The landscape of gene mutations and clinical significance of tumor mutation burden in patients with soft tissue sarcoma who underwent surgical resection and received conventional adjuvant therapy.

BACKGROUND: The aim of this study was to evaluate the landscape of gene mutations and the clinical significance of tumor mutation burden (TMB) in patients with soft tissue sarcoma who underwent surgical resection and received conventional adjuvant therapy. METHODS: A total of 68 patients with soft tissue sarcoma were included. Postoperative tumor tissue specimens from the patients were collected for DNA extraction. Targeted next-generation sequencing of cancer-relevant genes was performed for the detection of gene mutations and the analysis of TMB. Univariate analysis between TMB status and prognosis was carried out using the Kaplan-Meier survival analysis, and multivariate analysis was adjusted by the Cox regression model. RESULTS: No specific genetic mutations associated with soft tissue sarcoma were found. The mutation frequency of TP53, PIK3C2G, NCOR1, and KRAS of the 68 patients with soft tissue sarcoma were observed in 19 cases (27.94%), 15 cases (22.06%), 14 cases (20.59%), and 14 cases (20.59%), respectively. With regard to the analysis of TMB, the overall TMB of the 68 patients with soft tissue sarcoma was relatively low (median: 2.05 per Mb (range: 0∼15.5 per Mb)). Subsequently, TMB status was divided into TMB-Low and TMB-Middle according to the median TMB. Patients with TMB-Low and TMB-Middle were 37 cases (54.41%) and 31 cases (45.59%), respectively. Overall survival analysis indicated that the median overall survival of patients with TMB-Low and TMB-Middle was not reached, and 4.5 years, respectively (P=0.015). CONCLUSION: This study characterizes the genetic background of patients with STS soft tissue sarcoma. The TMB was of clinical significance for patients with soft tissue sarcoma who underwent surgical resection and received conventional adjuvant therapy.

Intentional marginal resection of periosteal osteosarcoma in combination with neoadjuvant chemotherapy: A report of two cases and a review of the literature.

A wide resection of the tumor with or without chemotherapy is the treatment of choice for periosteal osteosarcoma (PO) of the extremities, however, post-operative limb function and quality of life could be compromised. The present study reports two cases of 14-year-old boys who presented with progressively enlarging masses in their right knee regions. Computed tomography and magnetic resonance imaging scans indicated a fusiform space-occupying mass encircling the bone cortex, with stippled calcification. A diagnosis of PO was suspected. The histological findings confirmed the diagnosis of intermediate PO. Pre-operative chemotherapies were started, and good responses were detected by clinical evaluation and histological findings. Surgeries preserving the functional structures, including neurovascular bundles, tendons, muscles and epiphyses, were performed, followed by routine chemotherapy. The two patients experienced disease-free survival with follow-up times of 37 and 108 months, respectively. The patients were satisfied with the results of the treatment and they returned to normal life activities. These two cases indicated that a marginal resection of the tumor in conjunction with effective neoadjuvant chemotherapy may be an ideal alternative treatment for intermediate PO, since survival along with well-preserved limb function could be guaranteed. By contrast, a wide excision could result in the loss of limb function.

Impacts of Tumor Location, Nature and Bone Destruction of Extremity Osteosarcoma on Selection of Limb Salvage Operative Procedure.

OBJECTIVE: To study the impacts of tumor location, nature and extent of bone destruction on selection of operative protocol for extremity osteosarcoma (OS). METHODS: The medical records of 201 patients with extremity OS treated in our institute from December 1999 to June 2014 were retrospectively reviewed. Ninety eligible patients (56 males and 34 females) of average age 20 ± 11 years (range, 4-40 years) were enrolled. Tumor locations were categorized as diaphyseal (4; diaphysis group) or juxta-articular (86); the latter being subclassified as with (51, type III, epiphysis group) or without invasion beyond the epiphyseal line or plate (35, type I and II, metaphysis group) according to MRI images. Tumor nature (osteogenic, 51; osteolytic, 39) was determined radiologically. Extent of bone destruction was quantitated according to Mirel's scoring system to obtain an "invasion score". Regular postoperative follow-up included physical examination and imaging evaluation. RESULTS: Fifty-four patients underwent biological reconstruction and 36 mechanical reconstruction. The mean follow-up duration was 51 months (range, 6-176 months, including four deaths within 12 months). Biological reconstruction was performed more frequently in the diaphysis and metaphysis groups (31/39, 79.5%) than mechanical reconstruction (8/39, 20.5%, P < 0.05). Biological reconstruction and articular preservation were associated with more satisfactory limb function (MSTS scores: 25.0 ± 3.3 and 25.1 ± 3.6) than mechanical reconstruction and articular resection (MSTS scores: 23.4 ± 3.7 and 23.1 ± 3.4, P < 0.05). Reconstruction methods and articular preservation had no relationship with overall or tumor-free survival (P > 0.05). Osteolytic lesions were associated with more extensive bone destruction than osteogenic lesions according to invasion scores (P < 0.05). Following biological reconstruction, high invasion scores (>8) had a 13.5-fold risk of fracture compared with low scores (≤8) (P < 0.05). Twenty-one subjects had recurrences, 30 metastases and 26 died. Postoperative complications included infection (6), fracture (10), and prosthesis loosening (4). Kaplan-Meier analysis indicated 5- and 10-year survival rates of 68.9% and 62.8%, respectively, and 5- and 10-year tumor-free survival rates of 66.7% and 57.8%, respectively. CONCLUSION: Selection of limb salvage operative protocol for extremity OS should rely on tumor location, nature and extent of bone destruction. Regardless of tumor site, mechanical reconstruction is indicated for tumors with high invasion scores (>8), whereas biological reconstruction is preferred for those with low invasion scores (≤8). Tumors sparing the epiphyseal line or plate are ideal candidates for articular preservation.

Functional Results and Emotional Acceptance after Scapulectomy for Malignant Shoulder Tumors.

OBJECTIVES: To demonstrate the functional results and emotional acceptance after scapulectomy for various malignant shoulder tumors. METHODS: Eight patients with malignant shoulder tumors who had undergone scapulectomy between April 2004 and March 2014 were retrospectively reviewed. They comprised seven men and one woman their mean age was 54 years (range, 24-69 years). All patients were diagnosed by pathological examination of biopsy specimens. The tumors were metastatic in four cases, having originated from a primary carcinoma of the liver in one patient, the lung in one patient and the kidney in two patients. The other four patients had primary malignant tumors in their scapulae, specifically, two scapular malignant fibrous histiocytomas, one scapular Ewing sarcoma and one soft tissue synovial sarcoma. The four patients with metastases were staged as III, and other four were staged as IIB. Six patients underwent total and two subtotal scapulectomy. The remaining soft tissues were sutured together directly in seven of the patients. The remaining patient, who had soft tissue synovial sarcoma, required transfer of a pedicle latissimus dorsi muscle flap. The functional results and emotional acceptance were evaluated by clinician using the Musculoskeletal Tumor Society (MSTS) scoring system. RESULTS: The average duration of follow-up was 22.8 months. Four patients were continuously disease-free, three patients developed metastases and died of disease within 12 months of surgery and one patient with a scapular metastasis from the kidney survived with pulmonary nodules. No major complications, including infection or dislocation, occurred during or after surgery. The mean MSTS score was 16.3 (54%), which is similar to that previously reported in other studies of scapulectomy. There were no local tumor recurrences and only one patient developed pulmonary metastases. These outcomes are similar to those reported for scapular prostheses and there were fewer complications than in patients treated with allografts. The mean emotional acceptance score was 3.6 (72.5%). CONCLUSIONS: Performing scapulectomies on patients with malignant shoulder tumors without prostheses or allograft reconstruction achieves good functional results and emotional acceptance with a low rate of complications.

Use of negative pressure wound therapy as an adjunct to the treatment of extremity soft-tissue sarcoma with ulceration or impending ulceration.

Major wound complications of the extremities, following wide tumor resection and reconstruction for soft-tissue sarcomas (STSs), remain a challenge for limb-sparing surgery. Furthermore, STSs with ulceration or impending ulceration predispose patients to an increased risk of post-operative infection. The present study was conducted to assess the efficacy of negative pressure wound therapy (NPWT) in preventing wound complications associated with surgical treatment of STSs with ulceration or impending ulceration, in patients treated between February 2012 and January 2013. A total of 5 patients, with a mean age of 48 years (range, 24-68 years), were enrolled in the present study. The diagnoses consisted of undifferentiated pleomorphic sarcoma (n=2), leiomyosarcoma (n=1), synovial sarcoma (n=1) and epithelioid sarcoma (n=1). According to American Joint Committee on Cancer criteria, 3 cases were stage III tumors, and the remaining 2 cases were of stages IIA and IIB, respectively. A total of 3 patients exhibited ulceration at diagnosis, and the remaining patients demonstrated impending ulceration. The mean wound area following wide resection of the tumor was 73 cm2 (range, 45-110 cm2). A continuous suction mode, with pressures measuring -200 to -300 mmHg, was used for 7-10 days on the soft-tissue defects as preparation for wound closure. Soft-tissue reconstruction included muscle flaps (n=2) and skin grafts (n=5). No major wound complications occurred. Post-operative functional and cosmetic outcomes were acceptable. A single patient demonstrated local recurrence 12 months after surgery and re-excision of the tumor was performed. All patients remained alive at the conclusion of follow-up, with a mean follow-up time of 26 months (range, 12-36 months). The present study demonstrated that NPWT is effective and safe when used as an adjunct to wound closure following resection of extremity STS with ulceration/impending ulceration.

Giant cell tumor of the tendon sheath originating from the ankle capsule: A case report and literature review.

Giant cell tumor of the tendon sheath (GCTTS), also termed tendosynovial giant cell tumor, is a benign, slow-growing tumor that originates from the tendon sheath or bursa. GCTTS of the foot and ankle is much less frequently reported compared with GCTTS of the hand and knee. However, GCTTS should be considered as a differential diagnosis of soft tissue tumors of the foot and ankle. The optimal treatment strategy for GCTTS in the foot and ankle is controversial due to a scarcity of cases. The present study reports the case of a patient that presented with localized intra-articular GCTTS originating from the capsule of the ankle, which is a rare anatomical location for this tumor. Considering the proximity of the tumor to the adjacent non-tumorous structures, a less radical but complete resection of the tumor was performed, followed by a hydrogen peroxide lavage. There was no evidence of recurrence during a follow-up period of 12 months, and adjuvant radiotherapy was not administered to the patient. A pre-operative diagnosis for GCTTS in the foot and ankle is mainly based on the findings of clinical examination and magnetic resonance imaging, which also facilitates the determination of a surgical strategy. For a localized tumor, an integral resection, as opposed to a radical resection, with a hydrogen peroxide lavage may result in a favorable prognosis. However, the optimal treatment for diffuse GCTTS remains to be identified.

Postoperative infection and survival in osteosarcoma patients: Reconsideration of immunotherapy for osteosarcoma.

There is controversy regarding the impact of infection on long-term prognosis in osteosarcoma patients. Clinical trials and experiments relating to this field could bring reconsideration of immunotherapy for osteosarcoma. The clinical records were reviewed of 125 osteosarcoma patients with a mean follow-up of 5.1±3.9 years (range, 0.5-19.8 years), and a review of the literature was also carried out. Chronic localized infections (but not systemic infection) were determined in 6 patients (4.8%). Similar chemotherapeutic regimens (P=1.00) and histological reactions (P=0.65) were observed in patients with or without infection. Tumor location of proximal tibia (P=0.04) was more common in infected patients. More amputations (P<0.001) were necessitated in infected patients due to uncontrolled infection. The 5-year overall survival rate and event-free survival rate in infected patients were 100%, which were significantly higher than that of the non-infected patients, of whom the rates were 54 and 43% respectively (log-rank test: total survival, P=0.01; tumor-free survival, P=0.01). Distant metastasis was an independent risk factor for survival determined by Cox regression analysis (P<0.001, 95 confidence interval, 1.59-3.98). These findings suggested infection was likely to have positive effects on survival in osteosarcoma patients, however, underlying mechanisms remain to be elucidated. Reconsideration of the association of infection and survival in osteosarcoma patients will help to explore novel therapeutic routes and targets in these patients.

Giant cell tumor of the pelvis: a systematic review.

This is a systematic review of articles concerning the morbidity, recurrence rate, treatment and treatment complications of pelvic giant cell tumors (GCTs). The key words "giant cell tumor, pelvis" were used to identify articles which included data on patients with pelvic GCTs in English and Chinese databases of published reports from 1949-2012. The articles were filtered by title, abstract and full text. Thirty-eight articles and 165 patients were identified for this review. Data on all identified patients were studies; data in different articles on the same patients was not used repeatedly. The following patient data were collected where possible and subjected to systematic analysis; age, location of GCT, treatment, follow-up, complications, recurrence and whether alive or dead. The mean age of onset was 33.2 years (range, 14-73 years), the peak ages of onset being between 21 and 40 years. A pronounced sex difference was identified, the male : female ratio being 1:1.7. The acetabulum was the commonest area for pelvic GCTs. Forty-eight tumors were primarily located in the iliac, 60 in the acetabular and 31 in the ischiopubic area. Twenty-seven patients experienced complications of treatment. Patients who had been treated by wide resection had the most complications; these included incisional infection and delayed healing of incisions. Local recurrence was common, having occurred in 39/158 patients (24.6%), comprising 24/72 (33.3%) who had undergone intralesional surgery only; 9/20 (45.0%) who had undergone radiotherapy only; 1/51 (2.0%) who had undergone wide resection; and 5/14 patients (35.7%) who had undergone radiation therapy or cryotherapy plus intralesional surgery. Mortality was low (3.2%, 5/158). Pelvic GCT is not common, the acetabular area appears to the most frequent site and the peak age is the third and fourth decades. Although the recurrence rate is high for all pelvic GCTs, the mortality is low. Treatment has a critical influence on recurrence. In spite of the associated complications, the lower local recurrence rate makes wide resection a reasonable option for patients with extensive and/or aggressive GCTs.

Paclitaxel and etoposide co-loaded polymeric nanoparticles for the effective combination therapy against human osteosarcoma.

BACKGROUND: The combination of chemotherapeutic drugs with different pharmacological action has emerged as a promising therapeutic strategy in the treatment of cancers. Present study examines the antitumor potential of paclitaxel (PTX) and etoposide (ETP)-loaded PLGA nanoparticles for the treatment of osteosarcoma. RESULTS: The resulting drug-loaded PLGA NP exhibited a nanosize dimension with uniform spherical morphology. The NP exhibited a sustained release profile for both PTX and ETP throughout the study period without any sign of initial burst release. The combinational drug-loaded PLGA NP enhanced the cytotoxic effect in MG63 and Saos-2 osteosarcoma cell lines, in comparison to either native drug alone or in cocktail combinations. Additionally, NPs showed an appreciable uptake in MG63 cells in a time-based manner. Co-delivery of anticancer drugs resulted in enhanced cell cycle arrest and cell apoptosis. The results clearly showed that combinational drugs remarkably improved the therapeutic index of chemotherapeutic drugs. The greater inhibitory effect of nanoparticle combination would be of great advantage during systemic cancer therapy. CONCLUSION: Taken together, our study demonstrated that PTX-ETP/PLGA NP based combination therapy holds significant potential towards the treatment of osteosarcoma.

Alcohol-inactivated autograft replantation with joint preservation in the management of osteosarcoma of the distal femur: a preliminary study.

AIM: To evaluate clinical outcomes in patients who underwent alcohol-inactivated autograft replantation with joint preservation for the treatment of osteosarcoma of the distal femur. PATIENTS AND METHODS: 10 patients (7 men, 3 women; mean age: 20.1 years) were treated. 9 patients had Enneking stage IIb tumors and 1 patient had stage III. The mean follow-up time was 34 months. All patients obtained first-stage healing. RESULTS: 1 patient died of local recurrence and multiple metastases 13 months after surgery; 3 patients died of multiple metastases 9, 12, and 24 months after surgery, respectively. 3 patients required second surgery because of fracture of the inactivated autograft, 1 patient died 6 months later, 1 patient experienced bony healing 4 months later with no further complications, and 1 patient required subsequent open reduction and bone implantation with internal fixation (bony healing was evident 6 months later; however, joint instability and limited knee flexion were apparent). At final follow-up, the mean International Society of Limb Salvage (ISOLS) graft score was 31 (87%), whereas the mean Musculoskeletal Tumour Society (MSTS) function score was 23 (77%). CONCLUSIONS: These preliminary findings indicate that alcohol-inactivated autograft replantation with joint preservation may be effective in treating osteosarcoma of the distal femur in some patients. Larger-scale studies are needed to fully evaluate the efficacy/safety of this approach.

Long-term outcomes of epiphyseal preservation and reconstruction with inactivated bone for distal femoral osteosarcoma of children.

OBJECTIVES: To study the long-term outcomes of inactivated bone reimplantation with preservation of the epiphysis in children with distal femoral osteosarcomas. METHODS: Over 10 years, five children (mean age 9.2 years, one boy and four girls) with distal femoral osteosarcomas underwent inactivated bone reimplantation with preservation of the epiphysis following chemotherapy in our hospital. Three patients were type I on MRI classification (one with pathological fracture), and two type II. The therapeutic regime was two cycles of preoperative chemotherapy, surgery and six cycles of postoperative chemotherapy. RESULTS: Five patients were followed up for 60-126 months (mean 82 months). No local tumor recurrences or metastases occurred. Three patients with fractures of inactivated bone were treated by open reduction, bone grafting and internal fixation; their fractures had united by 6 months after reoperation. The mean functional score of the affected limbs was 25.6 points (13-30 points). CONCLUSIONS: Inactivated bone reimplantation with preservation of the epiphysis for distal femoral osteosarcomas in children optimizes recovery of limb function and preservation of limb length. The main measures for improving clinical outcomes include preoperative analysis of the lesion's boundaries and extent of tumor invasion, bone grafting between inactivated and host bone, and timely treatment of complications.

Flow perfusion culture of human fetal bone cells in large beta-tricalcium phosphate scaffold with controlled architecture.

One unsolved problem in bone tissue engineering is how to enable the survival and proliferation of osteoblastic cells in large scaffolds. In this work, large beta-tricalcium phosphate scaffolds with tightly controlled channel architectures were fabricated and a custom-designed perfusion bioreactor was developed. Human fetal bone cells in third passage were seeded onto the scaffolds and cultured in static or flow perfusion conditions for up to 16 days. Compared with nonperfused constructs, flow perfused constructs demonstrated improved cells proliferation and differentiation according to cell viability, glucose consumption, alkaline phosphatase activity, and osteopontin. Moreover, after 16 days of perfusion culture, a homogenous layer composed of cells and mineralized matrix throughout the whole scaffold was observed by scanning electron microscopy and histological study. In contrast, cells were located only along the scaffold perimeter in static culture. These results demonstrated the feasibility and benefit of perfusion culture in conjunction with well-defined three-dimensional environment for large bone graft construction. Porous scaffold with controlled architecture can be a potential tool to evaluate the effects of scaffold specific geometry on fluid flow configuration and cell behavior under perfusion culture.

Marginal resection for osteosarcoma with effective preoperative chemotherapy.

OBJECTIVE: To present the clinical results of marginal resection with effective preoperative chemotherapy for treatment of osteosarcoma. METHODS: Thirty-eight patients (20 male and 18 female, average age 17 years), underwent marginal resection after confirmation of effective preoperative chemotherapy between 1999 and 2008 and the results were analyzed retrospectively. The distal femur was involved in 22 cases, proximal tibia in 11, proximal humerus in 4, and proximal fibula in 1. Thirty-seven patients were stage IIB and one IIIB. Twenty-nine patients were treated with the DIA, and 9 with the MMIA protocol. Twenty-one patients underwent tumor resection and bone allograft transplantation. The epiphysis was preserved in 9 patients, and not in the other 12. Eleven patients underwent tumor resection and prosthetic replacement, and 4 tumor resection with autograft implantation. One patient underwent tumor resection and allograft with preservation of the epiphysis; another underwent marginal tumor resection only. RESULTS: All patients received effective preoperative chemotherapy. At a median follow-up of 52 months, local recurrence had developed in one patient (2.6% local recurrence rate). Pulmonary metastases developed in 9 patients (23.7%). Five patients died of metastases, one died of intracranial hemorrhage due to thrombocytopenia caused by postoperative chemotherapy. The overall 2-year survival rate was 87.3%, and event-free survival rate 75.5%. The overall 5-year survival rate was 74.7%, and event-free survival rate 60.8%. Excellent to good function of affected limbs was achieved in 60.5%. CONCLUSIONS: With careful preoperative evaluation and effective preoperative chemotherapy marginal resection of osteosarcoma can produce good results. Marginal resection of osteosarcoma should be performed by an experienced surgeon who is familiar with the limb salvage rules for osteosarcoma.

[Rotating three-dimensional dynamic culture of osteoblasts seeded on segmental scaffolds with controlled internal channel architectures for construction of segmental tissue engineered bone in vitro].

OBJECTIVE: To explore the feasibility, effectiveness, and mechanism of culturing osteoblasts on calcium phosphate cement (CPC) scaffolds with controlled internal channel architectures in a rotating bioreactor, and to develop a novel method for construction of segmental tissue engineered bone in vitro. METHODS: Self-hardening CPC scaffolds with controlled internal channel architectures were designed and fabricated using computer aided design (CAD) and indirect rapid prototyping (RP) techniques. A rotating bioreactor was developed. Osteoblasts were isolated from the skull of rabbit and seeded onto the CPC scaffolds, cultured for up to 21 days in static or rotating three-dimensional (3D) dynamic conditions. 7, 14, and 21 days after the incubation the proliferation, metabolic activity, and differentiation of the osteoblasts were determined by MTT, glucose consumption, and alkaline phosphate activity (ALP) assays respectively. The distribution of cells throughout the scaffolds was observed by scanning electron microscopy (SEM) and the sphere like structures which the SEM images showed within the extracellular matrix were assessed by energy dispersive X-ray (EDX) analysis. RESULTS: At all culture time points, the rotatingly cultured constructs demonstrated greater proliferation, metabolic activity, and osteoblastic differentiation than those of the statically cultured constructs as evidenced by MTT, glucose consumption and ALP assays. SEM indicated that 21 days after the distribution of cells in the scaffolds in the rotating culture was much more uniform than in the static culture. The sphere like structures was identified as calcium phosphate nodules by EDX analysis. CONCLUSION: As a novel method for construction of segmental tissue engineered bone in vitro, the rotating 3D dynamic culture of osteoblasts on CPC scaffolds with controlled internal channel architectures improves the properties such as proliferation, metabolic activity, osteoblastic differentiation, and uniform distribution of the seeded cells over those that maintain in static culture.