Yasuo Beppu

Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. METHODS This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. FINDINGS 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7-4·8) for pazopanib compared with 1·6 months (0·9-1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24-0·40; p<0·0001). Overall survival was 12·5 months (10·6-14·8) with pazopanib versus 10·7 months (8·7-12·8) with placebo (HR 0·86, 0·67-1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. INTERPRETATION Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy. FUNDING GlaxoSmithKline.

Immunohistochemical analysis of MDM2 and CDK4 distinguishes low-grade osteosarcoma from benign mimics.

Parosteal osteosarcoma and low-grade central osteosarcoma are two types of low-grade osteosarcoma that show similar clinical behaviors, histological features, and genetic background (ie, amplified sequences of 12q13–15, including MDM2 and CDK4). Low-grade osteosarcoma is often confused with benign lesions, and ancillary techniques to enhance diagnostic accuracy have been awaited. This study explores the use of MDM2 and CDK4 immunohistochemistry for the histological diagnosis of low-grade osteosarcoma. We studied 23 cases of low-grade osteosarcoma from 21 patients (parosteal osteosarcoma (n=14), low-grade central osteosarcoma (n=9)) and 40 cases of benign histological mimics (myositis ossificans (n=11), fibrous dysplasia (n=14), osteochondroma (n=6), desmoplastic fibroma (n=1), florid reactive periostitis (n=4), Noras lesion (n=3), and turret exostosis (n=1)). Low-grade osteosarcoma labeled for MDM2 in 16 cases (70%) and for CDK4 in 20 cases (87%). All low-grade osteosarcomas expressed one or both markers (100%), with 13 cases (57%) expressing both. Staining pattern was diffuse in most cases, and the majority expressed moderate or strong intensity for either antibody. MDM2/CDK4 immunostaining was shown irrespective of low-grade osteosarcoma histological subtype. In contrast, only 1 Noras lesion out of the 40 miscellaneous benign processes showed immunoreactivity for MDM2 or CDK4. The combination of these two markers thus shows 100% sensitivity and 97.5% specificity for the diagnosis of low-grade osteosarcoma. MDM2 and CDK4 immunostains therefore reliably distinguish low-grade osteosarcoma from benign histological mimics, and their combination may serve as a useful adjunct in this difficult differential diagnosis.

Pfetin as a Prognostic Biomarker of Gastrointestinal Stromal Tumors Revealed by Proteomics

Purpose: We aimed to develop prognostic biomarkers for gastrointestinal stromal tumors (GIST) using a proteomic approach. Experimental Design: We examined the proteomic profile of GISTs using two-dimensional difference gel electrophoresis. The prognostic performance of biomarker candidates was examined using a large-scale sample set and specific antibodies. Results: We identified 43 protein spots whose intensity was statistically different between GISTs with good and poor prognosis. Mass spectrometric protein identification showed that the 43 spots corresponded to 25 distinct gene products. Eight of the 43 spots derived from pfetin, a potassium channel protein, and four of the eight pfetin spots had a high discriminative power between the two groups. Western blotting and real-time PCR showed that pfetin expression and tumor metastasis were inversely related. The prognostic performance of pfetin was also examined by immunohistochemistry on 210 GIST cases. The 5-year metastasis-free survival rate was 93.9% and 36.2% for patients with pfetin-positive and pfetin-negative tumors, respectively (P < 0.0001). Univariate and multivariate analyses revealed that pfetin expression was a powerful prognostic factor among the clinicopathologic variables examined, including risk classification and c-kit– or platelet-derived growth factor receptor A mutation status. Conclusions: These results establish pfetin as a powerful prognostic marker for GISTs and may provide novel therapeutic strategies to prevent metastasis of GIST.

Synovial sarcoma of the soft tissues: Prognostic significance of imaging features

Objective: This study assessed the prognostic value of computed tomography (CT) and magnetic resonance (MR) imaging features in synovial sarcoma of the soft tissues. Methods: CT and MR imaging studies were performed in 30 patients with pathologically confirmed synovial sarcoma of the soft tissues. CT and MR imaging findings obtained by 2 radiologists with agreement by consensus were compared for histopathologic features including tumor grade. Univariate analyses were conducted to clarify the impact of imaging findings on overall survival with a medium duration of 32 months. Multivariate analysis was estimated using a Cox proportional hazards model with the relative risk of each variable. Results: Statistically significant imaging findings favoring a diagnosis of high-grade tumor included proximal distribution (P < 0.01), large tumor size (>10 cm, P < 0.05), the absence of calcification (P < 0.05), tumor possessing cyst (P < 0.01), the presence of hemorrhage (P < 0.05), and the presence of triple signal pattern (P < 0.05). Univariate analysis showed that proximal distribution (P < 0.05), tumor size larger than 5 cm (P < 0.01), the absence of calcification (P < 0.01), the presence of hemorrhage (P < 0.05), and the presence of triple signal pattern (P < 0.05) had a significant association with the disease-free survival (DFS). Multiple logistic regression models revealed that tumor size larger than 10 cm had a significant impact on the DFS with relative risk of 18.8 (P < 0.05). Conclusion: CT and MR imaging studies allow prognosis prediction in patients with synovial sarcoma of the soft tissues.

Clear cell sarcoma of tendons and aponeuroses: a study of 75 patients.

Clear cell sarcoma (CCS) of tendons and aponeuroses (malignant melanoma of soft parts) is a rare melanocytic soft tissue sarcoma. The objective of this study was to determine the clinical features, prognostic factors, and optimal treatment policy for patients with this rare disease.

Multiinstitutional phase II study of neoadjuvant chemotherapy for osteosarcoma (NECO study) in Japan: NECO-93J and NECO-95J

BackgroundOsteosarcoma is the most frequent primary malignant bone tumor. In Europe and the United States, its prognosis has been greatly improved by the use of multimodal treatment, including preoperative and postoperative chemotherapy as well as surgery. In Japan, however, only a few clinical studies on osteosarcoma have been carried out.MethodsTo evaluate the efficacy of neoadjuvant chemotherapy on nonmetastatic, operable osteosarcoma arising in the extremities, a prospective multiinstitutional phase II trial, the Neoadjuvant Chemotherapy for Osteosarcoma (NECO) study, was conducted. Preoperative chemotherapy included high-dose methotrexate (HD-MTX), cisplatin (CDDP), and adriamycin (ADR). If the induction therapy was assessed as not effective, high-dose ifosfamide (IFO) was added to the chemotherapy regimen. A total of 124 patients were enrolled in this trial, and ultimately 113 patients were eligible.ResultsThe 5-year overall survival (OAS) and event-free survival (EFS) rates in the NECO study were 77.9% and 65.5%, respectively. A good histological response to the induction chemotherapy resulted in favorable OAS (78.7%). The patients assessed as poor histological responders with progressive disease after the induction chemotherapy exhibited comparable outcomes (OAS 89.5%, EFS 68.2%). There were no significant differences between the OAS and EFS rates of the patients in terms of response to preoperative chemotherapy.ConclusionsWe analyzed the results of the intensive neoadjuvant chemotherapy and the effects of adding IFO on patients with osteosarcoma in Japan. The results suggest efficacy of the high-dose IFO addition to the standard three-drug chemotherapy regimen. However, a randomized clinical study is needed to establish the true impact of IFO on patients with osteosarcoma.

Primary dedifferentiated liposarcoma of the retroperitoneum. Prognostic significance of computed tomography and magnetic resonance imaging features.

Objectives To describe computed tomography (CT) and magnetic resonance (MR) imaging findings and to determine the prognostic significance of radiologic appearances in primary dedifferentiated liposarcoma of the retroperitoneum. Methods Initial CT and MR imaging studies of 20 pathologically confirmed cases of primary dedifferentiated liposarcoma of the retroperitoneum were retrospectively reviewed and assessed for correlations with the histopathologic features. CT and MR images were evaluated by 2 radiologists with agreement by consensus, and univariate analyses were conducted to evaluate survival with a mean clinical follow-up duration of 47 months (range, 5–114 months). Results Tumor invasion was more frequent in the anterior or posterior pararenal originating tumors than in pararenal tumors (P < 0.05). Well-defined nonlipomatous masses juxtaposed with fatty tumors were identified in all cases. Calcification or ossification was seen in 6 patients (30%) on unenhanced CT. Imaging findings including attenuation, signal characteristics, and enhancement patterns of nonlipomatous masses were nonspecific regardless of histologic variances. Recurrent tumors (n = 6) tended to invade surrounding organs. Univariate analysis revealed that calcification or ossification (P < 0.05) and first recurrence with duration of a mean 13 months (P < 0.05) identified by imaging studies had significant impacts on overall survival. Conclusions Calcification or ossification and first recurrence identified by CT and MR imaging studies are significant adverse prognostic factors in primary dedifferentiated liposarcoma of the retroperitoneum.

Expression of epidermal growth factor receptor, ERBB2 and KIT in adult soft tissue sarcomas : A clinicopathologic study of 281 cases

Little is known about the expression of receptor tyrosine kinases in adult soft tissue sarcomas (STS). In the current study, the authors analyzed the expression of epidermal growth factor receptor (EGFR), ERBB2, and KIT in 281 patients with STS who were treated in a single institution. Verification of the presence of an association with prognosis was performed.

Prognostic Relevance of a Histological Grading System Using MIB-1 for Adult Soft-Tissue Sarcoma

Several histological grading systems have been proposed and found as strong indicators of outcome in soft-tissue sarcomas. However, a putative independent prognostic influence of recently developed biological and molecular markers remains to be established. This study investigated the prognostic relevance of a histological grading system based on the assessment of proliferative activity in adult soft-tissue sarcomas of the extremities, trunk, head, and neck. Tissue blocks from 95 of 108 patients without distant metastases or regional lymph node involvement were available. Immunohistochemical staining for MIB-1 and p53 was done on paraffin-embedded sections. All clinicopathologic and immunohistochemical variables and patient survival were assessed using univariate and multivariate analyses. Variables included histological grading based on the modified Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system using the MIB-1 score for the estimation of the proliferative potential of the tumors. Variables associated with overall survival were tumor site in the trunk, head and neck, mitosis count, necrosis, MIB-1 score, FNCLCC grade, modified FNCLCC grade using the MIB-1 score, and stage (all p values <0.05). In multivariate analysis, the modified grade proved to be the most significant predictor of shortened overall survival, in addition to tumor site in the trunk, head, and neck. Overexpression of p53 did not correlate with increased risk of tumor mortality. Using MIB-1 to replace mitosis counts in the FNCLCC system improves grading of soft-tissue sarcomas, and this in conjunction with other important factors appear to be more accurate prognostic factors for survival, and for patient selection in investigational adjuvant treatment trials.

Pelvic ring reconstruction with the double- barreled vascularized fibular free flap

Background: Although hemipelvectomy has been the standard treatment for malignant tumors of the pelvis, limb salvage surgery is now the treatment of choice, even for patients with advanced tumors. For these patients, pelvic reconstruction is needed to maintain the stability of the pelvis and the spinal column and to allow ambulation. In this report, the authors’ experiences with pelvic ring reconstruction are described. Methods: Pelvic ring reconstruction with free double-barreled vascularized fibular grafts was performed after resection of malignant pelvic tumors in five patients. The graft was fixed with a fixation plate and screws in three patients and with the Cotrel-Dubousset rod system in two patients. After surgery, perioperative and postoperative findings were evaluated. Results: In one patient, a pedicled rectus abdominis musculocutaneous flap was transferred to repair defects of the skin and underlying soft tissue. The free fibular graft was transferred successfully in four of five patients; however, the graft was removed in one patient because of infection with methicillin-resistant Staphylococcus aureus. After surgery, three of the four patients with successful grafts could walk with full weight bearing and without a cane; the fourth patient died as a result of multiple metastases to the lung before walking was attempted. Conclusions: The double-barreled fibular graft is well vascularized and can achieve satisfactory bone union. It is a safe and effective method for reconstructing the pelvic ring. Furthermore, the Cotrel-Dubousset rod system can provide rigid fixation soon after surgery and is useful for early rehabilitation of walking.