohistochemical (IH) stained perioral skin biopsy sections. Similarly, histological sections were examined to evaluate dermoepidermic junction (DEJ) modifications. Three months after treatment, both the interincisal distance and oral perimeter significantly increased ( p < 0.001). At the same time, a significant skin neovascularization became evident, both considering the VC images ( p< 0.001) and MVD scores in IH sections ( p< 0.0001). Finally, some skin histological aspects also improved, as shown by the significant changes in DEJ flattening scores ( p < 0.0001). The present study suggests that, in patients with SSc, AFTG can improve mouth opening and function, induce a neovascularization, and partially restore the skin structure.

Objective . The aim of the study was to evaluate the pattern of the lymphoid organization in the synovial tissue of patients affected with juvenile idiopathic arthritis (JIA). Methods . A total of 40 JIA patients who underwent synoviectomy or synovial biopsies were enrolled. The mean age at surgery was 15.1 yrs (range 6–30 yrs) and the mean disease duration was 6.7 yrs (range 3 months to 22.2 yrs). Tissue specimens were grouped according to the following criteria: (i) diffuse perivascular infiltrate without lymphoid organization, (ii) T cell–B cell aggregates with or without germinal centre reaction. Results . Synovial tissues from 12 JIA patients did not show any sign of lymphoid organization, whereas 28 patients displayed a variable number of T–B cell aggregates. Typical features consistent with a germinal centre reaction were present in two JIA patients only. Lymphoid organization in JIA patients did not correlate with the duration and severity of the disease or with the degree of synovial inflammation, but did positively correlate with the presence of anti-nuclear antibodies. Moreover, a diffuse lymphocyte infiltration was significantly related to the presence of an acute phase of inflammation and the presence of lymphoid aggregates correlated with the degree of plasma cells infiltration. Conclusions . Lymphoid neogenesis in JIA represents a phase in the immunopathological process that characterize the development of inflammatory synovitis. It is not related to disease activity or severity, but appears to be more frequent in patients with circulating anti-nuclear antibodies.