Development of a New Focal Mouse Model of Bone Metastasis in Renal Cell Carcinoma.

BACKGROUND/AIM: Developing animal models of bone metastasis in renal cell carcinoma (RCC) is challenging as immunodeficient mice are required. The aim of this study was to develop a simple immune model of RCC bone metastasis. MATERIALS AND METHODS: RENCA tumor cells were injected into the right femurs of BALB/c mice. Sixty mice were grouped into each twenty-mouse group according to the tumor cell concentration, and the presence or absence and extent of bone metastasis in the total length of the femur were compared using hematoxylin and eosin staining of the excised tissues. RESULTS: Bone metastasis was significantly higher in the high concentration group than in the other groups (p<0.05), with 10 mice developing bone metastasis at two weeks and nine mice developing bone metastasis at three weeks. The extent of bone metastasis was significantly greater in the high concentration group than in the other groups (p<0.05). Multiple logistic regression analysis was performed to examine the factors influencing bone metastasis, and only the high concentration was a significant factor (p<0.05). CONCLUSION: We developed a normal immunity mouse model of local bone metastasis from RCC. This model could prove valuable for research into the treatment of bone metastases in RCC.

Coefficient of variation of T2-weighted MRI may predict the prognosis of malignant peripheral nerve sheath tumor.

BACKGROUND: We investigated whether non-enhancement MRI features, including measurement of the heterogeneity of the tumor with MR T2 imaging by calculating coefficient of variation (CV) values, were associated with the prognosis of non-metastatic malignant peripheral nerve sheath tumors (MPNST). METHODS: This retrospective study included 42 patients with MPNST who had undergone surgical resection (mean age, 50 years ± 21; 20 male participants). Non-enhancement MR images were evaluated for signal intensity heterogeneity on T1- and T2-weighted imaging, tumor margin definition on T1- and T2-weighted imaging, peritumoral edema on T2-weight imaging, and CV. We measured the signal intensities of MR T2-weighted images and calculated the corresponding CV values. CV is defined as the ratio of the standard deviation to the mean. The associations between factors and overall survival (OS) were investigated via the Kaplan-Meier method with log-rank tests and the Cox proportional hazards model. RESULTS: The mean CV value of MR T2 images was 0.2299 ± 0.1339 (standard deviation) (range, 0.0381-0.8053). Applying receiver operating characteristics analysis, the optimal cut-off level for CV value was 0.137. This cut-off CV value was used for its stratification into high and low CV values. At multivariate survival analysis, a high CV value (hazard ratio = 3.63; 95% confidence interval = 1.16-16.0; p = 0.047) was identified as an independent predictor of OS. CONCLUSION: The CV value of the signal intensity of heterogenous MPNSTs MR T2-weighted images is an independent predictor of patients' OS.

Effects of Soft Tissue Sarcoma and Doxorubicin on Bone Metabolism in Mice.

BACKGROUND/AIM: This study aimed to evaluate the effects of doxorubicin (Dox) on bone microstructure and metabolism in a mouse model of soft tissue sarcoma. MATERIALS AND METHODS: CCRF S-180II cells (2-4×105 cells/0.2 ml) were injected subcutaneously into the back of mice. The mice were divided into four groups according to tumor and treatment status and were reared and sacrificed after 2 or 4 weeks. Micro-computed tomography (CT) was performed to calculate the architecture of the femoral bone. The proximal tibia was double stained with tartrate-resistant acid phosphatase (TRACP) and alkaline phosphatase (ALP), and bone morphometry was performed. RESULTS: Trabecular bone mass was significantly reduced in the Sarcoma and Sarcoma+Dox groups. Cortical bone thickness was reduced in the DOX group, with a stronger effect observed in the Sarcoma+Dox group. In bone morphometry, osteoclast number at the bone surface (Oc.N/BS) was significantly lower in the Dox, Sarcoma, and Sarcoma+Dox groups than in the Control group at 2 weeks. The osteoblast surface at the bone surface (Ob.S/BS) was significantly lower in the Dox and Sarcoma groups than in the Control group at 2 weeks. At 4 weeks, the differences were smaller for both Oc.N/BS and Ob.S/BS. CONCLUSION: The use of doxorubicin alone worsened the cortical bone structure; however, the presence of both soft-tissue sarcoma and doxorubicin use worsened both cortical and trabecular bone structures from an early stage.

Soft Tissue Tumor Without Neurofibromatosis Type 1 With Histopathological Suspicion of Atypical Neurofibromatous Neoplasm of Uncertain Biological Potential (ANNUBP).

Atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP), defined as a borderline lesion that is difficult to distinguish whether benign or malignant, is one of the intermediate stages to malignant peripheral nerve sheath tumor, a peripheral nerve-derived malignant tumor that develops from nerve sheath cells. Because ANNUBP is a new concept, only a few cases have been reported, all in patients with neurofibromatosis type 1 (NF-1).An 88-year-old woman presented with a mass on the left upper arm persisting for one year. Magnetic resonance imaging showed a large tumor spreading between the humerus and biceps muscle, which was diagnosed as undifferentiated pleomorphic sarcoma by needle biopsy. Extensive tumor resection was performed, including partial cortical bone resection of the humerus. Based on the histological features, although the patient did not have NF-1, the tumor was strongly suspected to be ANNUBP. As malignant peripheral nerve sheath tumors have been sporadically reported in patients without NF-1, it is feasible that ANNUBP could also occur in patients without NF-1.

Macrophage numbers in the marginal area of sarcomas predict clinical prognosis.

Even when treated comprehensively by surgery, chemotherapy, and radiotherapy, soft-tissue sarcoma has an unfavorable outcome. Because soft-tissue sarcoma is rare, it is the subject of fewer clinicopathological studies, which are important for clarifying pathophysiology. Here, we examined tumor-associated macrophages in the intratumoral and marginal areas of sarcomas to increase our knowledge about the pathophysiology. Seventy-five sarcoma specimens (not limited to a single histological type), resected at our institution, were collected, and the number of CD68-, CD163-, and CD204-positive macrophages in the intratumoral and marginal areas was counted. We then performed statistical analysis to examine links between macrophage numbers, clinical factors, and outcomes. A high number of macrophages positive for all markers in both areas was associated with worse disease-free survival (DFS). Next, we divided cases according to the FNCLCC classification (Grade 1 and Grades 2/3). In the Grade 1 group, there was no significant association between macrophage number and DFS. However, in the Grade 2/3 group, high numbers of CD163- and CD204-positive macrophages in the marginal area were associated with poor DFS. By contrast, there was no significant difference between the groups with respect to high or low numbers of CD68-, CD163-, or CD204-positive macrophages in the intratumoral area. Multivariate analysis identified the number of CD163- and CD204-positive macrophages in the marginal area as an independent prognostic factor. Macrophage numbers in the marginal area of soft-tissue sarcoma may better reflect clinical behavior.

Intravascular Administration of Acridine Orange and Zoledronate in a Bone Metastasis Model of Breast Cancer.

BACKGROUND/AIM: This study evaluated the effect of haematogenous administration of acridine orange (AO) alone and in combination with zoledronate (ZOL) on bone metastases. MATERIALS AND METHODS: E0771 cells (1.0×105 cells/10 µl) were injected directly into the right femur of female mice. The mice were divided into five groups according to treatment (drugs and irradiation) and were reared and sacrificed after 6 weeks. Micro-computed tomography (µCT) was performed to calculate the destruction rate of the femur bone. We measured tumour weight and volume at sacrifice and performed terminal deoxynucleotidyl transferase dUTP Nick-End Labelling staining of tumours. RESULTS: At 4 weeks, the bone destruction rate was lower in the AO+ZOL group than in the radiation group. At 6 weeks, the AO+ZOL group had a lower bone destruction rate than the control and radiation groups; the ZOL group had a lower rate than the radiation group. The AO and AO+ZOL groups had suppressed tumour weight and volume compared to the control and radiation groups. The number of extraosseous apoptotic cells was higher in the AO+ZOL group than in all other groups except the AO group. CONCLUSION: In a model of local bone metastasis of breast cancer, haematogenous administration of AO reduced tumour size and more so when combined with ZOL.

Risk Factors of Early Distant Metastasis After Primary Tumor Treatment in Soft Tissue Sarcoma.

BACKGROUND/AIM: Distant metastasis has a strong influence on prognosis in patients with soft tissue sarcoma (STS). While various risk factors have been reported for distant metastases, risk factors for distant metastases early after treatment of primary tumor have not been investigated. This study aimed to evaluate the factors of early distant metastasis after primary tumor resection in patients with STS. PATIENTS AND METHODS: We retrospectively identified patients with STS involving the extremities or trunk without any metastasis at the first visit. Data on clinical information and detailed assessment were collected. We evaluated clinical information as a risk factor for distant or lung metastases. Additionally, we evaluated risk factors for metastases in patients with distant metastases as early as 6 months after the initial resection of the primary tumor. RESULTS: A total of 337 patients were included in the study. Multivariate analysis revealed that the size of the primary tumor (p=0.0011 and p=0.0167), consultation in a short period after onset (p=0.0325 and p=0.0402), histological high grade (p=0.0006 and p=0.0002), and inadequate surgical margin (p=0.0151 and p=0.0055) were significant predictors for poor prognosis for all distant and lung metastases, respectively. However, the only risk factor for early metastases within 6 months was young age (p=0.0148). CONCLUSION: The only risk factor for early distant metastasis after primary tumor resection in patients with STS was young age, even though large tumor diameter and histological high grade were risk factors for distant metastasis.

Non-ossifying fibromas and fibrous cortical defects around the knee - an epidemiologic survey in a Japanese pediatric population.

BACKGROUND: The aim of the present study was to evaluate the prevalence of non-ossifying fibroma (NOF) and fibrous cortical defect (FCD) in a Japanese pediatric population and the association between the lesion size and pain. METHODS: This retrospective study, conducted across 10 Japanese institutions, included patients aged 5-15 years who had undergone standard antero-posterior and lateral view radiography of the knee. Using these radiographs, we diagnosed the lesion as a NOF or FCD. Patient demographics, including age, sex, the size and location of the NOF, and chief complaint were recorded. The lesion size was determined using radiographs. Student's t-test was used to compare the associations between the lesion size and spontaneous pain. RESULTS: A total of 6222 subjects (3567 boys and 2455 girls) were included in this study. The number of NOF and FCD cases was 143 and 437, respectively, and the prevalence of NOF and FCD was 2.3% and 7.0%, respectively. The average size of NOF and FCD was 22.1 mm (range: 4-102 mm) and 13.2 mm (range: 5-21 mm), respectively. Three patients (2.1%) had pathological fractures due to NOF. Of the 140 NOFs and 437 FCDs, we obtained complaints from the medical records of 126 and 393 patients, respectively. The number of patients with spontaneous pain or other problems with NOF was 68 (54%) and 58 (46%), respectively, that of patients with FCD was 195 (50%) and 198 (50%) patients, respectively. The lesion size was not associated with spontaneous pain in either lesion (p = 0.67 and p = 0.27, respectively). CONCLUSION: The prevalence of NOF and FCD around the knee was lower than that reported in previous studies. The prevalence of NOF increased and that of FCD decreased with advancing age. In both lesions, the lesion size may not be associated with pain.

Development of New Mouse Breast Cancer Model of Local Bone Metastasis and Verification Using Bisphosphonates.

BACKGROUND/AIM: Local tumor injection models require complicated procedures. The purpose was to establish a simple local bone metastasis model using normal mice, and to study the usefulness of the model with bisphosphonates (BP). MATERIALS AND METHODS: This study used a versatile C57BL/6 mouse model and E0771 cells. Tumor cells were injected into the right femur. Mice were divided into groups depending on the concentration of cells injected and the use of BP or not. The degree of bone destruction between the different conditions was compared using micro-computed tomography (µCT). RESULTS: Bone destruction was confirmed in four mice in the high-concentration group at 3 weeks, and in all other mice at 4 and 6 weeks. At 6 weeks post-injection, bone destruction was significantly suppressed in the BP group (p<0.05). CONCLUSION: We created a breast cancer mouse model of local bone metastasis. Zoledronate showed the same usefulness as in previous models. It may be an effective model for evaluating treatments for bone metastasis.

Deep Angiomyxoma of the Thigh That Is Difficult to Diagnose: A Case Report and Literature Review.

We present an extremely rare case of deep angiomyxoma (DAM) in the thigh that was misdiagnosed as desmoid-type fibromatosis. A 40-year-old Japanese woman presented with a mass on the left thigh. The histological diagnosis by needle biopsy was desmoid-type fibromatosis; the tumor grew slowly and was resected 4 years later. The histological diagnosis from the resected tumor was DAM. As of 16 months post-surgery, the patient has not noticed any local recurrence. Although DAM in a lower extremity is extremely rare, clinicians must be aware of its possible occurrence in areas relatively close to the pelvis.

Impact of Primary Tumor Resection on Metastasis to the Lung in Patients With Bone and Soft-tissue Sarcoma.

BACKGROUND: Few reports have investigated the effect of primary tumor resection on lung metastasis and prognosis in patients with bone and soft-tissue sarcoma, and we evaluated its effect on lung metastasis and prognosis. PATIENTS AND METHODS: We retrospectively identified patients with lung metastasis from bone and soft-tissue sarcoma. We examined the factors affecting prognosis and the rate of lung metastasis increase. RESULTS: A total of 48 patients were included. The multivariate analysis revealed that poor prognosis was significantly associated with a large maximum diameter of lung metastasis at the first visit and a rapid rate of increase (p=0.0400 and p=0.0003, respectively). The multivariate logistic regression analysis revealed that the rate of increase of size of lung metastases was only significantly associated with a large maximum diameter at the first visit (p=0.0245). CONCLUSION: Primary tumor resection of bone and soft-tissue sarcoma in patients with lung metastasis was not shown to affect their prognosis.

Impact of a Specialized Outpatient Clinic on Bone Metastasis and Its Burden on Spine Surgeons.

BACKGROUND/AIM: It is important to perform early intervention on bone metastases using multidisciplinary approaches, however it is difficult to hold frequent meetings between patients and clinicians. We aimed to evaluate the usefulness of a specialized outpatient clinic on bone metastasis, instead of the multidisciplinary approach currently in practice. PATIENTS AND METHODS: We included 31 patients with vertebral metastases of various carcinomas, undergoing surgical treatment by spine surgeons. We divided the patients into two groups before and after their visit to the specialized outpatient clinic (pre and post groups), and compared their clinical characteristics. RESULTS: The post group demonstrated a longer period from consulting the spine surgeon to the surgery than the pre group (p=0.0129). A multivariate logistic regression analysis revealed that the period from spine surgeon consultation to surgery was significantly associated with a specialized outpatient clinic visit (p=0.0460). CONCLUSION: Specialized outpatient clinics on bone metastasis could possibly reduce the burden on spinal surgeons.

Tumor Lysis Syndrome due to Eribulin Administration for Metastatic Undifferentiated Pleomorphic Sarcoma of the Buttock.

Tumor lysis syndrome (TLS) is a complication of cancer treatment that requires urgent intervention. It is extremely rare in the treatment of soft tissue sarcoma (STS) of the limbs or trunk, and there are currently no reports of TLS occurrence from eribulin therapy. We report the case of a 78-year-old woman with an undiffer-entiated pleomorphic sarcoma on the right buttock. We initiated chemotherapy with intravenous eribulin mesylate. Deterioration of renal function, mild hyperkalemia, hyperuricemia, hypocalcemia, and hyperphos-phatemia were confirmed on examination, suggesting the presence of TLS. We present an extremely rare case of TLS from eribulin for STS.

Impact of Acridine Orange in Patients With Local Recurrent Soft Tissue Sarcoma.

BACKGROUND/AIM: Local recurrence in soft tissue sarcoma (STS) is a risk factor of worse prognosis. Although a few studies have shown that adjuvant therapy with acridine orange (AO) is effective for local control of primary STS, there have been no reports examining its effectiveness for local recurrence. PATIENTS AND METHODS: This retrospective study included 36 patients with first local recurrence of STS. Of them, 23 patients received wide excision without AO therapy (Wide group); the other 13 patients received marginal excision with AO therapy (AO group). We compared re-recurrence rates between these two groups. RESULTS: The total re-recurrence rate was 43.5% in the Wide group and 46.2% in the AO group. There was no significant difference in local re-recurrence-free survival and overall survival between the two groups. CONCLUSION: Adjuvant AO therapy combined with a marginal excision suppresses local re-recurrence rates of individuals with local STS recurrence.

Prognostic Significance of Histological Subtype in Soft Tissue Sarcoma With Distant Metastasis.

BACKGROUND/AIM: Few studies have examined the prognostic significance of histological subtypes in patients with soft tissue sarcoma (STS) and distant metastasis, and we evaluated the relationship between the histological subtypes and clinical outcomes. PATIENTS AND METHODS: This retrospective study evaluated the histological subtypes of 105 patients with STS and distant metastasis. The STS histological subtypes were compared based on the clinical information. RESULTS: The Kaplan-Meier curves for overall survival revealed that myxoid liposarcoma had a significantly better prognosis compared to Malignant Peripheral Nerve Sheath Tumor (MPNST) (p=0.0221). In the multivariate logistic regression analyses, the independent predictors of a poor prognosis were: i) large size, ii) advanced stage, and iii) non-surgical treatment for metastasis (p<0.05). The presence or absence of lung metastasis was not significantly associated with prognosis (p=0.4452). CONCLUSION: Myxoid liposarcoma had a better prognosis compared to MPNST in STS patients with distant metastasis. The surgical removal of distant metastatic lesions may improve the patient's prognosis.

The value of the black fiber sign on T1-weighted images for predicting stability of desmoid fibromatosis managed conservatively.

OBJECTIVES: It is challenging to know at the first which patients with desmoid fibromatosis (DF) are better suited to conservative or aggressive treatment. To investigate whether the low signal intensity bundles on T1- or T2-weighted images (WI), termed the "black fiber sign (BFS)," can predict non-progressive behavior in the conservative approach. METHODS: This retrospective study included 59 patients with primary DF managed with wait-and-see approach from 2005 to 2018 and serial MR images were analyzed. Three observers blinded to the patient information verified the presence or absence of BFS on baseline T1 or T2WI. The likelihood of progression-free survival (PFS) after ascertaining the presence or absence of the BFS was estimated using the Kaplan-Meier method and analyzed with the log-rank test. RESULTS: PFS was significantly higher in cases with BFS than without BFS on T1WI (p < 0.01), but there was no significant difference in PFS between cases with and without BFS on T2WI. Multivariable Cox proportional hazards analysis revealed that the absence of BFS on T1WI was a high-risk factor for progression (hazard ratio, 14.9; p < 0.01). Drastic tumor regression was apparent with significantly increased low-signal area in cases with BFS on T1WI. Intra- and interobserver reliabilities of BFS on T1WI were in almost-perfect agreement (κ > 0.8). CONCLUSION: Our retrospective observational data support that presence of BFS in baseline MRI may be a predictor for progression-free survival of DF. BFS on T1WI is easily identifiable and can be utilized clinically in patients with DF. KEY POINTS: • We proposed a new imaging marker for prediction of desmoid fibromatosis progression. • The absence of black fiber sign predicted a high risk of disease progression.

Prognostic Factors in Patients with Distant Soft Tissue Metastasis of Carcinoma: A Clinicopathological Study of 16 Cases.

OBJECTIVES: Soft tissue metastasis (STM) is an uncommon condition in carcinoma. Although various case series related to STM have been reported, few reports have examined prognostic factors. This study aimed to evaluate the characteristics of STM and the factors affecting its prognosis. MATERIALS AND METHODS: Patients with STM from carcinoma were retrospectively studied. The patients' information, including age, sex, primary tumor, metastasis location, size of the metastatic tumor, presence of pain, histological classification, history of primary tumor treatment, and other metastasis at diagnosis of STM were collected and associated with prognosis. RESULTS: Overall, 16 patients with a mean age of 68.7 years were evaluated. The overall survival rate was not significantly different between lung cancer and non-lung cancer patients. The overall survival rate was significantly better in patients undergoing definitive treatment for the primary tumor than in those without history of treatment (p = 0.046). The overall survival rate of STM patients with no metastasis was significantly better than those with other metastasis at the diagnosis of STM (p = 0.041). On multivariate analysis, no history of primary tumor treatment and STM without pain were risk factors for prognosis (p = 0.0340 and 0.0474, respectively). None of the patients who developed STM under the skin experienced pain, while 92.3% of the patients who developed STM in the deep layer had pain. CONCLUSION: The risk factors for poor diagnosis of STM were no past treatment of the primary tumor and absence of pain. STM in the deep layer is prone to pain.

Pigmented Villonodular Synovitis Around the Elbow Joint That Required Upper Arm Amputation.

Pigmented villonodular synovitis (PVNS) is a relatively rare benign proliferative disorder of the synovium, and it commonly occurs in the knee joint. A unique case of huge PVNS originating around the elbow joint that required upper arm amputation is reported. A 74-year-old woman had a 5-month history of right elbow pain and noticed a mass measuring 8 × 5 cm on the olecranon side. She had a past history of undergoing tumor resection and flap surgery 9 years earlier, diagnosed as a giant cell tumor involving the right elbow region. She had chronic renal failure, with a shunt on the right forearm. On magnetic resonance imaging, the tumor around the elbow joint showed low signal intensity on T1-weighted images and low to high intensity on T2-weighted images. It was thought that it was difficult to preserve the limb because of the size of the tumor and the shunt blood vessel. Therefore, upper arm amputation was performed. The histological diagnosis was PVNS. There was no recurrence of PVNS postoperatively. In the treatment of PVNS, initial surgery with complete resection of the synovial membrane and careful postoperative follow-up are considered important.

De Novo Granulocytic Sarcoma of the Humerus in an 82-Year-Old Woman: A Case Report.

Granulocytic sarcoma is a rare solid malignant tumor that occurs in patients with acute myeloid leukemia. As such, granulocytic sarcoma without leukemia occurring in long bones is quite rare. This case report describes an isolated granulocytic sarcoma of the right humerus in an 82-year-old woman in the absence of acute myeloid leukemia. The patient was admitted to our hospital with a pathological fracture of the right humerus. An incisional biopsy was performed, and the pathological diagnosis was granulocytic sarcoma. Radiotherapy (45 Gy) to the humerus resulted in a good clinical outcome with no evidence of myeloid leukemia at 9.5 years of follow-up. Radiotherapy was effective for pain relief and maintenance of good quality of life in this patient. Although laboratory evaluation has not revealed any abnormalities 9.5 years after radiotherapy, periodic observation is required.