Differential Diagnosis of Lipomatous Tumors Using 18F-Fluorodeoxygulcose Positron Emission Tomography/Computed Tomography: A Retrospective Observational Study.

Background/Aim: Lipomatous tumors, including lipomas, atypical lipomatous tumors (ALTs), myxoid liposarcomas (MLs), and dedifferentiated liposarcomas (DLs), are often diagnosed using magnetic resonance imaging (MRI). Differential diagnosis of lipomas and ALTs by MRI is often challenging. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has recently been used for the diagnosis and evaluation of tumor staging and recurrence of soft tissue tumors. The maximum standardized uptake value (SUVmax) is positively associated with malignant grade in several cancers. This study aimed to evaluate SUVmax of 18F-FDG PET/CT in the differential diagnosis of lipomatous tumors. Patients and Methods: Patients who underwent 18F-FDG PET/CT for the diagnosis of lipomatous tumors between January 2013 and September 2021 were included in the study. Patients with lipomatous tumors, confirmed by pathological diagnosis or surgical specimens, were evaluated for lipomatous tumor SUVmax. Results: This study included 44 patients with lipomas (n=19), ALTs (n=12), MLs (n=9), and DLs (n=4). The mean SUVmax of lipomas, ALTs, MLs, and DLs was 0.99±1.41, 1.92±0.95, 5.21±4.94, and 9.29±1.43, respectively. Lipomas showed a significantly lower SUVmax than did ALTs, MLs, and DLs (p<0.05). ALTs demonstrated a significantly lower SUVmax than did MLs and DLs (p<0.05). No significant differences were observed between MLs and DLs. Conclusion: Lipomas or ALTs had a significantly lower SUVmax than lipomatous sarcomas. Lipomas had a significantly lower SUVmax than ALTs, aiding in their preoperative differentiation. 18F-FDG-PET/CT could serve as a potent tool for the differential diagnosis of lipomatous tumors.

Rare coexistence of multiple osteochondromas and solitary osteoid osteoma: A case report.

Multiple osteochondromas (MOs) are inherited in an autosomal-dominant manner, with a penetrance of ~96 and 100% in female and male patients, respectively. Osteochondromas primarily involve the metaphyses and diaphyses of long bones, including the ribs. Osteoid osteomas account for ~3 and 11% of all bone tumors and benign bone tumors, respectively. Furthermore,1 the male-to-female ratio is 2-3:1, and they generally occur in the long bones of the lower extremities, with the femoral neck being the most frequent site. The present study describes the case of a 16-year-old male patient with a bony mass around the left knee joint and pain in the left calf. Radiography revealed MOs in the upper and lower extremities, while computed tomography showed a nidus in the cortex of the tibial shaft. The patient's family history included the presence of MOs, and the patient was diagnosed with MOs and a solitary osteoid osteoma. Surgical excision of the osteochondroma and curettage of the osteoid osteoma in the proximal tibia and tibial shaft, respectively, were performed simultaneously. Postoperative pathological examination revealed osteochondroma and osteoid osteoma. Furthermore, the pain resolved, and no recurrence was observed 7 months post-operation. To the best of our knowledge, no reports exist on coexisting MOs and osteoid osteoma; therefore, the present study describes the first case of such a condition. Marginal excision for osteochondroma and curettage for osteoid osteoma effectively improved the symptoms.

Oncological and functional outcomes of modified arthroscopic resection for intra-articular tenosynovial giant cell tumor of the knee using multiple portals.

BACKGROUND: Arthroscopic resection of tenosynovial giant cell tumor (TS-GCT) presents favorable outcomes. However, there are reportedly higher recurrence rates in patients who had incomplete resection. To minimize incomplete resection, we established a multiple portal approach depending on the location of the disease. In this study, we aimed to retrospectively evaluate the clinical outcomes of arthroscopic resection for both localized and diffuse types of TS-GCT of the knee. METHODS: From 2009 to 2019, 13 patients who underwent arthroscopic synovectomy of the knee and were histologically diagnosed with TS-GCT were included in this study. The pre- and postoperative range of motion (ROM) of the knee was measured. The Japanese Orthopaedic Association (JOA) score and the Knee Injury and Osteoarthritis Outcome Score (KOOS) were assessed at the final follow-up examination. Magnetic resonance imaging was performed to detect incomplete resection or local recurrence. RESULTS: Among the 13 patients, seven and six had localized and diffuse type TS-GCT, respectively. Regarding the knee ROM, preoperative knee flexion in patients with the localized type was limited compared with that in those with the diffuse type. However, the ROM was significantly improved in patients with both types postoperatively. The JOA score and KOOS of patients with both types at the final follow-up were favorable, and there were no significant differences between both types. There was neither recurrence nor incomplete resection in any patient for both types. CONCLUSION: All patients, regardless of the TS-GCT type, achieved favorable outcomes after arthroscopic surgery; especially, the failure rate was 0%.

Intraoperative cone-beam computed tomography-guided curettage for osteoid osteoma.

Recently, cone-beam computed tomography (CBCT)-guided surgeries have been developed for bone and soft tissue tumors. The present study aimed to evaluate the efficacy of CBCT-guided curettage for osteoid osteoma. Our study population included 13 patients who underwent primary curettage for osteoid osteoma using intraoperative CBCT in a hybrid operating room between April 2019 and November 2022. We collected the following data: sex, age, follow-up period, symptom onset to time of surgery, tumor size and location, length of skin incision, operating time, radiation dose, recurrence, postoperative complications, and visual analog scale for pain during the last follow-up. There were 10 male and 3 female patients, and the mean age was 25.0 years (range, 9-49 years). The mean follow-up period was 10.6 months (range, 0.4-24.0 months). The locations of the tumors were the proximal femur in 6 patients, the acetabular region in 2 patients, and the ilium, tibial shaft, calcaneus, cuboid, and talus in 1 patient each. The mean time of symptoms onset to surgery was 18.7 months (range, 2.3-69.9 months). The mean maximum diameter of the tumor was 5.9 mm (range, 3.5-10.0 mm). The mean length of the skin incision was 2.2 cm (range, 1.5-3.5 cm). The mean operating time was 96.9 minutes (range, 64-157 minutes). The mean dose of radiation was 193.2 mGy (range, 16.3-484.0 mGy). No recurrences, postoperative complications, and reoperation were observed in this study. All the patients reported 0 mm on the visual analogue scale for pain on the last follow-up. CBCT-guided curettage for osteoid osteoma was minimally invasive and reliable. This procedure can be effective for the treatment of lesions found in deep locations such as the pelvic bone and proximal femur or an invisible lesion that cannot be detected by regular fluoroscopy.

Denosumab administration for bone metastases from solid tumors: a retrospective cross-sectional study.

BACKGROUND: Little is known on how denosumab reduces skeletal-related events (SREs) by bone metastases from solid tumors. We sought to evaluate the effect of denosumab administration in patients with bone metastases from solid tumors. METHODS: Data of patients treated with denosumab were collected from electronic medical charts (n = 496). Eligible participants in this study were adult patients (age ≥ 18 years) with metastatic bone lesions from solid tumors treated with denosumab. SREs, surgical interventions, the spinal instability neoplastic score (SINS) for spinal region, and Mirels' score for the appendicular region were evaluated. To assess whether denosumab could prevent SREs and associated surgery, the SINS and Mirels' score were compared between patients with and without SREs. RESULTS: A total of 247 patients (median age, 65.5 years old; median follow-up period, 13 months) treated with denosumab for metastatic bone lesions from solid tumors were enrolled in this study. SREs occurred in 19 patients (7.7%). SREs occurred in 2 patients (0.8%) who took denosumab administration before SREs. Surgical interventions were undertaken in 14 patients (5.7%) (spinal and intradural lesions in five patients and appendicular lesions in nine patients). The mean SINS of patients without SREs compared to those with SREs were 7.5 points and 10.2 points, respectively. The mean Mirels' scores of non-SREs patients and those with SREs were 8.07 points and 10.7 points, respectively. Patients with SREs had significantly higher Mirels' score than non-SREs patients (p < 0.01). Patients with SREs had higher SINS than non-SREs patients (p = 0.09). CONCLUSIONS: SREs occurred in patients with higher SINS or Mirels' scores. Two patients suffered from SREs though they took denosumab administration before SREs. Appropriate management of denosumab for patients with bone metastasis is significant. Surgical interventions may be needed for patients who with higher SINS or Mirel's scores.

Long-lasting Limb Salvage After Malignant Femoral-Bone Tumor Resection Reconstructed With a Thin-mantle Titanium Stem Fixated With Cement.

BACKGROUND/AIM: The purpose of the present study was to review and report clinical outcomes of the Kyocera Modular Limb Salvage System (KMLS) using a thin-mantle titanium stem fixated with cement, for reconstruction after resection of malignant femoral-bone tumors. PATIENTS AND METHODS: Twenty consecutive patients who had undergone reconstruction using the KMLS with cemented thin-mantle titanium stem fixation between July 2010 and December 2019 at Ryukyu University Hospital were included. We retrospectively collected the following data: age, sex, follow-up period, tumor location, histological diagnosis, stem size, overall implant survival, radiolucency, postoperative complications, overall survival, and oncological survival. RESULTS: The median follow-up period was 63 months (range=10.7-261 months). The bone tumors were in the proximal part of the femur in 9 patients and in the distal part of the femur in 11 patients. The 5-year overall implant survival rate was 90.9% among surviving patients. A revision surgery was required for only one patient (5%), due to infection. Radiolucency, due to an instability of the implant, was observed in 7 out of 20 patients: 6 patients with distal femoral reconstruction, and 1 patient with proximal femoral reconstruction. However, none of the patients complained of any symptoms or required revision surgeries at the last follow-up. The 5-year overall patient-survival rate was 67.6%. CONCLUSION: The KMLS with cemented thin-mantle titanium stem fixation for femoral bone reconstruction after resection for bone malignancy resulted in long-term patient benefit.

Imaging characteristics of tenosynovial giant cell tumors on 18F-fluorodeoxyglucose positron emission tomography/computed tomography: a retrospective observational study.

BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) is useful for assessing location, metastasis, staging, and recurrence of malignant tumors. Tenosynovial giant cell tumor (TSGCT) is a benign tumor; however, some studies have reported that TSGCTs have a high uptake of FDG. Few studies have reported on the detailed evaluation of TSGCT using 18F-FDG-PET/CT. The purpose of the current study is to evaluate the image characteristics and locations, particularly where possible, with or without, extra-articular invasion from TSGCT of the knee in 18F-FDG-PET/CT could occur. METHODS: We retrospectively reviewed the patients with TSGCT who were diagnosed pathologically either by biopsy or surgical specimen. Furthermore, we evaluated the difference of the maximum standardized uptake value (SUVmax) between diffused TSGCT with extra-articular invasion and TSGCT with intra-articular localization in the knee. RESULTS: The study consisted of 20 patients with TSGCT. The mean SUVmax of TSGCT was 12.0 ± 6.50. There were five patients with TSGCT arising in the knee with extra-articular invasion and six with TSGCT with intra-articular localization. The mean SUVmax of TSGCT with extra-articular invasion and those with intra-articular localization were 14.3 ± 6.00 and 5.94 ± 3.89, respectively. TSGCT with extra-articular invasion had significantly higher SUVmax than TSGCT with intra-articular localization (p < 0.05). CONCLUSIONS: TSGCT revealed high FDG uptake. Furthermore, SUVmax was higher in diffused TSGCT with extra-articular invasion than in intra-articular localized TSGCT; this may reflect its local aggressiveness.

Reconstructed bone fracture 28 years after hip rotationplasty for Ewing sarcoma: A case report.

Hip rotationplasty is a surgical method used to treat malignant tumors of the proximal femur. A 52-year-old woman, who underwent hip rotationplasty for Ewing sarcoma of the proximal left femur at the age of 24, fell and hit the left buttock. The patient was then admitted to the Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus. Radiography and computed tomography (CT) revealed a comminuted fracture of the reconstructed bone distally. The patient underwent open reduction and internal fixation (ORIF) and external fixator. External fixation was removed 1 month after the surgery. At two years after surgery, at the latest follow-up, bone union was confirmed by 3-dimensional CT. The combination of ORIF and temporal external fixation was effective for the reconstructed bone fractures after hip rotationplasty.

Progressive scoliosis associated with microphthalmia with limb anomalies: A case report.

RATIONALE: Microphthalmia with limb anomalies is a rare, autosomal recessive, multiple congenital anomaly syndrome. Patients with this syndrome particularly present with monocular or bilateral anophthalmia/microphthalmia and distal limb anomalies. However, details regarding associated spinal deformities have not been fully elucidated. PATIENT CONCERNS: A 12-year-old girl initially presented with progressive scoliosis, who was previously diagnosed with microphthalmia with limb anomalies. However, 4 years after the initial visit, the scoliosis deformity gradually progressed. The patient and family requested the surgical treatment to preserve standing/sitting balance. DIAGNOSES: She was diagnosed with microphthalmia with limb anomalies and progressive scoliosis. INTERVENTIONS: A posterior corrective fusion surgery (including a pelvic fusion) was performed to prevent future standing/sitting imbalance. OUTCOMES: Significant improvement of spinal deformity was observed, with no adverse events. LESSONS: This report demonstrated a case of progressive scoliosis associated with microphthalmia with limb anomalies. A posterior corrective spinal fusion was effective to preserve standing/sitting balance. To the best of our knowledge, this is the first report of surgical treatment of progressive scoliosis associated with microphthalmia with limb anomalies.

Reconstruction of the lateral collateral ligament using the plantaris tendon after wide excision of soft tissue sarcoma of the knee: A case report.

An 83-year-old woman presented with a 1-year history of a growing mass on the lateral surface of the right knee. Magnetic resonance imaging revealed a large soft tissue tumor in the subcutis of the right knee. The mass in the right knee rapidly increased, due to hemorrhage from the tumor. A needle biopsy revealed that the diagnosis was synovial sarcoma. The patient underwent wide excision and lateral collateral ligament reconstruction using the plantaris tendon. The patient had a Musculoskeletal Tumor Society Score of 86% at the lateset follow-up. In conclusion, reconstruction of the lateral collateral ligament using the plantaris tendon may be useful for preserving the function of the knee joint after resection of the soft tissue due to sarcoma of the knee.

Synergy of oral recombinant methioninase (rMETase) and 5-fluorouracil on poorly differentiated gastric cancer.

Gastric cancer is highly malignant and recalcitrant to first line chemotherapies that include 5-fluorouracil (5-FU). Cancer cells are addicted to methionine for their proliferation and survival. Methionine addiction of cancer is known as the Hoffman effect. Methionine restriction with recombinant methioninase (rMETase) has been shown to selectively starve cancer cells and has shown synergy with cytotoxic chemotherapy including 5-FU. The present study aimed to investigate the efficacy of rMETase alone and the combination with 5-FU on poorly differentiated human gastric cancer cell lines (MKN45, NUGC3, and NUGC4) in vitro and vivo. rMETase suppressed the tumor growth of 3 kinds of poorly differentiated gastric cancer cells in vitro. The fluorescence ubiquitination-based cell cycle indicator (FUCCI) demonstrated cancer cells treated with rMETase were selectively trapped in the S/G2 phase of the cell cycle. In the present study, subcutaneous MKN45 gastric cancer models were randomized into four groups when the tumor volume reached 100 mm3: G1: untreated control; G2: 5-FU (i.p., 50 mg/kg, weekly, three weeks); G3: oral-rMETase (o-rMETase) (p.o., 100 units/body, daily, three weeks); G4: 5-FU with o-rMETase (5-FU; i.p., 50 mg/kg, weekly, three weeks o-rMETase; p.o., 100 units/body, daily, three weeks). All mice were sacrificed on day 22. Body weight and estimated tumor volume were measured twice a week. 5-FU and o-rMETase suppressed tumor growth as monotherapies on day 18 (p = 0.044 and p = 0.044). However, 5-FU combined with o-rMETase was significantly superior to each monotherapy (p < 0.001 and p < 0.001, respectively) and induced extensive necrosis compared to other groups. The combination of 5-FU and o-rMETase shows promise for transformative therapy for poorly differentiated gastric cancer in the clinic.

Wide excision alone for elderly patients aged > 70 years old with soft tissue sarcomas.

The purpose of the present study was to clarify clinical outcomes of elderly patients with soft tissue sarcoma who underwent surgery neither with neoadjuvant nor adjuvant chemotherapy. The median follow-up period was 46.3 (range 6.7-99.0) months. All patients underwent surgical resections. R0 margins were achieved in 24 cases (92.3%) and R1 margins in 2 cases (7.7%). The 1-, 2-, and 5-year sarcoma-specific survival (SSS) rates were 92.3%, 88.5%, and 83.8%, respectively. Multivariate analysis showed no significant risk factors for SSS. No significant relationship of histological grades and local recurrences (P = .56) or distant metastases (P = .54) was shown. In the current study, we observed a comparable survival ratio, despite no neoadjuvant or adjuvant chemotherapies performed. Tumor resections with adequate margins might, at least in part, have contributed to the decent survival ratio regardless of histological grade. Twenty-six consecutive patients aged ≥ 70 years, who underwent surgical resections of soft tissue sarcoma between January 2013 and December 2019, were included. SSS were analyzed by the Kaplan-Meier method, and the relationships between SSS and clinical parameters were evaluated by Cox proportional hazards analysis.

High Incidence of Lymph-node Metastasis in a Pancreatic-cancer Patient-derived Orthotopic Xenograft (PDOX) NOG-Mouse Model.

BACKGROUND/AIM: Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) model. An important goal of PDOX-model development is facile visualization of metastasis in live mice. In the present report we evaluated tumor growth and metastasis in pancreatic cancer PDOX NOG [Non-obese diabetes (NOD)/Scid/IL2Rγnull]-and nude-mouse models using red fluorescent protein (RFP)-expressing tumor stroma to visualize the primary tumor and metastasis. MATERIALS AND METHODS: A patient-derived pancreatic cancer was initially implanted in transgenic RFP-expressing nude mice. Then, tumor fragments, which acquired RFP expressing stroma while growing in RFP-expressing nude mice were orthotopically implanted in nude and NOG mice. The primary pancreatic tumor and metastasis were observed 8 weeks after implantation. RESULTS: Lymph-node metastases expressing red fluorescence were detected only in NOG mice. Significantly faster growth of primary pancreatic tumors and a higher incidence of lymph-node metastasis occurred in NOG mice compared to nude mice. CONCLUSION: RFP-expressing tumor stroma, which traffics together with cancer cells to lymph nodes, is useful to observe tumor behavior, such as lymph-node metastasis in a PDOX NOG-mouse model which can be used for evaluation of novel anti-metastatic agents, as well as personalized therapy to identify effective drugs.

Packing with alpha-tricalcium phosphate followed by curettage and phenol-ethanol ablation for appendicular giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is an intermediate and locally aggressive bone tumor. Alpha-tricalcium phosphate (alpha-TCP) is an adjustable bone substitute used to fill various sizes of bone cavities after curettage for GCTB. This study aimed to evaluate the surgical outcome of packing with alpha-TCP followed by curettage and phenol-ethanol ablation. We retrospectively reviewed data of 16 patients with GCTB who underwent primary surgery in our institute between January 2009 and April 2021. Data of Campanacci grading system; number of local recurrences and distant metastases; local recurrence-free survival rate using the Kaplan-Meier method; oncological outcomes; and complications after surgery (secondary osteoarthritis and postoperative fracture) were evaluated in this study. Regarding the Campanacci grading system, 2 patients were classified as grade I, 14 as grade II, and none as grade III. The 5-year local recurrence-free survival rate was 77.8% in all cases. Lung metastasis was not detected in this study. Oncological outcomes were: continuous disease free, 13 patients; alive with disease, 3 patients; and no evidence of disease or death of disease, none of the patients. Secondary osteoarthritis after surgery was not detected in the present study. Packing with alpha-TCP followed by curettage and phenol-ethanol ablation for appendicular GCTB may be safe and effective in suppressing the risk of secondary osteoarthritis.

Veno-accompanying artery fasciocutaneous flaps following wide excision of soft tissue tumors in the lower legs.

BACKGROUND: Soft tissue defects following wide excision of malignant soft tissue tumors (STTs) are sometimes too large for primary closure, especially in the lower legs where available soft tissue is limited. This study aimed to determine the clinical outcomes of reconstruction of a defect after wide excision of an STT with a veno-accompanying artery fasciocutaneous (VAF) flap in the lower leg. METHODS: This study comprised 9 patients with malignant STTs who had undergone reconstructive surgeries using VAF flaps after wide excisions, between October 2010 and September 2017. We retrospectively reviewed and collected data involving age, sex, follow-up period, histological diagnosis, surgical procedures, size and location of defects, size and location of the flaps, venous source of the flaps, direction of the pedicles, closing of donor sites, perioperative chemotherapies, postoperative complications, and the presence of postoperative local recurrence and metastasis. RESULTS: The median follow-up period was 91.5 (range, 15.5-189.0) months. Four patients had defects located around the knee, 3 patients had defects located on the calf, and 2 patients had defects located around the ankle. The mean flap size was 95.6 × 119.4 (range, 50 × 100-130 × 140) mm. Six patients had venous sources from the small saphenous vein and 3 patients had venous sources from the great saphenous vein. The pedicles were proximally based in 4 patients and distally based in 5 patients. All flaps remained viable without any complications. CONCLUSIONS: Our findings showed that the VAF flap was easily elevated and reliable. Furthermore, it was effective in reconstructing soft tissue defects following wide excisions of STTs in the lower leg.

Combination of CDK4/6 and mTOR Inhibitors Suppressed Doxorubicin-resistant Osteosarcoma in a Patient-derived Orthotopic Xenograft Mouse Model: A Translatable Strategy for Recalcitrant Disease.

BACKGROUND: Osteosarcoma is the most frequent malignant bone neoplasm. The efficacy of combination therapy of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and a mammalian-target-of-rapamycin (mTOR) inhibitor was previously reported in several cancer types. In the present study, we evaluated the efficacy of a combination of palbociclib (CDK 4/6 inhibitor) and everolimus (mTOR inhibitor) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: osteosarcoma PDOX mouse models were randomized into five treatment groups of seven mice each: Group 1, untreated control; group 2, doxorubicin treatment; group 3, palbociclib treatment; group 4, everolimus treatment; group 5, palbociclib-everolimus combination treatment. Treatment duration was 2 weeks. RESULTS: The palbociclib-everolimus combination reduced the tumor-volume ratio in the osteosarcoma PDOX mouse model compared with the control and doxorubicin (p=0.018). Everolimus alone also inhibited osteosarcoma PDOX growth compared to the control (p=0.04), but less than the combination. Palbociclib alone and doxorubicin were ineffective. There were no significant body-weight losses in any group. Only the palbociclib-everolimus combination induced extensive tumor necrosis observed histopathologically. CONCLUSION: The present study demonstrated that the combination of CDK4/6 and mTOR inhibitors can be a translatable approach for doxorubicin-resistant osteosarcoma in the clinic.

Reconstruction of the elbow using pedicle joint freezing after wide excision for soft tissue sarcoma: A case report.

A 35-year-old man presented with a four-year history of a growing mass on the anterior aspect of his left elbow. Magnetic resonance imaging revealed a soft tissue tumor in the brachialis muscle extending to the cubital fossa. Following an open biopsy, the tumor was diagnosed as a monophasic fibrous synovial sarcoma. After neoadjuvant chemotherapy, the patient underwent wide excision and reconstruction of the elbow joint with a pedicle frozen autograft. At the final follow-up four years after surgery, the elbow range of motion was 0-120˚. Although there were signs of osteoarthritis, there was no narrowing of the joint -, and the patient experienced only mild pain. To the best of our knowledge, the present case report is the first to describe wide tumor excision and reconstruction using a pedicle frozen autograft of the elbow. This method should be considered after excision of malignant bone and soft tissue tumors, especially in non-weight-bearing joints. Further cases have to be evaluated to understand the complications and long-term prognosis of this procedure.

An mTOR and VEGFR inhibitor combination arrests a doxorubicin resistant lung metastatic osteosarcoma in a PDOX mouse model.

In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma patient who failed doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo Gelfoam fluorescence angiogenesis mouse model implanted with osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2, doxorubicin (DOX); Group 3, everolimus (EVE, an mTOR and VEGF inhibitor); Group 4, pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination. Tumor volume and body weight were monitored 2 times a week. The in vivo Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed tumor growth in the osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo Gelfoam fluorescent angiogenesis model, compared with all other groups (p < 0.05). There was no significant body-weight loss in any group. Only the EVE-PAZ combination caused tumor necrosis. The present study demonstrates that a combination of an mTOR-VEGF inhibitor and a VEGFR inhibitor was effective for a DOX-resistant lung-metastatic osteosarcoma PDOX mouse model, at least in part due to strong anti-angiogenesis efficacy of the combination.

A Novel Orthotopic Mouse Model of Lung Metastasis Using Fluorescent Patient-derived Osteosarcoma Cells.

BACKGROUND: A mouse model of metastatic osteosarcoma is imperative to identify effective agents for metastatic osteosarcoma, which is a recalcitrant disease. In the present study, we established osteosarcoma patient-derived cells (OS-PDCs) and transfected them with green fluorescent protein (GFP). MATERIALS AND METHODS: The OS-PDCs were transfected with GFP-lentivirus. GFP-expressing OS-PDCs (2.0×105) were then injected into the tibia of nude mice to establish the patient-derived orthotopic cell (PDOC) model (n=3). Six weeks after injection, the primary tumor and each organ were resected and imaged. RESULTS: Primary orthotopic tumors were established in two out of three mice. The GFP-expressing OS-PDCs in the PDOC model were visualized. Multiple GFP-expressing lung metastases were detected in one of the two mice with primary tumor. CONCLUSION: The present study proves the concept that a GFP-expressing PDOC model can mimic clinical lung-metastatic osteosarcoma. This model can serve as a paradigm to screen for effective drugs for osteosarcoma lung metastasis.

A novel patient-derived orthotopic xenograft (PDOX) mouse model of highly-aggressive liver metastasis for identification of candidate effective drug-combinations.

Liver metastasis is a recalcitrant disease that usually leads to death of the patient. The present study established a unique patient-derived orthotopic xenograft (PDOX) nude mouse model of a highly aggressive liver metastasis of colon cancer. The aim of the present study was to demonstrate proof-of-concept that candidate drug combinations could significantly inhibit growth and re-metastasis of this recalcitrant tumor. The patient's liver metastasis was initially established subcutaneously in nude mice and the subcutaneous tumor tissue was then orthotopically implanted in the liver of nude mice to establish a PDOX model. Two studies were performed to test different drugs or drug combination, indicating that 5-fluorouracil (5-FU) + irinotecan (IRI) + bevacizumab (BEV) and regorafenib (REG) + selumetinib (SEL) had significantly inhibited liver metastasis growth (p = 0.013 and p = 0.035, respectively), and prevented liver satellite metastasis. This study is proof of concept that a PDOX model of highly aggressive colon-cancer metastasis can identify effective drug combinations and that the model has future clinical potential.