Clinical analysis of patients with skeletal metastasis of lung cancer.

BACKGROUND: Many factors influence bone metastases of lung cancer, and several studies report about survival of skeletal metastasis. However, few studies have focused on identifying the prognostic factors for skeletal metastasis of lung cancer, especially following orthopedic surgery. We conducted a retrospective analysis of the clinical characteristics of skeletal metastasis from lung cancer and discuss the prognostic factors. METHODS: We performed a medical record review of 202 patients who were diagnosed with skeletal metastasis from lung cancer. Adenocarcinoma was found in 116 patients (57.4%), squamous cell carcinoma in 29 (14.4%), small-cell lung cancer (SCLC) in 37 (18.7%), and large-cell carcinoma and other types of cancer in 20 patients (9.9%). Orthopedic surgery for skeletal metastasis was performed in 41 patients (20.3%). RESULTS: Lung cancer survival was 12.1 months. After diagnosis of lung cancer, skeletal metastasis was found at a mean of 2.5 months, and skeletal metastasis survival was 9.8 months. Lung cancer survival in patients younger than 60 years was 13.8 months, and lung cancer survival in patients 60 years or older was 10.8 months (p = 0.009). Skeletal metastasis survival in patients younger than 60 years was 11.0 months, and skeletal metastasis survival in patients 60 years or older was 8.8 months (p = 0.002). Mean skeletal metastasis survival with surgery was 12.6 months and without surgery was 9.1 months (p < 0.000). In the multivariate analysis of lung cancer survival, age under 60 years [HR (95% CI) 1.549 (1.122-2.139), p = 0.008], non-small cell lung cancer pathology type [HR (95% CI) 1.711 (1.157-2.532), p = 0.008], chemotherapy for skeletal metastasis [HR (95% CI) 8.064 (3.981-16.332), p < 0.000], and radiation therapy for skeletal metastasis [HR (95% CI) 1.791 (1.170-2.742), p = 0.007] were significant, independent, good prognostic factors. In the multivariate analysis of skeletal metastasis survival, age under 60 years [HR (95% CI) 1.549 (1.124-2.134), p = 0.007], non-small cell lung cancer pathology type [HR (95% CI) 2.045 (1.373-3.047), p < 0.000], chemotherapy for skeletal metastasis [HR (95% CI) 7.121 (3.542-14.317), p < 0.000], and orthopedic surgical treatment for skeletal metastasis [HR (95% CI) 1.710 (1.148-2.547), p = 0.008] were significant, independent, good prognostic factors. CONCLUSIONS: Patients who survived longer were less than 60 years old, received chemotherapy as treatment for skeletal metastasis, had NSCLC rather than SCLC, and underwent orthopedic surgery for skeletal metastasis.

Differences in the Efficacies of Pazopanib and Gemcitabine/Docetaxel as Second-Line Treatments for Metastatic Soft Tissue Sarcoma.

BACKGROUND: We retrospectively investigated the treatment outcomes of second-line treatment with pazopanib or gemcitabine/docetaxel in patients with advanced soft tissue sarcoma (STS). METHODS: Ninety-one patients who were treated with pazopanib or gemcitabine/docetaxel for advanced STS between 1995 and 2015 were analyzed. RESULTS: Forty-six and 45 patients received pazopanib and gemcitabine/docetaxel, respectively. The median progression-free survival for the group treated with pazopanib was 4.5 months compared with 3.0 months for the gemcitabine/docetaxel group (p = 0.593). The median overall survival for the group treated with pazopanib was 12.6 months compared with 14.2 months for the gemcitabine/docetaxel group (p = 0.362). The overall response rates (ORRs) were 6.5 and 26.7% in the pazopanib and gemcitabine/docetaxel groups, respectively. The following parameters had ORRs favoring gemcitabine/docetaxel: age ≥50 years (31.6 vs. 2.9%, p = 0.006), histologic grade 1-2 (40.9 vs. 0%, p = 0.001), and poor first-line treatment response (23.3 vs. 3.0%, p = 0.022). Gemcitabine/docetaxel was associated with better ORRs for the following histologic subtypes: leiomyosarcoma (p = 0.624), malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma (p = 0.055), and angiosarcoma (p = 0.182). However, the ORR of synovial sarcoma favored pazopanib (p = 0.99). CONCLUSIONS: The efficacies of pazopanib and gemcitabine/docetaxel as second-line treatments after doxorubicin or ifosfamide failure differed among clinical and histologic subgroups and appeared to facilitate a more personalized treatment approach for advanced STS.

Optimal radiotherapy strategy for primary or recurrent fibromatosis and long-term results.

PURPOSE: Although locally invasive or recurrent fibromatosis is primarily treated with surgery, radiotherapy (RT) produces local control for recurrent/unresectable tumors or those with positive surgical margins. Herein, we describe our updated institutional experience with RT to treat fibromatosis. METHODS: Forty-seven patients with fibromatosis received RT between 1990 and 2015, and were followed for ≥12 months. Eight patients received RT for gross tumors, and 39 received postoperative RT after single/multiple prior surgeries. A median dose of 54 Gy was prescribed for definitive RT; 48.6, 50.4, and 54 Gy were prescribed for R0, R1, and R2 resected tumors, respectively. Recurrences were classified as in-field, marginal, or out-field. Prognostic factors were also evaluated. RESULTS: Seven recurrences were noted, including 2 in-field, 4 marginal, and 1 out-field, after a median follow-up of 60 months. In-field recurrences occurred in 1 patient who received 40.5 Gy of salvage RT after postoperative recurrence and another who received 45 Gy for R1 resection after multiple prior operations. All marginal failures were due to insufficient clinical target volume (CTV) margins regardless of dose (3 with 45 Gy and 1 with 54 Gy). On multivariate analysis, a CTV margin ≥5 cm and dose >45 Gy were significant predictors of non-recurrence (p = 0.039 and 0.049, respectively). Subgroup analysis showed that patients with both an CTV margin ≥5 cm and a dose >45 Gy showed a favorable outcome. CONCLUSIONS: RT is a valuable option for treating aggressive fibromatosis; doses ≥45 Gy and a large field produce optimal results. For in-field control, a higher dose is more necessary for gross residual tumors than for totally excised lesions.

Response evaluation of giant-cell tumor of bone treated by denosumab: Histogram and texture analysis of CT images.

BACKGROUND: This study aimed to compare computed tomography (CT) features, including tumor size and textural and histogram measurements, of giant-cell tumors of bone (GCTBs) before and after denosumab treatment and determine their applicability in monitoring GCTB response to denosumab treatment. METHODS: This retrospective study included eight patients (male, 3; female, 5; mean age, 33.4 years) diagnosed with GCTB, who had received treatment by denosumab and had undergone pre- and post-treatment non-contrast CT between January 2010 and December 2016. This study was approved by the institutional review board. Pre- and post-treatment size, histogram, and textural parameters of GCTBs were compared by the Wilcoxon signed-rank test. Pathological findings of five patients who underwent surgery after denosumab treatment were evaluated for assessment of treatment response. RESULTS: Relative to the baseline values, the tumor size had decreased, while the mean attenuation, standard deviation, entropy (all, P = 0.017), and skewness (P = 0.036) of the GCTBs had significantly increased post-treatment. Although the difference was statistically insignificant, the tumors also exhibited increased kurtosis, contrast, and inverse difference moment (P = 0.123, 0.327, and 0.575, respectively) post-treatment. Histologic findings revealed new bone formation and complete depletion or decrease in the number of osteoclast-like giant cells. CONCLUSION: The histogram and textural parameters of GCTBs changed significantly after denosumab treatment. Knowledge of the tendency towards increased mean attenuation and heterogeneity but increased local homogeneity in post-treatment CT histogram and textural features of GCTBs might aid in treatment planning and tumor response evaluation during denosumab treatment.

Prognostic implications of polycomb proteins ezh2, suz12, and eed1 and histone modification by H3K27me3 in sarcoma.

BACKGROUND: Polycomb repressive complex 2 (PRC2; formed by EZH2, SUZ12, and EED protein subunits) and PRC1 (BMI1 protein) induce gene silencing through histone modification by H3K27me3. In the present study, we characterized the PRC expression pattern and its clinical implication in sarcoma. METHODS: Using immunohistochemistry, we analyzed PRC expression in 105 sarcoma patients with 5 subtypes: synovial sarcoma (n = 18), rhabdomyosarcoma (n = 28), Ewing sarcoma (n = 15), osteosarcoma (n = 30), and others (n = 14). RESULTS: The median age at diagnosis in the patient cohort was 26.8 years (range: 1-78 years) and the male-to-female ratio was 1:4. Initial disease presentation was locoregional disease in 83% of patients and initial metastatic disease in the remaining 17%. PRC expression was not significantly different according to histologic subtype (P = 0.400). Overall survival (OS) was significantly poor for SUZ12 high (P = 0.001), EED1 high (P = 0.279), and H3K27me3 high (P = 0.009). Ultimately, patients with PRC2high had significantly inferior OS than the no expression group (P = 0.009). In the Cox proportional hazard model adjusted for stage, histologic grade, surgery, margin and initial metastasis, SUZ12 expression (P = 0.020, HR 29.069, 95% CI 1.690-500.007), H3K27me3 (P = 0.010, HR 3.743, 95% CI 1.370-10.228) expression was significantly associated with shorter OS. CONCLUSION: We detected PRC expression in various sarcomas and demonstrated its independent negative prognostic role, suggesting the PRC axis as promising therapeutic target for treating sarcoma.

Reassessment of alkaline phosphatase as serum tumor marker with high specificity in osteosarcoma.

The goal of this study was to reassess serum alkaline phosphatase (ALP) as tumor marker in osteosarcoma. We retrospectively examined serum ALP levels at diagnosis, every therapeutic step (neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy), metastasis, and follow-up and analyzed the role of ALP as tumor marker in 210 osteosarcomas. The diagnostic performances of ALP were validated with pathology-proven 899 other primary bone lesions. Elevated ALP at diagnosis was associated with inferior overall survival (OS) (Log Rank P < 0.001) and disease-free survival (Log Rank P = 0.005) and independently significant for OS in multivariate analysis (hazard ratio [HR]=2.12, P = 0.032). During therapy, the ALP level significantly changed according to therapeutic steps (P < 0.001 for patients ≥15 years old, P < 0.001 for patients <15 years old) and survival (P = 0.015 for ≥15 years, P = 0.002 for <15 years), and the response of ALP to therapy and survival were associated (P = 0.042 for ≥15 years, P = 0.036 for <15 years). Initial ALP level was linearly correlated with tumor burden (total tumor volume; P = 0.016 for ≥15 years, bone tumor volume; P = 0.012 for ≥15 years). The sensitivity and specificity of ALP on diagnosis were 53.2% (95% Confidence Interval [CI]: 0.475-0.586) and 90.1% (95% CI: 0.888-0.913). The sensitivity of ALP on metastasis was 53.2% (95% CI: 0.431-0.624), and the specificity was 78.2% (95% CI: 0.720-0.839) at15 months postoperative and 90.0% (95% CI: 0.824-0.952) at 3 years postoperative. Serum ALP was found to be a valuable tumor marker with high specificity in osteosarcoma.

Location of residual viable tumor cells after neoadjuvant chemotherapy: A new concept with high prognostic performance in osteosarcoma.

BACKGROUND AND OBJECTIVES: The purpose of this study was to establish a new concept for evaluating responses to neoadjuvant chemotherapy in osteosarcoma. METHODS: A total of 56 high-grade extremity osteosarcoma patients were retrospectively reviewed. A new conceptual method was derived from locations of residual viable tumor cells (LRVTC) after chemotherapy, whether extracompartmental or intracompartmental, rather than quantitative measurements of necrosis rates of tumor cells. RESULTS: LRVTC after chemotherapy was independently associated with overall survival ([OS]hazard ratio [HR] = 6.502, P = 0.008) after adjustment for Huvos grade (HR = 3.694, P = 0.045), alkaline phosphatase ([ALP] HR = 2.140, P = 0.226), size (HR = 0.318, P = 0.133), joint extension (HR = 2.309, P = 0.162), and metastasis at diagnosis (HR = 8.228, P = 0.009). LRVTC was also independently associated with metastasis (HR = 5.096, P = 0.002) after adjustment for Huvos grade (HR = 2.261, P = 0.101), ALP (HR = 2.558, P = 0.053), size (HR = 1.280, P = 0.641), and joint extension (HR = 1.800, P = 0.254). AUC values of LRVTC for OS and metastasis were superior to those of Huvos grade: AUCs for OS (LRVTC: 0.757, Confidence Interval [CI] = 0.618 to 0.865 vs Huvos grade: 0.590, [CI] = 0.445 to 0.725; AUC = 0.167, P = 0.086) and metastasis (LRVTC: 0.769, CI = 0.631 to 0.874 vs Huvos grade: 0.606, [CI] = 0.461 to 0.739; AUC = 0.163, P = 0.046). CONCLUSIONS: LRVTC after chemotherapy may be useful as a new method with high performance for evaluating chemo-responses in osteosarcoma.

Outcomes of Treatment for Malignant Peripheral Nerve Sheath Tumors: Different Clinical Features Associated with Neurofibromatosis Type 1.

PURPOSE: Malignant peripheral nerve sheath tumors (MPNSTs) are a rare subtype of sarcoma that occur spontaneously or in association with neurofibromatosis type 1 (NF-1). This study aimed to clinically differentiate these types of MPNSTs. MATERIALS AND METHODS: The study reviewed 95 patients diagnosed with and treated for MPNST at Yonsei University Health System, Seoul, Korea over a 27-year period. The clinical characteristics, prognostic factors, and treatment outcomes of sporadic MPNST (sMPNST) and NF-1 associated MPNST (NF-MPNST) cases were compared. RESULTS: Patients with NF-MPNST had a significantly lower median age (32 years vs. 45 years for sMPNST, p=0.012), significantly larger median tumor size (8.2 cm vs. 5.0 cm for sMPNST, p < 0.001), and significantly larger numbers of imaging studies and surgeries (p=0.004 and p < 0.001, respectively). The 10-year overall survival (OS) rate of the patients with MPNST was 52±6%. Among the patients with localized MPNST, patients with NF-MPNST had a significantly lower 10-year OS rate (45±11% vs. 60±8% for sMPNST, p=0.046). Univariate analysis revealed the resection margin, pathology grade, and metastasis to be significant factors affecting the OS (p=0.001, p=0.020, and p < 0.001, respectively). Multivariate analysis of the patients with localized MPNST identified R2 resection and G1 as significant prognostic factors for OS. CONCLUSION: NF-MPNST has different clinical features from sMPNST and requires more careful management. Further study will be needed to develop specific management plans for NF-MPNST.

Prognostic implications of PD-L1 expression in patients with soft tissue sarcoma.

BACKGROUND: The PD-1/PD-L1 axis plays a paramount role in the immune escape of tumor cells by negative regulation of T-cell functions. The aim of the present study was to characterize the PD-L1 expression pattern and its clinical implication in soft-tissue sarcomas (STS). METHODS: We analyzed PD-L1 expression in 82 STS patients with 5 subtypes: rhabdomyosarcoma, synovial sarcoma, Ewing sarcoma, epithelioid sarcoma, and mesenchymal chondrosarcoma. RESULTS: The median age at diagnosis was 26 (range: 1-78) and the male to female ratio was 1.6. The majority (80 %) of patients showed locoregional disease rather than metastatic disease at diagnosis. Thirty-five cases (43 %) showed PD-L1 expression and the proportion of PD-L1 expression was significantly different according to histologic subtypes (P = 0.004); highest in epithelioid sarcoma (100 %, 7/7), followed by synovial sarcoma (53 %, 10/19), rhabdomyosarcoma (38 %, 12/32), and Ewing sarcoma (33 %, 6/18), while it was not expressed in mesenchymal chondrosarcoma (0 %, 0/6). STS patients with PD-L1 expression had worse overall survival compared with those without PD-L1 expression (5-year survival rate: 48 % vs. 68 %, P = 0.015). The Cox proportional hazard model adjusted for histologic subtype, initial metastasis, and PD-L1 expression showed that PD-L1 expression was significantly associated with shorter overall survival (P = 0.037, HR 2.57, 95 % CI 1.060-6.231). CONCLUSION: We have confirmed PD-L1 expression in various STS of young population and demonstrated its independent negative prognostic role, thereby suggesting the PD-1/PD-L1 axis as a potential therapeutic target for the treatment of young STS patients.

Prognostic Model to Predict Survival Outcome for Curatively Resected Liposarcoma: A Multi-Institutional Experience.

PURPOSE: We performed this study to analyze the clinical features and prognosis of Korean patients with liposarcoma. PATIENTS & METHODS: Between October 1986 and April 2013, 231 patients who were diagnosed with liposarcoma by histologic examination were enrolled in this study. RESULTS: The distribution of histologic subtypes was well-differentiated (n = 97, 42%), myxoid (n = 74, 32%), dedifferentiated (n = 32, 13.9%), pleomorphic (n = 15, 6.5%), and round-cell liposarcoma (n = 13, 5.6%). The majority of liposarcomas were located in the lower extremities (35.5%) and retroperitoneum (34.2%). Prognosis was worse for the trunk group compared with the extremity group (median disease-free survival [DFS] 3.3 vs. 9.9 years, respectively, P <0.001). Median DFS was significantly worse in patients with high grade histology compared to those with low grade histology (16.9% vs. 65.7%, P <0.001). The independent prognostic factors associated with survival were histology (hazard ratio [HR] 3.01; 95% confidence interval [CI], 1.82-4.97; P <0.001) and primary site (HR 1.80; 95% CI, 1.12-2.89; P = 0.015). Three risk groups with different survival outcomes were identified: group 1 (n = 98), no risk factors; group 2 (n = 92), one risk factor; and group 3 (n = 41), two risk factors. CONCLUSIONS: Histologic subtype and primary site were independent prognostic factors for curatively resected liposarcoma. A prognostic model for patients with liposarcoma clarified distinct groups of patients with good prognostic discrimination.

Prognostic implications of PIK3CA amplification in curatively resected liposarcoma.

BACKGROUND: We investigated the epidemiologic characteristics and prognostic significance of PIK3CA mutations/amplifications in curative resected liposarcoma. PATIENTS AND METHODS: A total of 125 liposarcoma tissue samples were collected over a 12-year period. PIK3CA mutations and gene copy number amplifications were analyzed by pyrosequencing and fluorescence in situ hybridization (FISH). RESULTS: Nine of the 105 liposarcomas (8.6%) had activating PIK3CA mutation. PIK3CA mutations were more frequent in myxoid/round cell and pleomorphic tumors compared with well-differentiated/dedifferentiated tumors (13.3% vs. 2.2%, P=0.043). In FISH PIK3CA analysis, copy number gain was detected in 14 of the 101 tumors (13.9%): 11 (10.9%) tumors had increased gene copy number (polysomy) and 3 (3.0%) exhibited gene amplification. In survival analysis, patients with PIK3CA copy number gain had a worse prognosis compared to patients without PIK3CA amplification (median disease-free survival [DFS] 22.2 vs. 107.6 months p=0.005). By multivariate analysis, PIK3CA copy number gain was an independent prognostic factor for worse DFS (P=0.027; hazard ratio, 2.400; 95% confidence interval 1.105 to 5.213). PIK3CA mutation was not associated with DFS and overall survival. CONCLUSIONS: We demonstrated PIK3CA mutation and amplification in liposarcoma. PIK3CA copy number gain was an independent poor prognostic factor for DFS. Further studies are needed to evaluate the potential diagnostic and therapeutic role of PIK3CA mutations and amplifications in liposarcoma.

Femur bowing could be a risk factor for implant flexion in conventional total knee arthroplasty and notching in navigated total knee arthroplasty.

PURPOSE: This study aimed to investigate the relationship between preoperative femoral axes and femoral implant position and to determine how femoral sagittal axes, including femoral anterior bowing, influence the femoral component position in total knee arthroplasty (TKA). METHODS: The relationship between femoral axes (femoral anterior bowing, mechanical axis and the anterior cortical line, intramedullary axis) and implant position was compared in 50 conventional and 50 navigated TKAs. Outliers with more than a 3° margin of error in placement of the femoral component compared with the mechanical axis in the sagittal plane were calculated. RESULTS: The femoral component flexion angle was 3.1° in the conventional group and 1.6° in the navigation group (p < 0.001). Anterior femoral bowing correlated positively with the angle between the mechanical axis and implant (r = 0.360, p = 0.010) in the conventional group and negatively with the angle between the anterior cortical line and flange of the femoral component (r = -0.355, p = 0.010) in navigated TKAs. Incidence of outliers was 48 % (24 patients) in the conventional group compared with 10 % (five patients) in the navigated group (p = 0.008). CONCLUSIONS: Femoral anterior bowing was an influential factor for implant position and could be a risk factor for both femoral implant flexion in conventional TKAs and notching in navigated TKAs. The results of this study should be considered by surgeons when assessing the risk factors for femoral geometry before performing TKAs, as these results may help them to avoid an overly flexed or extended position of the femoral component, which would affect clinical long-term survival. LEVEL OF EVIDENCE: Retrospective comparative study, Level III.

Leiomyosarcoma: investigation of prognostic factors for risk-stratification model.

BACKGROUND: We performed this study to define distinctive clinical features of leiomyosarcoma by assessing prognostic factors. METHODS: Between 1988 and 2011, 129 leiomyosarcoma patients who underwent surgical resection with curative intent were retrospectively reviewed. RESULTS: Of the 129 leiomyosarcoma patients, the distribution of anatomic locations was: extremity (n = 25), pelvis (n = 40), thoracic cavity (n = 11), intra-abdomen (n = 19), retroperitoneum (n = 23), and head/neck (n = 11). We classified the anatomic locations into two categories as abdominal (intra-abdomen and retroperitoneum, n = 42) and extra-abdominal (extremity, pelvis, thoracic cavity, and head/neck, n = 87). Prognosis was worse for the abdominal group than for the extra-abdominal group (median DFS 2.9 9.0 years, P = 0.04). Similarly, overall survival (OS) was also significantly worse for abdominal group (P = 0.027). Independent prognostic factors for survival were primary site (P = 0.041, hazard ratio (HR) 1.7; 95 % CI 1.2-2.8), tumor size (P = 0.038, HR 1.9; 95 % CI 1.13-3.38), margin status (P = 0.019, HR 2.1; 95 % CI 1.13-3.88), and histology grade (P = 0.01, HR 3.59; 95 % CI 1.64-7.87). We identified four different risk groups with different survival outcome: group 1 (n = 8), no adverse factors; groups 2 (n = 37) and 3 (n = 61) with one and two adverse factors, and group 4 (n = 23) with 3 or 4 adverse factors. CONCLUSION: Primary site, tumor size, resection margin, and histology subtype were independently associated with survival outcome. A prognostic model for leiomyosarcoma patients revealed four distinct groups of patients with good prognostic discrimination.

A new relative tumor sizing method in epi-metaphyseal osteosarcoma.

BACKGROUND: The goal of this study was to develop a new method for determining tumor size to predict prognosis with high performance in osteosarcoma. METHODS: This study was approved by the institutional review board. We retrospectively reviewed 41 magnetic resonance (MR) images at diagnosis and 57 MR images after neoadjuvant chemotherapy from 59 patients with non-metastatic, high-grade extremity osteosarcoma, who had undergone surgery between October 1994 and October 2009. RESULTS: A new parameter of tumor axial ratio (TAR) was designed to normalize tumor size by dividing the absolute tumor axial size by the reference bone axial size (RBS) of the affected bone. RBS was defined using anatomical landmarks for each type of bone. Absolute tumor length (ATL), absolute tumor volume (ATV), and relative tumor volume (RTV) were comparatively analyzed. TAR was only significantly decreased after chemotherapy in the survival (P = 0.009) and metastasis-free (P = 0.018) group in the paired t-test. With the Kaplan-Meier method, significant differences in overall survival (log rank P = 0.004) and disease-free survival (Log Rank P = 0.009) were noted between decreased TAR after chemotherapy and increased TAR. After Cox regression analysis, TAR showed an odds ratios of 5.931 for survival (95% Confidence Interval [CI], 1.153-30.513) and 14.144 for metastasis (95% CI, 2.826-70.784), whereas ATL, ATV, and RTV showed no associations with these clinical variables. The AUC value of TAR was 0.713 (95% CI, 0.548 to 0.878) for survival and 0.759 (95% CI, 0.608 to 0.909) for metastasis. CONCLUSIONS: TAR is a novel sizing method with potential as a prognostic tool in osteosarcoma.

Efficacy of pazopanib monotherapy in patients who had been heavily pretreated for metastatic soft tissue sarcoma: a retrospective case series.

BACKGROUND: We retrospectively reviewed outcomes of treatment with pazopanib, an oral multi-tyrosine kinase angiogenesis inhibitor, in patients with advanced soft tissue sarcoma, a rare and heterogeneous tumor group with limited treatment options. METHODS: Between 2009 and 2013, 43 patients with metastatic soft tissue sarcoma received pazopanib as salvage chemotherapy after one or more cytotoxic regimens. Response rate, progression-free survival, and overall survival were analyzed according to histological subtype, Eastern Cooperative Oncology Group performance status, and metastatic site. RESULTS: Common histological subtypes included leiomyosarcoma (n = 9), angiosarcoma (n = 6), malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma (MFH/UPS, n = 5), malignant peripheral nerve sheath tumor (MPNST, n = 5), and synovial sarcoma (n = 4). Nineteen patients (44.2%) received more than two chemotherapy regimens before pazopanib. At the time of analysis, 208 treatment cycles of pazopanib had been administered (median, 4.8 cycles per patient), and no treatment-related mortality occurred. The disease control rate was 61.0% (95% confidence interval [CI], 46.1-75.9%), and the overall response rate was 17.1% (partial response, n = 7; complete response, n = 0). Partial response was achieved in two patients with synovial sarcoma, two with MFH/UPS, one with MPNST, one with leiomyosarcoma, and one with angiosarcoma. The median lengths of progression-free survival and overall survival were 5.0 months (95% CI, 3.6-6.4 months) and 8.2 months (95% CI, 5.8-10.6 months), respectively. Progression-free survival was shorter in the patients with liposarcoma and rhabdomyosarcoma (1.3 and 0.9 months, respectively) than in those with leiomyosarcoma, MPNST, MFH/UPS, and synovial sarcoma (5.6, 6.5, 7.1, and 7.7 months, respectively). CONCLUSIONS: Pazopanib demonstrated acceptable antitumor activity in the Asian patients who had been heavily pretreated for sarcoma, with seemingly more favorable results in the patients with leiomyosarcoma, MPNST, MFH/UPS, and synovial sarcoma than in those with liposarcoma and rhabdomyosarcoma.

Incidence and Survival of Pediatric Soft Tissue Sarcomas: Comparison between Adults and Children.

PURPOSE: Pediatric-type sarcomas such as rhabdomyosarcoma (RMS), Ewing sarcoma (EWS), primitive neuroectodermal tumor (PNET), and desmoplastic small round-cell tumor (DSRCT) are rare in adults, with limited studies on their prognosis and optimal treatment strategies. We aimed to examine the outcome of children and adult patients with RMS, EWS, PNET, and DSRCT and relevant prognostic factors. MATERIALS AND METHODS: We retrospectively reviewed 220 pediatric-type sarcoma patients at a single institution between 1985 and 2011. Comparisons were made in order to examine differences in demographics, disease characteristics, and survival. Survival analyses were performed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards models. RESULTS: A total of 220 consecutive patients were identified at our institute. Median age was 15.6 years (range, 0 to 81 years) and there were 108 children (49%) and 112 adult patients (51%). According to histological classification, 106 patients (48.2%) had RMS, 60 (27.3%) had EWS, 50 (22.7%) had PNET, and 4 (1.8%) had DSRCT. With a median follow-up period of 6.6 years, the estimated median overall survival (OS) of all patients was 75 months (95% confidence interval [CI], 27.2 to 122.8 months) and median event-free survival (EFS) for all patients was 11 months (95% CI, 8.8 to 13.2 months). No significant difference in OS and EFS was observed between adults and children. In multivariate analysis, distant metastasis (hazard ratio [HR], 1.617; 95% CI, 1.022 to 2.557; p=0.040) and no debulking surgery (HR, 1.443; 95% CI, 1.104 to 1.812; p=0.012) showed independent association with worse OS. CONCLUSION: Metastatic disease and no surgical treatment are poor prognostic factors for OS among pediatric-type sarcomas for both adults and children.

Secondary malignant neoplasms after osteosarcoma: early onset and cumulative alkylating agent dose dependency.

PURPOSE: To analyze the impacts of chemotherapeutic agent exposures on the development of secondary malignant neoplasms (SMP) after osteosarcoma. METHODS: Of 132 patients who had been treated for high-grade extremity osteosarcoma from September 1992 to September 2008, 90 survivors were retrospectively reviewed. Fifty-eight of the survivors received a doublet of doxorubicin (ADR) and cisplatin (DDP), and 32 received a triplet of ADR, DDP, and ifosfamide (Ifos). On the basis of the dose distributions in the study cohort, the association between SMN and the cumulative dose of each agent was evaluated. RESULTS: After a mean of 13.1 years of follow-up, six SMNs were noted, three in each regimen. There were no SMNs among 42 patients who died of osteosarcoma. In Kaplan-Meier estimates, the triplet regimen group showed a higher cumulative incidence and shorter latency for SMNs than the doublet group (log rank P = 0.032). Fifteen years' cumulative incidence of SMNs in the triplet and doublet regimen group was 9.4 and 3.8%, respectively. In the independent t test, the mean latency to SMN in the triplet group (3.7 ± 1.3 years) was shorter than that in the double group (13.1 ± 2.8 years) (P = 0.017). In Cox regression, the alkylating agent score (AAS) [hazard ratio (HR) = 2.459, P = 0.015] and DDP (HR = 1.779, P = 0.046) showed a significant relationship with SMNs, whereas ADR (HR = 0.896, P = 0.664) and Ifos (HR = 3.694, P = 0.119) did not. AAS was also significant after adjusting for ADR and DDP (HR = 3.319, P = 0.020). CONCLUSIONS: High cumulative AAS is an independent risk factor for SMN and its early-onset development after osteosarcoma.

Postoperative nomogram to predict the probability of metastasis in Enneking stage IIB extremity osteosarcoma.

BACKGROUND: Metastasis is the most crucial prognostic factor in osteosarcoma. The goal of this study was to develop a new nomogram to predict the probability of metastasis in Enneking stage IIB extremity osteosarcoma after neoadjuvant chemotherapy and limb salvage surgery. METHODS: We examined medical records of 91 patients who had undergone surgery between March 1994 and March 2007. A nomogram was developed using multivariate logistic regression. The nomogram was validated internally by bootstrapping-method (200 repetitions) and externally in independent validation set (n = 34). A Youden-derived cutoff value was assigned to the nomogram to predict dichotomous outcomes for metastasis. RESULTS: The nomogram was built from four predictors of tumor site, serum alkaline phosphatase, intracapsular extension, and Huvos grade, and an additional clause that the cutoff value should be added to the total points in the cases of incomplete surgical resection. P-value of Hosmer and Lemshow Goodness-of-fit test of this model was 0.649. Area under receiver operating curve values of 0.83 (95% confidence interval [CI], 0.75 to 0.92) in the training set and 0.80 (95% CI, 0.63 to 0.96) in the validation set were obtained. The accuracy of dichotomous outcomes was 79.1% (95% CI, 0.69 to 0.86) and 82.4% (95% CI, 0.63 to 0.92) in the training and validation sets. CONCLUSIONS: We have developed a new high-performance nomogram to predict the probability of metastasis in Enneking stage IIB extremity osteosarcoma after limb salvage surgery.

Vascular soft-tissue sarcomas: a prognostic model from a retrospective single-center study.

BACKGROUND: Vascular soft-tissue sarcomas are a rare form of sarcoma. Malignant subtypes exhibit a variety of biological behaviors. We describe the clinicopathological characteristics and patient survival outcomes of malignant vascular soft-tissue sarcomas. METHODS: We conducted a retrospective study on a cohort of 84 patients diagnosed with vascular tumors by histological examination at the Yonsei University College of Medicine between April 1987 and August 2011. The primary end point was overall survival (OS). RESULTS: The angiosarcoma patients had a significantly shorter OS than the patients with other subtypes of sarcomas (59.0 and 142.7 months, respectively; p < 0.001). Upon multivariate analysis of survival in patients who underwent surgical resection, the following independent prognostic factors were identified: primary site (trunk, p = 0.001), age (older than 65 years, p < 0.001), pathology (angiosarcoma, p = 0.006) and R2 resection (p = 0.002). CONCLUSION: The independent prognostic factors for shorter survival are the trunk as the primary site, malignant angiosarcoma and age (>65 years). Complete excision should be attempted for providing a survival advantage in the patients with localized disease. In addition, bleeding episodes are much more frequent in patients with a poor survival outcome.

Potential of nucleofected human MSCs for insulin secretion.

The goal of this experiment was to generate insulin-producing human mesenchymal stem cells (hMSCs) as a therapeutic source for type I diabetes mellitus, which is caused by insulin deficiency due to the destruction of islet ß cells. In various trials for the treatment of type I diabetes, cell-based therapy using adult stem cells is considered to be one of the most useful candidates for the treatment. In this experiment, a non-viral method called nucleofection was used to transfect hMSCs with pEGFP-C2 and furin-cleavable human preproinsulin gene (hPPI) to produce insulin-secreting cells as surrogate ß cells. Transfection efficiency was determined using flow cytometry analysis. Expression and production of insulin were tested using RT-PCR and ELISA. The expression, production and maturation of insulin from the genetically engineered hMSCs showed an increase when compared with a non-transfected control group. Insulin expression from hMSCs using nucleofection in this study has shown the potential for type I diabetes therapy. For further study, an evaluation for in vivo experiments and clinical applications must be supplemented.