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Malignant peripheral nerve sheath tumor (MPNST) often does not respond well to chemotherapy and develops against a background of NF1. The purpose of our study was to examine the efficacy of pazopanib against MPNST. Our study was designed as a physician-initiated phase II clinical trial in patients with advanced MPNST. Patients were registered from 11 large hospitals. The primary endpoint was set to clarify the clinical benefit rate (CBR) at 12 weeks according to response evaluation criteria in solid tumors (RECIST). Progression-free survival (PFS), overall survival (OS) and the CBR based on modified Choi evaluation at week 12 were set as secondary endpoints along with treatment-related safety. The study enrolled 12 patients. Median age was 49 years. Seven had Grade 2 and five Grade 3 according to the FNCLCC evaluation. Median follow-up period was 10.6 months. CBR at 12 weeks was both 50.0% (RECIST and Choi). The median PFS was 5.4 months for both RECIST and Choi, and the median OS was 10.6 months. Of special interest, the median PFS was 2.9 months for patients with FNCLCC Grade 2 and 10.2 months for Grade 3 (both RECIST and Choi). Grade 4 adverse events of neutropenia and lipase elevation were noted in one patient each. The results of this pazopanib therapy were generally better than those of any of the other single molecular targeted therapies reported previously. Although accumulation of more cases remains necessary, we conclude pazopanib treatment for MPNST to be a safe and promising treatment after doxorubicin-based chemotherapy., (© 2020 Union for International Cancer Control.)

Background and Objectives: The aim of this study is to assess the survival, function, radiographic appearance, and modes of failure of extracorporeal irradiated (ECI) autografts in a long-term setting., Methods: We retrospectively reviewed 87 patients who were treated for bone and soft tissue tumors using ECI autografts between 1988 and 2009., Results: The 56 patients had a minimum follow-up of 10 years, and the median follow-up period was 16.5 years. The reimplantation procedures included 24 osteoarticular grafts, 16 intercalary grafts, 10 autograft-prosthetic composite grafts, and 6 hemicortical grafts. The 15-year graft and event-free survival rates were 76.8% and 47.9%, respectively. Infection and structural failure were the most common reasons for additional surgery. The time for additional surgery was significantly longer in patients with composite grafts (P < .01). The median Musculoskeletal Tumor Society score and the International Society of Limb Salvage score were 80% and 84%, respectively., Conclusions: ECI autografts are a durable option for reconstruction after resection of musculoskeletal tumors and provide good function over more than 15 years. Most graft failures occurred within 5 years of the index surgery. However, composite grafts showed a tendency to fail more than 10 years after the surgery., (© 2020 Wiley Periodicals, Inc.)

Granular cell tumors (GCTs) are rare mesenchymal tumors that exhibit a characteristic morphology and a finely granular cytoplasm. The genetic alterations responsible for GCT tumorigenesis had been unknown until recently, when loss-of-function mutations of ATP6AP1 and ATP6AP2 were described. Thus, we performed whole-exome sequencing, RNA sequencing, and targeted sequencing of 51 GCT samples. From these genomic analyses, we identified mutations in genes encoding vacuolar H + -ATPase (V-ATPase) components, including ATP6AP1 and ATP6AP2, in 33 (65%) GCTs. ATP6AP1 and ATP6AP2 mutations were found in 23 (45%) and 2 (4%) samples, respectively, and all were truncating or splice site mutations. In addition, seven other genes encoding V-ATPase components were also mutated, and three mutations in ATP6V0C occurred on the same amino acid (isoleucine 136). These V-ATPase component gene mutations were mutually exclusive, with one exception. These results suggest that V-ATPase function is impaired in GCTs not only by loss-of-function mutations of ATP6AP1 and ATP6AP2 but also through mutations of other subunits. Our findings provide additional support for the hypothesis that V-ATPase dysfunction promotes GCT tumorigenesis., (© 2018 Wiley Periodicals, Inc.)

Paraneoplastic syndromes (PNSs) associated with mesenchymal tumors are uncommon. Previous reports sporadically described inflammatory PNSs with elevated serum C-reactive protein (CRP) levels and leukocytosis in patients with inflammatory malignant fibrous histiocytoma (MFH) of soft tissue; however, the relationship between other subtypes of MFH and PNS has not been extensively investigated. Forty-six patients with primary MFH of soft tissues who underwent radical surgery were retrospectively analyzed. These patients were divided into 2 groups according to preoperative serum CRP level: normal (<1.0 mg/dl) and elevated (> or = 1.0 mg/dl). The correlation between serum CRP level and several clinicopathologic factors was analyzed. Correlation between preoperative serum CRP level and metastasis-free and overall survival was also investigated by univariate and multivariate analyses. Elevated preoperative serum CRP levels were found in 65% of patients with a mean of 3.7 mg/dl. There were statistically significant relationships regarding tumor size, depth, histologic subtypes, grade, stage and metastatic rate among normal and elevated CRP groups (p < 0.001, p < 0.02, p < 0.005, p < 0.001, p < 0.001 and p < 0.05, respectively). When the tumor was removed, the elevated CRP level subsided into the normal range and other abnormal laboratory findings diminished in all cases. In 11/14 relapsed cases that showed elevated CRP preoperatively, the serum CRP level re-elevated with tumor relapse. The normal CRP group showed significantly more favorable prognosis than the elevated CRP group in metastasis-free and overall survival on univariate analysis (p < 0.02, p < 0.05, respectively). Patients with MFH frequently present with an inflammatory PNS, such as elevated serum CRP level, which can be a useful marker of disease activity and a valuable prognostic indicator., (Copyright 2002 Wiley-Liss, Inc.)

Background and Objectives: Tumor size is one of the independent factors affecting prognosis of patients with soft tissue sarcoma (STS). We evaluated the significance of tumor size in combination with tumor depth in each histologic grade., Methods: A total of 162 adult patients with localized STS in the extremities and trunk were selected. Patient ages ranged from 15 to 84 (median 46.5) years with a male-to-female ratio of 1.19. Histologic grade of tumors was low in 53 cases, intermediate in 51, and high in 58. Two types of categorization were set, and their significance in predicting the prognosis of patients in each grade was evaluated. In the first category (intermediate grade), tumors were dichotomized at 10 cm: Group A comprised patients with deeply seated tumors measuring > 10 cm; Group B comprised patients other than those in Group A. In the second category (high grade), tumors were dichotomized at 5 cm: Group C comprised patients with deeply seated tumors measuring > 5 cm; Group D comprised patients other than those in Group C., Results: Categorization was not useful in the prognosis of low grade tumors. In the intermediate grade group, the 5-year-survival rate of Group B patients (78%) was higher than in Group A patients (59%) (P < 0.05), showing that dichotomization at 10 cm was useful. In the high grade group, the 5-year survival rate in Group C patients (32%) was lower than in Group D patients (56%), showing that dichotomization at 5 cm was useful., Conclusions: These findings show that tumor size for the prognosis of patients with STS differs according to each histologic grade.

Transgenic mice deficient for the p53 gene were reported to frequently develop angiosarcoma (AS), suggesting that alterations in the gene are associated with tumorigenesis of AS. However, little is known about genetic changes, including p53 gene alterations, in human AS because of its rarity. We analyzed p53 mutations on paraffin-embedded specimens from 33 patients with AS by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) followed by direct sequencing. Age of patients ranged from 18 to 91 (median 70) years, with a male to female ratio of 1.5:1. Sites of tumor were the head in 13 patients, the trunk in 4, the extremities in 4, the heart in 4, bones in 2 and others in 6. PCR-SSCP revealed aberrant mobility shifts of bands in 17 cases: 11 in exon 5, 5 in exon 7 and 4 in exon 8. Direct sequencing on these 17 cases revealed a total of 20 mutations. The frequency of p53 mutations was different by site of tumors: 7 of 13 in head, all 4 in extremities, 2 of 4 in heart and none of 4 in trunk. Our findings suggest that occurrence of p53 mutation is a major pathway for development of human AS.

Malignant lymphomas frequently develop in the pleural cavity of patients with long-standing pyothorax. The term pyothorax-associated lymphoma (PAL) has been proposed for this type of tumor. Most PALs are diffuse lymphomas of the B-cell type and contain Epstein-Barr virus (EBV) DNA. We have established 2 lymphoma cell lines from biopsy specimens of PAL cases, OPL-1 and OPL-2, and examined their growth characteristics and the expression of EBV latent infection genes and oncogenes. OPL-2 exhibited a more rapid growth and higher saturation density than OPL-1, and only OPL-2 exhibited colony-forming activity in soft agar. OPL-1 and -2 were positive for B-cell differentiation markers and showed clonal surface immunoglobulins. Both line contained a single predominant form of episomal EBV DNA, indicating clonal cellular proliferation of an EBV-infected progenitor cell. OPL-1 and -2 contained type B and A EBV genome, respectively. Expression of EBV nuclear antigen (EBNA)2 mRNA and protein was detected by Northern and Western blot analysis in OPL-1, but not in OPL-2. On the other hand, the expression of latent membrane protein (LMP)1 mRNA in both OPL-1 and -2 was extremely weak and detectable only by reverse transcription-polymerase chain reaction. Protein expression of LMP1 was not observed by Western blot analysis or immunocytochemistry. Both lines expressed c-myc mRNA. Only OPL-1 expressed mRNA of c-fgr, an oncogene whose expression is upregulated by EBNA2. Both OPLs expressed bcl-2 mRNA without detectable expression of LMP1 protein.

Data for prognostic factors in angiosarcoma (AS) are limited, prompting a large-scale study of AS with multivariate analysis. To analyze prognostic factors in angiosarcoma (AS), clinical and histologic findings in 55 patients collected from hospitals in Japan were reviewed. Prognostic factors were evaluated by univariate and multivariate Cox's proportional hazards models. The study involved 32 males and 23 females, ages 18-93 (median, 69) years. The primary sites of tumors included head and neck (32 cases), trunk (10), extremities (3), spleen (3), breast (3), and other (4). The overall 2-year survival rate was 21%. Univariate analysis of clinical factors including age, sex, size and depth of tumor, tumor-related symptoms, interval between onset of symptoms and admission, surgical procedures, adjuvant chemotherapy, and adjuvant radiotherapy showed that age, tumor size, and mode of treatment were significant for survival. Histologic factors analyzed were mitotic counts, cellularity, cellular pleomorphism, extent of necrosis, vascular differentiation, and nonspecific diagnosis. Only mitotic counts were significant for prognosis. Multivariate analysis on these four factors revealed that tumor size, mode of treatment, and mitotic counts were independent prognostic factors.

In order to define the significant factors for a staging system of soft-tissue sarcomas (STS), histologic and clinical findings in 190 adult patients with localized STS in the extremities and trunk were reviewed. The male-to-female ratio was 1.21. The histologic grading of tumors was defined according to the criteria recently proposed by us: tumors were low-grade in 65 cases, intermediate-grade in 57 cases and high-grade in 68 cases. The initial surgical procedure was as follows: intracapsular excision in 9 cases, marginal excision in 104 and wide local excision in 77, including 15 amputations. The mode of treatment was surgery alone (101 patients), surgery and chemotherapy (58), surgery and radiotherapy (22) and surgery and combined chemo- and radiotherapy (9). Univariate analysis revealed histologic grade, sex, tumor size and tumor depth to be significant prognostic factors. Multivariate analysis revealed histologic grade to be the only independent factor for prognosis. Significant clinical factors in each histologic grade were then evaluated. In the low-grade group, local recurrence significantly affected prognosis. Most of the patients with local recurrence had had marginal resection as the initial surgical procedure. No clinical factors affecting prognosis in the intermediate-grade group could be determined. In the high-grade group, patients with wide local excision and adjuvant chemotherapy had a better prognosis than those with marginal excision with or without adjuvant chemotherapy and wide local excision without chemotherapy (p = 0.09). In conclusion, histologic grade was the only significant factor for the staging of STS. On the basis of our staging system, different modalities of treatment for each grade of STS might be indicated; adequate surgery is essential for the prevention of local recurrence, which resulted in reduced mortality in patients with low-grade STS. For high-grade STS, the prevention of distant metastasis by combined extensive surgery and adjuvant chemotherapy may make long-term survival possible.

Accurate histologic grading is essential for making a proper therapy decision in soft-tissue sarcomas (STS). The usefulness of the argyrophilic stain for nucleolar organizer region (AgNOR) in assessing the histologic grade of STS has been examined. One hundred and forty-two patients with STS confined to the extremity and trunk were selected. Tumors were classified based on the criteria of Enzinger and Weiss ["Soft-Tissue Tumors." St. Louis: C. V. Mosby, 1983]. In addition, non-specific classification was made based on the shape of proliferating cells occupying more than 50% of the field in the sections such as pleomorphic cell, small round cell, spindle cell, epithelioid cell, myxoid, and unclassified tumors. The mean number of AgNOR dots per nucleus of tumor cells was calculated in 200 cells (AgNOR count). Each category of non-specific classification was divided into a high-count group (< 8 AgNOR count) and a low-count group (> 8 NOR). The low-count group showed a significantly better prognosis than the high-count group in small round cell and spindle cell tumors (P < 0.007 and P < 0.0005, respectively). Similar results were obtained in pleomorphic cell tumors, though they were statistically not significant because of the relatively small number of examined cases. Most patients with epithelioid cell and myxoid tumors were in the low-count group. These findings suggest that the assessment of histologic grading of STS could be made effectively by the non-specific classification and the aid of AgNOR staining.