Favorable outcomes of localized synovial sarcoma patients with a high utilization rate of neoadjuvant and/or adjuvant chemotherapy.

Synovial sarcoma (SS) is considered to be a chemosensitive, soft tissue sarcoma. Therefore, neoadjuvant and/or adjuvant chemotherapy (N/AC) is used for the treatment of high-risk SS patients. However, the role of N/AC remains controversial. The present study aimed to review the clinical outcomes of surgically treated localized SS and investigate the effects of N/AC with long-term observation. The clinical outcomes of 54 patients with surgically treated localized SS were retrospectively analyzed. The median patient age was 42 years (range, 8-81 years), and the median follow-up period was 94 months for survivors (range, 7-220 months). A total of 38 patients (70%) received chemotherapy. Of these, 32 (59%) patients received neoadjuvant chemotherapy, 33 (61%) received adjuvant chemotherapy, and 27 (50%) received neoadjuvant and adjuvant chemotherapy. Fourteen patients (26%) received adjuvant radiotherapy. Three patients (6%) had local recurrence and 13 patients (24%) developed distant metastasis. The overall survival (OS) rates at 5 and 10 years were 87 and 84%, respectively. N/AC did not improve survival. In conclusion, we found satisfactory long-term OS among patients with a high utilization rate of N/AC. Further study should be necessary to evaluate which population of SS would benefit from N/AC.

Prognostic implication of adjuvant/neoadjuvant chemotherapy consisting of doxorubicin and ifosfamide in patients with extraskeletal osteosarcoma.

BACKGROUND: Extraskeletal osteosarcoma (ESOS) is an extremely rare soft tissue sarcoma. Their prognosis remains poor. Our purposes were to identify the effective chemotherapeutic regimen for ESOS. METHODS: We retrospectively reviewed 16 patients with ESOS treated at the Osaka University Orthopaedic Oncology Group between 1992 and 2012. We extracted the clinical data on patients. Kaplan-Meier method and the log-rank test were used for survival analyses. RESULTS: Median age of the patients was 61.5 years (range 25-79 years). Wide local excision was performed for 11 patients and 9 patients were treated combined with chemotherapy. The 5-year disease-specific survival (DSS) rate was 53.9%. The 5-year DSS rates for patients treated with adjuvant/neoadjuvant chemotherapy or not were 66.7% or 25%, respectively (p = 0.0215). Furthermore, the 5-year DSS rates for patients treated with adjuvant/neoadjuvant chemotherapy consisting of doxorubicin and ifosfamide and those treated with other regimens were 100% or 40%, respectively (p = 0.0327). CONCLUSION: The present study demonstrated that adjuvant/neoadjuvant chemotherapy, especially consisting of doxorubicin and ifosfamide, was potentially efficacious for ESOS. Further prospective study using this multimodality treatment approach to patients with ESOS should be strongly warranted.

Survival analysis of elderly patients with osteosarcoma.

BACKGROUND: Few studies have described the characteristics and prognostic factors of elderly patients with osteosarcoma. We retrospectively investigated clinico-pathological features and prognostic factors in osteosarcoma patients > 40 years old. METHODS: Patients with high-grade osteosarcoma > 40 years old who were treated at our institutions from 2000 to 2016 were recruited for this study. Information on patient, tumour, and treatment-related factors was collected and statistically analyzed. The median follow-up was 26.5 months (range, 5-139 months) for all patients. RESULTS: Fifty patients (30 males and 20 females) were included. The median age at diagnosis was 59.5 years (range, 41-81 years). The primary lesions were found in the limbs in 32 patients, trunk in 12, and craniofacial bones in six. Primary and secondary osteosarcoma occurred in 41 and 9 patients, respectively. Eight patients exhibited initial distant metastasis. Definitive surgery and chemotherapy were performed in 39 patients each. The rate of good responders after neoadjuvant chemotherapy was 38%. The five year overall survival (OS) rates for all patients and those without distant metastasis at diagnosis were 44.5% and 51.1%, respectively. Multivariate analysis showed that definitive surgery was the only significant prognostic factor in non-metastatic patients. The five year OS and disease-free survival (DFS) rates for non-metastatic patients who received definitive surgery were 64.3% and 60%, respectively. Among these patients, neoadjuvant and/or adjuvant chemotherapy significantly improved both OS and DFS. CONCLUSIONS: Complete surgical resection and intensive chemotherapy should be performed for osteosarcoma patients > 40 years old despite distinct clinicopathological characteristics from those of younger patients.

Clinical outcomes of patients with epithelioid sarcomas: impact and management of nodal metastasis.

PURPOSE: An epithelioid sarcoma is a rare histological subtype of a soft tissue sarcoma with a high local recurrence rate, which frequently shows lymph node metastasis. However, because of the rarity of this tumor, the impact of nodal metastasis and its appropriate management remain unclear. The present study investigated the clinical outcomes of patients with epithelioid sarcomas, with a focus on lymph node metastasis. METHODS: We retrospectively evaluated the clinical outcomes of 27 patients with epithelioid sarcomas treated between 1985 and 2015. The log-rank test was used to assess the prognostic variables. RESULTS: The overall local recurrence rate was 33%, and the estimated overall 5-year survival rate was 62%. Hand and foot locations were associated with favorable overall survival. During the follow-up period, new nodal metastasis was noted in 14 patients (52%). The incidence of local recurrence was higher in patients with new nodal metastasis than in patients who did not develop nodal metastasis. The development of new nodal metastasis had a tendency to worsen survival; however, this association was not statistically significant. Lymphadenectomy did not affect overall survival. CONCLUSIONS: Peripheral tumor location is associated with a better prognosis. The development of new nodal metastasis tends to be associated with poor prognosis; however, among patients with nodal metastasis, resection of the metastatic lesions has a low impact on survival.

Comparison of clinical and functional outcome between surgical treatment and carbon ion radiotherapy for pelvic chondrosarcoma.

BACKGROUND: As there are no reports of studies in patients with pelvic chondrosarcoma treated with carbon ion radiotherapy (CIRT), the aim of this study was to evaluate the applicability of CIRT for patients with chondrosarcoma of the pelvis. METHODS: The medical records of 31 patients with chondrosarcoma of the pelvis treated either by surgical resection or by CIRT between 1983 and 2014 were reviewed. There were 22 males and 9 females with a median age of 43 years (range 16-77 years). The median duration of follow-up was 66 months (range 5-289 months). Twenty-four patients underwent surgery, and 7 patients received CIRT (70.4 GyE in 16 fractions over 4 weeks). RESULTS: The overall local recurrence rate was 32 %, and the estimated overall 5- and 10-year survival rates were 72 and 57 %, respectively. The mean Musculoskeletal Tumor Society functional score was 59 %. The treatment procedures (surgery or CIRT) did not affect overall survival (P = 0.347). However, the patients who underwent surgery had impaired function compared with those who received CIRT (P = 0.03). CONCLUSION: Although more patients need to be monitored to assess the clinical and functional outcomes of CIRT for patients with chondrosarcoma of the pelvis, this treatment might offer an acceptable alternative.

Choroid Plexus Metastasis of Follicular Thyroid Carcinoma Diagnosed due to Intraventricular Hemorrhage.

Choroid plexus metastasis (CPM) is extremely rare and originates most frequently from renal cell carcinoma (RCC). We herein report the case of a 58-year-old man who developed a solitary CPM lesion derived from follicular thyroid carcinoma in addition to intraventricular hemorrhage. Computed tomography revealed acute hydrocephalus as a result of the hemorrhage, and we planned endoscopic hematoma evacuation. Since it was too difficult to reach the hematoma, we considered the possibility of a neoplasm and performed a biopsy of the lesion, the results of which led to an accurate diagnosis of CPM in this case. We also review previous reports of CPM originating from thyroid carcinoma compared with RCC.

Knee reconstruction with endoprosthesis after extra-articular and intra-articular resection of osteosarcoma.

OBJECTIVE: Extra-articular resection is necessary to obtain a wide margin for primary osteosarcomas invading the knee joint, and the limb is often reconstructed using a prosthesis. Here, outcomes of extra-articular and intra-articular procedures were compared. METHODS: Between 1999 and 2012, 14 patients with osteosarcoma underwent extra-articular excision (n = 6; ages 23-65 years; mean follow-up 82.8 months) or intra-articular excision (n = 8; ages 8-58 years; mean follow-up 96.4 months). In the extra-articular group, there was one Enneking Stage IIA case and five Enneking Stage IIB cases. No local recurrences were noted in either group. RESULTS: Patient outcomes were as follows (extra-articular cases vs. intra-articular cases): continuous disease-free (2 vs. 7), alive with disease (2 vs. 0) and death from disease (1 vs. 1). Average Musculoskeletal Tumor Society functional scores were 69.4% (range 63.3-83.3%) and 88.3% (range 70.0-96.7%) in the extra-articular and intra-articular groups, respectively, constituting a significant difference (P < 0.05). The 5-year oncological overall survival exceeded 80% in both groups. Amputation was necessary for one patient in the extra-articular group. The 5-year event-free prosthesis survival rates in the extra-articular and intra-articular groups were 33.3 and 75.0%, respectively (P < 0.05). CONCLUSION: The extra-articular excision group developed more complications than the intra-articular excision group, as a result of extensive bone and muscle excision. The limb survival rates were similar in both groups. Our results suggest that extra-articular resection was a necessary and clinically acceptable procedure.

[Effect of transarterial chemoembolization for recurrent desmoid tumor - a case report].

Desmoid fibromatosis is classified as a benign soft tissue tumor regardless of its local invasive behavior and its, local recurrence rate is 57-85% after local resection. A 19 y/o male patient with post-operative recurrence of a desmoid tumor in the shoulder was initially treated by arterial embolization; however, no improvement of symptoms was obtained. As second-line treatment, 20 mg of epirubicin, 50 mg of cisplatin and 250 mg of 5-FU were infused to tumor-related arteries and embolization was performed with a super absorbent polymer microsphere. After a single session of treatment, reduction of tumor size and improvement of symptoms were achieved. The same treatment was repeated three times without major complications. Considerable reduction of tumor was obtained after treatment. Chemo-embolization should be considered for the postoperative recurrence of desmoid fibromatosis, in order to prevent loss of function and maintain a high QOL for the patient.

Primary amyloidoma in epidural and paravertebral space of the lumbar spine.

BACKGROUND CONTEXT: Localized amyloid deposits result in a mass, that is, so-called amyloidoma; it has been reported in every anatomic site, although systemic amyloid deposition is much more common. However, primary lumbar epidural amyloidoma without bony involvement is extremely rare. To the best of our knowledge, only one case has been reported previously. PURPOSE: To report and review the clinical presentations, imaging studies, and treatment of epidural and paravertebral amyloidoma. STUDY DESIGN: A case report and review of the literature. METHODS: Lumbar epidural and paravertebral amyloidoma in a 75-year-old man with neurologic compromise is presented. Laminectomy with mass resection was performed. RESULTS: After surgery, almost complete neurologic improvement was observed. Histologically, definite diagnosis was obtained only after the specific staining of tissue. No sign of local recurrence was evident 1 year after surgery. CONCLUSIONS: Primary amyloidoma, although rare, should be included in the differential diagnosis of epidural mass of the spine. Diagnosis before surgery is difficult as there were no characteristic findings in clinical and imaging studies. Special histologic technique and stains are useful to make a definite diagnosis.

Neoadjuvant and adjuvant chemotherapy with high-dose ifosfamide, doxorubicin, cisplatin and high-dose methotrexate in non-metastatic osteosarcoma of the extremities: a phase II trial in Japan.

From 1997 to 2003, 40 patients (all <40 years of age) with non-metastatic osteosarcoma of the extremities were treated with OOS-D and definitive surgery. Two cycles of doxorubicin 90 mg/m(2) plus cisplatin 120 mg/m(2) and ifosfamide 15 g/m(2) were given as neoadjuvant chemotherapy, and two cycles of doxorubicin/cisplatin and ifosfamide, and two cycles of high-dose methotrexate (10-12 g/m(2)) were given post-operatively. All patients underwent limb salvage surgeries, and 66% showed good response to neoadjuvant chemotherapy. With a median follow-up period of 117 months, 31 of the evaluable 40 patients were continuously disease-free, 7 were currently alive with no evidence of disease, and 2 died of disease. There was no local recurrence. The 5-year event-free and overall survival rates were 83 and 98%, respectively. The 10-year event-free and overall survival rates were 80 and 95%, respectively. The major form of toxicity was haematological one.

Novel fully interconnected porous hydroxyapatite ceramic in surgical treatment of benign bone tumor.

BACKGROUND: Large bone defects remaining after curettage of benign bone tumors should be filled with a substitute to restore mechanical strength. In 2000, we developed a fully interconnected porous calcium hydroxyapatite ceramic (IPCHA, NEOBONE) and have utilized it as a bone substitute. IP-CHA has a finely organized, three-dimensional interconnecting pore structure. The large interconnecting channels (average diameter 40 microm) permit easy penetration of tissue into the deep pores, so IP-CHA can itself induce local bone repair processes. The purpose of this study was to evaluate the clinical outcomes with the use of IP-CHA as bone substitute after curettage of benign bone tumors. METHODS: We reviewed the results of 71 patients with benign bone tumors sequentially treated by curettage followed by implantation of IP-CHA between 2000 and 2006. There were 29 women and 42 men, with a mean age of 28 years. Assessment was based on radiography at each time point during the follow-up. Radiographic findings were classified into five stages: stage 0, no change; stage 1, slight bone formation; stage 2, moderate bone formation; stage 3, consolidation; stage 4, absorption. RESULTS: In 70 of 74 operated lesions, radiographs showed that implanted IP-CHA proceeded to stage 2 or more within an average of 8 months after the surgery. In addition, 17 lesions proceeded to stage 4 within 35 months after surgery, on average. However, there were 10 local recurrences, which is similar to the recurrence rate for such tumors treated with or without implantation of CHAs and reflects the biological nature of each tumor. CONCLUSIONS: In this study, we utilized IP-CHA as a bone substitute after curettage of benign bone tumors and demonstrated its usefulness in the clinical situation. IP-CHA comparatively exhibited excellent bone formation at an early stage although the problem of recurrence of the tumor remained. We conclude that IP-CHA is a useful bone substitute for the treatment of benign bone tumors.

Orphan receptor tyrosine kinase ROR2 as a potential therapeutic target for osteosarcoma.

Osteosarcoma is the most prevalent bone malignant tumor in children and adolescents, and displays heterogeneous histology and high propensity for distant metastasis. Although adjuvant chemotherapy remarkably improved treatment outcome over the past few decades, prognosis for osteosarcoma patients with pulmonary metastasis is still unsatisfactory. To identify novel therapeutic targets for osteosarcoma, we investigated the gene expression profile of osteosarcomas by cDNA microarray analysis and found transactivation of receptor tyrosine kinase-like orphan receptor 2 (ROR2) expression in the majority of osteosarcoma samples. Treatment of osteosarcoma cell lines with siRNA against ROR2 significantly inhibited cell proliferation and migration. We also identified wingless-type MMTV integration site family, member 5B (WNT5B) as a putative ROR2 ligand and that the physiological interaction of WNT5B and ROR2 could enhance cell migration, indicating the possible roles of ROR2 and WNT5B in the metastatic property of osteosarcoma cells. Taken together, our findings revealed that the WNT5B/ROR2 signaling pathway is a promising therapeutic target for osteosarcoma.

Validation of radiographic response evaluation criteria of preoperative chemotherapy for bone and soft tissue sarcomas: Japanese Orthopaedic Association Committee on Musculoskeletal Tumors Cooperative Study.

BACKGROUND: The radiographic evaluation of the response to preoperative chemotherapy for bone and soft tissue sarcomas is based mostly on the change in primary tumor size before and after chemotherapy, as is done for many solid cancers. Its prognostic correlation, however, has hardly been validated. METHODS: We conducted a retrospective validation study of the Japanese Orthopaedic Association (JOA) radiographic response evaluation criteria of preoperative chemotherapy for bone and soft tissue sarcomas as a JOA Committee on Musculoskeletal Tumors cooperative study. A total of 125 consecutive patients with high-grade bone (n = 77) and soft tissue (n = 48) sarcomas treated with neoadjuvant chemotherapy and definitive surgery in 25 tertiary referral hospitals were selected for the study. We investigated the correlation between the tumor size-based radiographic response evaluation criteria of preoperative chemotherapy for bone and soft tissue sarcomas provided by the JOA Committee on Musculoskeletal Tumors (hereafter called the JOA criteria) and the patients' overall survival using the Kaplan-Meier method and the log-rank test. RESULTS: The JOA criteria correlated relatively well with survival for malignant bone tumors (mostly comprising osteosarcoma and Ewing's sarcoma) but not for soft tissue sarcomas, suggesting that the tumor size-based radiographic evaluation criteria for the response to preoperative chemotherapy in patients with soft tissue sarcomas is invalid. CONCLUSIONS: The JOA criteria, based on the change in primary tumor size, is valid for malignant bone tumors but invalid for soft tissue sarcomas. Other new evaluation modalities of the response to preoperative chemotherapy using innovative functional imaging techniques are needed for soft tissue sarcomas.

Usefulness of limb salvage surgery for bone and soft tissue sarcomas of the distal lower leg.

PURPOSE: The usefulness of limb salvage surgery for distal lower leg sarcoma remains controversial. We analyzed the long-term prognosis, limb function, and complications after limb salvage treatment of patients with distal lower leg sarcoma. METHODS: Ten patients treated with limb salvage surgery for primary distal lower leg sarcoma were retrospectively reviewed. The median follow-up period after the first operation was 9.0 years. We performed three types of reconstructive techniques for the skeletal defect after a wide resection, including (1) arthrodesis with a combination of autograft and intraoperative autoclaved tumor bone graft in two patients, or allograft in one patient, (2) ankle joint preserving surgery using intraoperative extracorporeal irradiated tumor bone graft in five patients, and (3) prosthesis in two patients. RESULTS: The overall survival rate was 80%. The 5-year disease-free survival was 80%. The rate of limb preservation at the final follow-up was 90%. The mean functional score according to the scoring system of the Musculoskeletal Tumor Society was 88% at the final follow-up. Postoperative complications occurred in seven patients. Skin trouble occurred in three patients, infectious non-union in one patient, fracture in three patients, and loosening of prosthesis in one patient. CONCLUSIONS: Despite the high rate of complications, patients treated with limb salvage surgery for the distal lower leg sarcoma revealed excellent final functional results without impairing the oncologic results. Limb salvage surgery is therefore considered to be an effective treatment option for distal lower leg sarcoma when adequate informed consent can be obtained from the patient.

Prognostic implication of SYT-SSX fusion type in synovial sarcoma: a multi-institutional retrospective analysis in Japan.

The prognostic implication of SYT-SSX fusion type in synovial sarcomas is still controversial. The aim of this study is to clarify the prognostic impact of fusion type, in association with other clinical factors, in patients with synovial sarcoma in Japan. Data on 108 SYT-SSX fusion transcript-positive patients with synovial sarcoma, treated in 11 tertiary referral cancer centers in Japan, were retrospectively analyzed. The following parameters were examined for their potential prognostic impact: SYT-SSX fusion type, patient age at presentation, sex, primary tumor location, tumor size, histological subtype, histological grade, treatment modalities and disease stage at presentation. Among the patients with localized disease at presentation, 5-year overall survival (OS) for SYT-SSX1 and -2 subgroups were 84.4 and 74.9%, respectively (P=0.244). Five-year metastasis-free survival (MFS) rates were 67.8% for SYT-SSX1 and 68.5% for SYT-SSX2 (P=0.949). Univariate survival analyses for 91 patients with localized disease at presentation showed that tumor size was the only significant prognostic factor for OS (P=0.0033) and MFS (P=0.0029) and the histological grade was marginally significant for MFS (P=0.0785), whereas the SYT-SSX fusion type and other variables were not. Multivariate survival analyses further indicated that tumor size was the most significant independent prognostic factor for OS and MFS and the histological grade was also significant for MFS. In conclusion, the SYT-SSX fusion type is not a significant prognostic factor unlike tumor size, followed by histological grade for patients with localized synovial sarcoma in Japan.

Analysis of germline and tumor mutations of p53 gene in familial occurrence of soft tissue sarcomas.

BACKGROUND: Familial soft tissue sarcomas are extremely rare. There is little information available on the clinical features and molecular findings of the hereditary occurrence of mesenchymal tumor. PATIENTS AND METHODS: A woman and her younger brother had malignant fibrous histiocytoma (pleomorphic type) and liposarcoma (pleomorphic type) in the lower limbs, respectively. Analysis of p53 mutations in exons 5-9 of the tumor and in germ-line was done. RESULTS: A guanine to adenine substitution occurred in CGC, codon 175 of exon 5 in p53 gene, to CAC in the tumor sample of Case 1. Likewise, a thymine to cytosine substitution occurred in TTT, codon 270 of exon 8 in p53 gene, to TCT in tumor sample of Case 2. Germline mutations were not seen in the either patients. CONCLUSIONS: Different missense mutations of p53 were detected in each tumor, however no germline mutations of p53 were found. The alteration of codon 175 in Case 1 is relatively common mutation. On the contrary, the mutation in codon 270 in Case 2 was extremely rare in cancers. Further molecular investigation is needed to understand the mechanism in familial occurrence of sarcomas.

Prognostic significance of activated AKT expression in soft-tissue sarcoma.

PURPOSE: AKT is a serine/threonine kinase which is important in tumorigenesis. Several molecules involved in AKT pathway are dysregulated in various kinds of human cancers. PATIENTS AND METHODS: Ninety-three patients (53 males and 40 females), ages ranging from 19 to 77 years (median, 57 years), with localized soft-tissue sarcomas arising in the trunk and extremities, were analyzed. Immunoperoxidase procedure (avidin-biotin complex method) was done on paraffin-embedded sections with anti-phosphorylated AKT (Thr308), anti-phosphorylated p44/42 extracellular signal-regulated kinase 1 and 2 (ERK1/2) (Thr202/Tyr204), anti-phosphorylated forkhead in rhabdomyosarcoma (FKHR) (Ser256), and anti-Ki 67 antibodies. Expression levels of phosphorylated AKT (p-AKT), phosphorylated ERK1/2 (p-ERK1/2), and phosphorylated FKHR (p-FKHR) were categorized as either weaker (level 1) or equal to or stronger (level 2) compared with those in the endothelial cells of the same specimens. Percentage of cells showing intranuclear staining with Ki-67 was shown as the Ki-67 labeling index (LI). Cases were divided into two groups: level 1, Ki-67 LI < 20%; level 2, Ki-67 LI > or = 20%. RESULTS: Twenty-six (28.0%), 6 (6.5%), and 46 (44.1%) of the tumors showed level 2 expression for p-AKT, p-ERK1/2, and Ki-67 LI, respectively. Tumors with level 2 p-AKT expression showed a higher ratio of level 2 p-FKHR expression (P < 0.01). Multivariate analysis revealed p-AKT expression and Ki-67 LI to be independent prognosticators for overall survival, and p-AKT expression for disease-free survival. CONCLUSION: p-AKT expression level is a significant prognosticator in soft-tissue sarcoma.

Reassessment of the 1993 Osaka grading system for localized soft tissue sarcoma in Japan.

BACKGROUND: The Osaka system for soft-tissue sarcoma grading was proposed through an analysis of soft-tissue sarcoma (STS), treated from 1964 to 1989. The present study was conducted to evaluate the utility of the Osaka system under recent therapeutic regimens. PATIENTS AND METHODS: One hundred and eleven patients with localized STSs arising in the trunk and extremities (66 males and 45 females; median age 57) were selected. Histological factors, argyrophilic nucleolar organizer region (AgNOR) count and Ki-67 labeling index (LI) were evaluated for prognostic significance. RESULTS: Univariate analysis revealed that histological classification, mitotic count, cellularity, AgNOR count, and Ki-67 LI were prognostically significant for survival. Multivariate analysis revealed Ki-67 LI as an independent prognostic factor. The five-year survival rate for low-, intermediate-, and high-grade STSs in Osaka grading was 94.6%, 75.2%, and 68.4%, respectively. CONCLUSION: Osaka grading is a useful system for the decision-making of therapeutic modalities for STS.