Hisaki Aiba

Preoperative evaluation of the efficacy of radio-hyperthermo-chemotherapy for soft tissue sarcoma in a case series

Purpose Radio-hyperthermo-chemo (RHC) therapy, which combines radiotherapy, hyperthermia, and chemotherapy, for malignant soft tissue tumors has been introduced with the aim of decreasing the possibility of local recurrence after surgery. To avoid unnecessary neoadjuvant therapy and to plan the appropriate surgical treatment, surveillance of RHC therapeutic efficacy during treatment is necessary. In this study, we determined the optimal response criteria to evaluate the efficacy of RHC by comparing preoperative images before and after RHC with pathological evaluation of necrosis in the resected tumor. Patients and methods From 2004 to 2014, 20 patients were enrolled into this study. Needle biopsy revealed 6 cases of myxoid liposarcoma, 6 cases of undifferentiated pleomorphic sarcoma, 4 cases of myxofibrosarcoma, and 4 cases of synovial sarcoma. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or modified RECIST, we calculated the responses to RHC therapy by comparing pre- and post-RHC therapy images. In addition, resected specimens underwent pathological analysis to evaluate response based on tumor necrosis. The correlation between assessment based on preoperative images and resected tumors were evaluated by the Spearman’s rank-order correlation coefficient. Result From the surgical specimens, pathological assessment of necrosis in resected tumor were assessed as less than 50% (2 cases), 50–90% (9 cases), 90–99% (6 cases), and total necrosis (3 cases). Use of the RECIST 1.1 underestimated good responders as stable disease (SD) or progressive disease (PD) in 5 out of 15 cases; on the other hand, use of the modified RECIST did not underestimate the pathological assessment of necrosis. The correlations between responses based on preoperative images and those based on histological assessments were 0.23 (RECIST 1.1) and 0.76 (modified RECIST). Conclusion Because pathological responses can be underestimated using the RECIST 1.1, the modified RECIST, which take into consideration tumor viability, as assessed by contrast MRI, should also be considered when evaluating the efficacy of RHC.

Clinical outcomes of radio-hyperthermo-chemotherapy for soft tissue sarcoma compared to a soft tissue sarcoma registry in Japan: a retrospective matched-pair cohort study

Regional hyperthermia is considered to enhance the antitumor effects of chemotherapy and radiotherapy. In this study, we confirmed the efficacy of concomitant radiotherapy, hyperthermia, and chemotherapy (RHC) for neoadjuvant treatment of malignant soft tissue sarcoma (STS). From 1994 to 2013, we performed RHC in 150 patients. This study was limited to 60 patients using the following exclusion criteria: salvage for recurrence or unplanned excision, trunk location, metastasis at initiation, non‐STS, and no definitive surgery. As a control group, we collected data from 11,031 patients in the Bone and Soft Tissue Tumor Registry in Japan (BSTT). We performed multivariate logistic regression analysis, and propensity scores were created for comparisons between groups. The primary outcome of this study was to compare oncologic outcomes (5‐year local control rate [LC] and overall survival rate [OS]). In the RHC group, two local recurrences (3.3%) occurred, and no patients underwent amputation. Margins of definitive surgery were not identical between groups [wide margins (60.0% vs. 85.3%), marginal margins (28.3% vs. 10.5%), and intralesional margins (7.4% vs. 4.2%), RHC and BSTT groups, respectively, P < 0.001]. After adjustment, the difference in OS was not significant between groups (HR = 1.26, P = 0.532); however, a statistically significant difference in LC was observed (HR = 4.82, P = 0.037). RHC resulted in a high LC at 5 years compared to the BSTT group, and amputation was averted in the RHC group, despite the wider margins in the BSTT group. This indicates that less invasive surgery might be achieved with effective neoadjuvant therapy.

Efficacy of radio-hyperthermo-chemotherapy as salvage therapy for recurrent or residual malignant soft tissue tumors

Abstract Background: Recurrence after wide excision or residual tumor after an unplanned excision of a malignant soft tissue sarcoma (STS) is a complex problem, due to a higher recurrence rate and poorer survival rate compared with primary resection. Regional hyperthermia was used, with the expectation that it will enhance the anti-tumor effects of chemotherapy and radiotherapy. This study aimed to assess the efficacy of neoadjuvant concomitant radiotherapy, hyperthermia, and chemotherapy (RHC) for salvage of recurrent or residual malignant STS. Methods: We identified 64 patients with recurrent or residual STS treated between 1994 and 2013. After excluding those with low-grade malignancy, with recurrent bone tumor in the soft tissues, with truncal STS, and who declined to participate, 23 patients (7 with recurrence and 16 with residual tumor) underwent RHC. The histologic diagnoses were undifferentiated pleomorphic sarcoma (n = 11), synovial sarcoma (n = 3), leiomyosarcoma and myxoid liposarcoma (n = 2 each), and other histologic types. As primary outcomes, the 5-year overall survival (OS), distant metastasis-free survival (D-MFS), and local control (LC) rates were evaluated by Kaplan-Meier analysis. Results: The median follow-up period was 112.3 months. The 5-year OS, D-MFS, and LC were 86.4%, 77.4%, and 86.7%, respectively. In the univariate analysis, tumor depth was considered as a negative prognostic factor for OS and D-MFS, and a positive margin was also a negative prognostic factor for OS, D-MFS LC with retained on Cox proportional hazards model in OS, and D-MFS. Conclusion: RHC is an effective option for salvage treatment of recurrent and residual STS.

Anti-tumor effects of a nonsteroidal anti-inflammatory drug zaltoprofen on chondrosarcoma via activating peroxisome proliferator-activated receptor gamma and suppressing matrix metalloproteinase-2 expression

Surgical resection is the only treatment for chondrosarcomas, because of their resistance to chemotherapy and radiotherapy; therefore, additional strategies are crucial to treat chondrosarcomas. Peroxisome proliferator‐activated receptor gamma (PPARγ) is a ligand‐activated transcription factor, which has been reported as a possible therapeutic target in certain malignancies including chondrosarcomas. In this study, we demonstrated that a nonsteroidal anti‐inflammatory drug, zaltoprofen, could induce PPARγ activation and elicit anti‐tumor effects in chondrosarcoma cells. Zaltoprofen was found to induce expressions of PPARγ mRNA and protein in human chondrosarcoma SW1353 and OUMS27 cells, and induce PPARγ‐responsible promoter reporter activities. Inhibitory effects of zaltoprofen were observed on cell viability, proliferation, migration, and invasion, and the activity of matrix metalloproteinase‐2 (MMP2); these effects were dependent on PPARγ activation and evidenced by silencing PPARγ. Moreover, we showed a case of a patient with cervical chondrosarcoma (grade 2), who was treated with zaltoprofen and has been free from disease progression for more than 2 years. Histopathological findings revealed enhanced expression of PPARγ and reduced expression of MMP2 after administration of zaltoprofen. These findings demonstrate that zaltoprofen could be a promising drug against the malignant phenotypes in chondrosarcomas via activation of PPARγ and inhibition of MMP2 activity.

Efficacy and Limitations of F-18-fluoro-2-deoxy-D-glucose Positron Emission Tomography to Differentiate Between Malignant and Benign Bone and Soft Tissue Tumors

Background/Aim: Positron emission tomography (PET) using 18fluorine-labelled fluorodeoxyglucose (FDG), is the most widely applied molecular imaging technique in oncology. The present study assessed the efficacy and limitations of FDG-PET by comparing FDG accumulation in bone and soft tissue lesions, as well as histopathological features. Patients and Methods: The study included 122 patients with 165 lesions, as assessed by histopathological examinations. The maximum standardized uptake values (SUVmax) of benign lesions were compared to those of primary, recurrent, or metastatic sarcomas, as well as those of other malignancies. Results: The sensitivity, specificity, and accuracy of SUVmax for differentiation between benign lesions and primary sarcomas were 67.9%, 92.9%, and 80.4%, respectively. There were no significant differences between benign lesions and recurrent or metastatic sarcomas. Conclusion: Although FDG-PET is a useful imaging modality to differentiate primary sarcomas from benign lesions, it is difficult to differentiate residual or metastatic sarcomas from benign lesions.

Factors Associated With Discharge Destination in Advanced Cancer Patients With Bone Metastasis in a Japanese Hospital

Objective To analyze patient characteristics of cancer rehabilitation and outcomes at our hospital. Methods This retrospective study analyzed 580 patients, who underwent cancer rehabilitation at our hospital and rehabilitation outcome after therapy were investigated. The relationship between the initial Barthel index and discharge outcomes was investigated, with a special focus on cancer patients with bone metastasis. The Barthel index and performance status (Eastern Cooperative Oncology Group) before and after rehabilitation were analyzed, and threshold value of home discharge was calculated from a receiver operating characteristic curve (ROC). General criteria for home discharge from our hospital included independence in performing basic activities of daily living such as bathing, feeding, and toileting or availability of home support from a family member/caregiver. Results The outcomes after rehabilitation among all the patients were as follows: discharge home 59%, death 13%, and others 27%. Statistical differences were observed between the initial and final values of the Barthel index in patients with bone metastasis, who could be discharged home (p=0.012). ROC analysis of the initial Barthel index for predicting home discharge revealed a threshold value of 60, sensitivity of 0.76, and specificity of 0.72. Conclusion The patients with bone metastasis had a lower rate of home discharge and a higher rate of mortality than all the study patients who underwent cancer rehabilitation at our hospital. It is proposed that at the time of initiation of rehabilitation for patients with bone metastasis, an initial Barthel index lower than 60 might predict a worse outcome than home discharge.

Sequential histological findings and clinical response after carbon ion radiotherapy for unresectable sarcoma

Background and purpose The efficacy of carbon ion radiotherapy (CIRT) for bone and soft tissue sarcoma has been reported recently. Although histological assessment after CIRT requires skilled interpretation, little information is presently available. In this study, we report sequential histological findings after treatment with CIRT, and evaluate the association between these findings and clinical response. Material and methods Seven patients with unresectable sarcoma underwent needle biopsy 12 times at an average of 14.3 months after CIRT and were included in this study. Results One patient underwent two biopsies after CIRT for chordoma. Although a few suspected residual chordoma cells were observed at 19 and 30 months after CIRT, the tumor continued to shrink at 75 months. Immunohistochemical analysis of post-CIRT specimens revealed CK AE1/3, EMA, and S100 expression, as in the pre-CIRT specimen. In total, viable tumor cells were found in 9 of 12 specimens; however, only 2 patients showed recurrent masses on radiological examination. The other 5 patients had stable disease. Conclusions Viable tumor cells after CIRT did not always cause recurrence. This may be due to observation of dying cells or radiation-induced deformed cells. Histological evaluation after CIRT should be done carefully.