Poor Histologic Response Research Articles

The prognostic significance of circulating serum amyloid A and CXC chemokine ligand 4 in osteosarcoma.

Osteosarcoma (OS) is the most common pediatric bone cancer. Despite advances in treatment regimens, the survival rate remains 60-70%. There is an urgent need to identify prognostic biomarkers, so that targeted therapies can be developed to improve the outcome. Our laboratory has previously identified that circulating serum amyloid A (SAA) and CXC chemokine ligand 4 (CXCL4) are upregulated in patients with OS. In this study, we tested if they could be used as prognostic biomarkers. We used enzyme-linked immunosorbent assays to measure their concentrations in serum samples (n = 233) and immunohistochemistry to examine their expressions in primary tumors (n = 37). Prognostic significance of the serum concentrations and tumor expressions of the biomarkers was then evaluated. Patients with "high SAA" and "low CXCL4" circulating levels at diagnosis significantly correlated with a worse outcome (HR = 1.68, P = 0.014), which was independent of the metastatic status. These patients also exhibited a significantly higher rate of poor histologic response to chemotherapy. Furthermore, low tumor expression of CXCL4 correlated with poor survival (HR = 3.57, P = 0.005). Our results demonstrate that circulating SAA and CXCL4 may serve as prognostic biomarkers in OS. Targeting CXCL4 has been reported, suggesting that it may be exploited as a therapeutic target in OS.

Immune-infiltrate characterization in localized osteosarcoma patients treated within protocol ISG-OS1.

11025 Background: We hypothesized that immune-infiltrates were associated with survival, and examined a primary osteosarcoma tissue microarrays (TMAs) to test this hypothesis. Methods: Biopsies of patients (pts) treated from 04/2001 to 11/2006 were analyzed. TMAs from representative areas were assembled. Clinical and pathological characteristics at diagnosis, expression of CD8, CD4, CD3, FOXP3, CD20, CD68/CD163 (tumor associated macrophage), Tia-1 (cytotoxic T cell), CD303 (plamacytoid dendritic cells: pDC), Arginase-1 (myeloid derived suppressor cells: MDSC), PD-1 on immuno-cells (IC), and PD-L1 both on tumor cells (TC) and IC were correlated with patients outcome. A TMA of surgical specimens of the same cases also was assembled, and chemotherapy-induced changes analysis is ongoing. Results: 86 pts identified. Median age: 16 (range 4-39); high LDH: 36/86; high serum alkaline phosphatase (SAP): 18/86. All pts underwent neoadjuvant chemotherapy and surgery. A good pathologic response (≥90% necrosis) was achieved by 45/86 pts. IHC results are displayed in the Table. With a median follow-up of 8 years (range 1-13), the 5-year overall survival (5-yr OS) was 74% (95% CI 64-85). Univariate analysis showed better 5-yr OS for: a) good responders (good 89% vs poor 57%, p=0.0001); b) pts with CD8/Tia1 tumoral infiltrates (+/+ 81% vs +/- 60% vs -/- 45% p=0.002); c) pts with normal SAP (normal 85% vs high 44%, p=0.04). A numerically lower 5-yr OS was found in PD-L1 (IC) positive (+ 58% vs - 77%, p=0.14) and CD163 negative (+ 81% vs - 56%, p=0.17) cases. After multivariate analysis, poor histologic response (p=0.007) and lack of CD8/Tia1 infiltration (p=0.02) were independently correlated with poorer survival. In the subset of CD8+ patients, poorer (p= 0.02) OS was observed for PD-L1 (IC) + cases. Conclusions: Our findings support the hypothesis that CD8/Tia1 (cytotoxic T cells) infiltrate in tumor microenvironment at diagnosis is associated with superior survival for patients with localized osteosarcoma, while PD-L1 expression is associated with poorer survival. [Table: see text]

MRE11 and ATM Expression Levels Predict Rectal Cancer Survival and Their Association with Radiotherapy Response.

BackgroundAberrant expression of DNA repair proteins is associated with poor survival in cancer patients. We investigated the combined expression of MRE11 and ATM as a predictive marker of response to radiotherapy in rectal cancer.MethodsMRE11 and ATM expression were examined in tumor samples from 262 rectal cancer patients who underwent surgery for rectal cancer, including a sub-cohort of 54 patients who were treated with neoadjuvant radiotherapy. The relationship between expression of the two-protein panel and tumor regression grade (TRG) was assessed by Mann–Whitney U test and receiver operating characteristics area under curve (ROC-AUC) analysis. The association between expression of the two-protein panel and clinicopathologic variables and survival was examined by Kaplan-Meier methods and Cox regression analysis.ResultsA high score for two-protein combined expression in the tumor center (TC) was significantly associated with worse disease-free survival (DFS) (P = 0.035) and overall survival (OS) (P = 0.003) in the whole cohort, and with DFS (P = 0.028) and OS (P = 0.024) in the neoadjuvant subgroup (n = 54). In multivariate analysis, the two-protein combination panel (HR = 2.178, 95% CI 1.115–4.256, P = 0.023) and perineural invasion (HR = 2.183, 95% CI 1.222–3.899, P = 0.008) were significantly associated with DFS. Using ROC-AUC analysis of good versus poor histological tumor response among patients treated preoperatively with radiotherapy, the average ROC-AUC was 0.745 for the combined panel, 0.618 for ATM alone, and 0.711 for MRE11 alone.ConclusionsThe MRE11/ATM two-protein panel developed in this study may have clinical value as a predictive marker of tumor response to neoadjuvant radiotherapy, and a prognostic marker for disease-free and overall survival.

Pathologic fracture in childhood and adolescent osteosarcoma: A single-institution experience.

Pathologic fractures occur in 5-10% of pediatric osteosarcoma (OS) cases and have historically been considered a contraindication to limb salvage. Our purpose was to describe the radiographic features of pathologic fracture and examine its impact on local recurrence rates, functional outcomes, and overall survival. We retrospectively analyzed patients at our institution from 1990 to 2015 with pathologic fracture at diagnosis or during neoadjuvant chemotherapy. We selected a control group of 50 OS patients of similar age and gender without pathologic fracture from 1990 to 2015. Functional outcomes were scored using Musculoskeletal Tumor Society criteria. Chi-square test was used for comparative analysis of groups. Thirty-six patients with 37 pathologic fractures form the study cohort. Of patients who received surgery, 18 of 34 patients with fracture underwent amputation compared to 8 of 48 patients in the nonfracture group (P = 0.007). Indications for amputation in fracture patients were tumor size (n = 7), neurovascular involvement (n = 6), and tumor progression during neoadjuvant chemotherapy (n = 5). Only one patient (2.9%) in the fracture group who underwent limb salvage suffered local recurrence. Of patients who received neoadjuvant chemotherapy, 25 of 34 fracture patients showed poor histological response compared to 24 of 47 nonfracture patients (P = 0.044). There was no statistically significant difference in overall survival (P = 0.96). Functional outcomes were significantly lower in fracture patients (median = 17.5) than nonfracture patients (median = 24) (P = 0.023). Radiographic features of pathologic fractures were highly variable in this population. Limb salvage surgery can be performed without increased risk of local recurrence. Patients with pathologic fracture suffer worse functional outcomes but no decrease in overall survival.

Analysis of Prognostic Factors in High-Grade Osteosarcoma of the Extremities in Children: A 15-Year Single-Institution Experience.

The aim of this retrospective study was to define clinical and pathological features and prognostic factors among children and adolescents diagnosed with high-grade osteosarcoma of the extremities. A total of 73 patients younger than 18 years diagnosed with primary osteosarcoma of the extremities between January 1998 and December 2013 were retrospectively evaluated. Prognostic factors, such as age, gender, primary tumor site, alkaline phosphatase and lactate dehydrogenase levels, metastatic disease, pathological fracture, histological response, and surgery type, were analyzed to evaluate their effects on overall survival (OS) and event-free survival (EFS). At a median follow-up of 30 months (1.5-152), OS and EFS at 5 years were 64.5 ± 8.1 and 48.5 ± 8.7% for patients with localized disease; and 16.2 ± 7.9 and 14.4 ± 7.3% for patients with initial metastatic disease, respectively. In patients with localized disease, conservative surgery was performed on 22 of 46 patients (43.5%), and there was no significant difference in survival rates among patients who had conservative vs. radical surgery (p = 0.65). Although tumor size (>12 cm) was significant prognostic factor in univariate analysis; multivariate analysis identified elevated levels of alkaline phosphatase (p = 0.033) and poor response to neoadjuvant chemotherapy (p < 0.001) only as independent prognostic factors. Age, histological type, pathological fracture, and primary tumor site did not significantly affect prognosis. Initial elevated presence of alkaline phosphatase in serum and poor histological response after neoadjuvant chemotherapy were significant factors for unfavorable prognosis. It is necessary to optimize staging and treatment intensification to improve survival rates, especially among patients with metastasis at initial presentation.

Risk-Based Therapy for Localized Osteosarcoma.

The outcome of localized osteosarcoma has remained constant over the past 30 years. Histological response to preoperative chemotherapy is the best predictor of outcome. Strategies to alter treatment based on histological response have not resulted in increased survival. Patients with localized osteosarcoma received preoperative chemotherapy with cisplatin, doxorubicin, and methotrexate. Patients whose tumors had a good histological response (≥90% necrosis) continued with the same treatment postoperatively. Patients with poor histological response (<90% necrosis) received three courses of melphalan 100 mg/m(2) on day -4, cyclophosphamide 2,000 mg/m(2) on days -3, and -2 followed by stem cell infusion. Fifty-two patients were enrolled. Median age was 14 years, and 56% of patients were male. The femur was the most common site. Forty patients underwent limb salvage surgery and amputation was performed in six patients. Forty-eight percent of tumors showed good histological response. Forty patients were evaluable for outcome; 18 patients with poor histologic response received high-dose chemotherapy. The 5-year event-free survival (EFS) and overall survival (OS) for patients treated on the high-dose chemotherapy arm were 28% (95% confidence interval [CI], 10-49) and 48% (95% CI, 23-69), respectively. The 5-year EFS and OS for patients treated on the standard chemotherapy arm were 62% (95% CI, 36-80) and 74% (95% CI, 44-90), respectively. All patients who received high-dose chemotherapy developed grade 3 or higher hematological toxicity. There were no treatment-related deaths. Postoperative alkylator intensification with high-dose cyclophosphamide and melphalan in patients with localized osteosarcoma with poor histological response failed to improve survival.

Response to chemotherapy estimates by FDG PET is an important prognostic factor in patients with Ewing sarcoma.

Response to chemotherapy is a prognostic factor in patients with Ewing sarcoma (ES); the role of FDG PET to predict response in these patients has not been thoroughly investigated. We evaluated the diagnostic accuracy and the potential of FDG PET to predict response to chemotherapy (CHT). We analyzed data of 50 patients with ES (median age 12.6 years). All patients were treated with neoadjuvant CHT, and underwent surgery for local control. All patients had (18)F-FDG PET/CT at diagnosis and after induction CHT, prior to local control. We compared response assessed by histopathology with FDG PET using standard uptake values (SUVs). Median SUV at diagnosis (SUV I) was 5 (range 1.2-17), and median SUV after neoadjuvant chemotherapy (SUV II) was 1.8 (range 0-8.4). Median SUV II/I ratio was 0.3 (range 0-1). SUV at diagnosis was significantly lower in patients with good histological response than in patients with poor histological response (median 3.8 vs. 7.2, p 0.02). We found a significant correlation between SUV II and outcome; the positive predictive value of an SUV II ≤ 2.5 for favorable response was 84.21 %, and the median SUV II was significantly higher in patients with disease progression (2.3 vs. 1.6, p = 0.04). In multivariate analysis, necrosis and SUV II were significant predictors of outcome. (18)F-FDG PET demonstrates high diagnostic accuracy for response to initial chemotherapy in patients with ES and it correlates with outcome. The role of FDG PET in predicting response and outcome should be further investigated.

Prognostic Factors and Patterns of Relapse in Ewing Sarcoma Patients Treated With Chemotherapy and R0 Resection

To identify prognostic factors and patterns of relapse for patients with Ewing sarcoma who underwent chemotherapy and R0 resection without radiation therapy (RT). We reviewed the medical records of patients who underwent surgical resection at our institution between 2000 and 2013 for an initial diagnosis of Ewing sarcoma. The associations of demographic and clinical factors with local control (LC) and patient outcome were determined by Cox regression. Time to events was measured from the time of surgery. Survival curves were estimated by the Kaplan-Meier method and compared by the log-rank test. A total of 66 patients (median age 19 years, range 4-55 years) met the study criteria. The median follow-up was 5.6 years for living patients. In 43 patients (65%) for whom imaging studies were available, the median tumor volume reduction was 73%, and at least partial response by Response Evaluation Criteria in Solid Tumors was achieved in 17 patients (40%). At 5 years, LC was 78%, progression-free survival (PFS) was 59%, and overall survival (OS) was 65%. Poor histologic response (necrosis ≤95%) was an independent predictor of LC (hazard ratio [HR] 6.8, P=.004), PFS (HR 5.2, P=.008), and OS (HR 5.0, P=.008). Metastasis on presentation was also an independent predictor of LC (HR 6.3, P=.011), PFS (HR 6.8, P=.002), and OS (HR 6.7, P=.002). Radiologic partial response was a predictor of PFS (HR 0.26, P=.012), and postchemotherapy tumor volume was associated with OS (HR 1.06, P=.015). All deaths were preceded by distant relapse. Of the 8 initial local-only relapses, 5 (63%) were soon followed by distant relapse. Predictors of poor postrecurrence survival were time to recurrence <1 year (HR 11.5, P=.002) and simultaneous local and distant relapse (HR 16.8, P=.001). Histologic and radiologic response to chemotherapy were independent predictors of outcome. Additional study is needed to determine the role of adjuvant radiation therapy for patients who have poor histologic response after R0 resection.

IL-17 and IL-23 in lupus nephritis - association to histopathology and response to treatment.

BackgroundRecent studies indicate a central role for the IL-23/IL-17 axis in the pathogenesis of lupus nephritis (LN) but the importance in the context of treatment outcome is unknown. We studied various cytokines, including the IL-23/IL-17 axis, in association to histopathology and response to therapy.MethodsFifty-two patients with active LN were included. Renal biopsies were performed at baseline and after immunosuppressive treatment. Serum levels of TNF-α, IFN-γ, IL-6, IL-10, IL-17, IL-23 and TGF-β were analysed at both biopsy occasions and in 13 healthy controls. IL-17 expression in renal tissue was assessed by immunohistochemistry. Biopsies were evaluated regarding WHO-classification and renal disease activity was estimated using the BILAG-index. Improvement of 2 grades in renal BILAG was regarded complete response, and 1 grade partial response.ResultsAt baseline, all patients had high disease activity (BILAG A/B). Baseline levels of IL-6, IL-10, IL-17, IL-23 (p < 0.001) and IFN-γ (p = 0.03) were increased in patients vs. controls. In contrast, TGF-β was lower in patients compared to controls (p < 0.001).Baseline levels of IL-17 were higher in patients with persisting active nephritis (WHO III, IV, V) after treatment, i.e. a poor histological response, vs. WHO I-II (p < 0.03). At follow-up, IL-23 were higher in BILAG-non-responders vs. responders (p < 0.05). Immunostaining of renal tissue revealed IL-17 expression in inflammatory infiltrates.ConclusionsHigh baseline IL-17 predicted an unfavourable histopathological response, and BILAG-non-responders had high IL-23, indicating that that a subset of LN-patients has a Th-17 phenotype that may influence response to treatment and could be evaluated as a biomarker for poor therapeutic response.

High-dose methotrexate (HD-MTX) used as an adjunct with other chemotherapeutics for the treatment of osteosarcoma.

The objective of this study is to evaluate retrospectively the effectiveness of multiple-drug chemotherapeutics regimen that included high-dose methotrexate (HD-MTX) for treating primary osteosarcoma. 148 newly diagnosed patients with Stage I and II osteosarcoma who received HD-MTX/HD-MTX/DDP(cisplatin)/ADM(doxorubicin) and/or HD-MTX/IFO(Ifosfamide)/DDP/ADM before and after the surgery were retrospectively analyzed to measure the efficacy of this regimen. The significance of various variables as predictive prognostic factors of the patient survival rate was also evaluated. The overall 3-year survival rate of the patients was 79.73%. The survival rate was improved to 85.71% in the patients who received surgery and a complete 4-cycle chemotherapy. In addition, the rates of disease-free survival (DFS), local recurrence, and distant metastasis were 68.13, 3.30, and 10.81%, respectively. Our analysis showed that completing 4-cycle chemotherapy produced a significant impact on the overall 3-year survival and DFS rates (P<0.05). The overall 3-year survival was correlated with pathological fracture, chemotherapy completion, histological response, local recurrence, and distance metastasis (single-factor P<0.05). Multivariate analysis further evidenced that these predictive factors were independently correlated to the survival rate (multi-factor P<0.05). The complete 4-cycle multiple-drug chemotherapy consisting of HD-MTX, doxorubicin, cisplatin, and ifosfamide combined with surgical resection was found to be effective in improving the survival rate of osteosarcoma patients. Furthermore, the presence of pathological fracture, poor histological response, local recurrence, and distant metastasis was negatively correlated with the survival rate. Patient age, gender, location of primary tumor, and serum alkaline phosphatase level were not found to show the prognostic significance.

May Patient Genetic Characteristics Explain Heterogeneity of Treatment Efficacy in Ewing Sarcoma? a Gwas Study

ABSTRACT Aim: In the collaborative Euro-EWING99 study (EE99), Ewing sarcoma patients (EW pts) received vincristine ifosfamide doxorubicin etoposide induction (VIDE); maintenance treatment was stratified by initial staging and histological response. We conducted a genome-wide association study (GWAS) to identify Single Nucleotide Polymorphisms (SNPs) which may influence efficacy outcomes. Methods: 289/807 French pts registered in EE99 before 2010 were genotyped for 598821 SNPs. Association of each SNP with poor histological response to VIDE (>10% viable cells) was assessed by logistic regression adjusted for age, gender and the 2 first eigenvectors to correct for population stratification. Three genetic models were tested: additive, dominant and recessive. Multivariate Cox models were used to test for association with progression-free and overall survival (PFS, OS). To account for multiple comparisons, we set the p-value threshold for significant associations at 5.10-7. Results: After quality control, 277 pts (median age 14.7y [0.5; 48.4]; 96/277 metastatic; median follow-up 6.9y) and 561924 SNPs are included in the analysis. 146/194 pts operated after VIDE induction were good responders. We detected no genome-wide significant association with histological response. The lowest p-value was obtained for SNP rs2247119 (OR=4.5 [95%CI 2.4; 8.3] p=2.10-6, additive model) located in the PHF11 gene (transcription factor). An association between PHF11 down-regulation through hypermethylation in EW samples and poor prognosis has been described (Alholle 2013). Two SNPs were associated with PFS: rs4653137 (chr 1, KIAA0319L gene, HR=3.9 [2.3; 6.6] p=3.10-7) and rs9489215 (chr 6, DCBLD1 gene, HR=2.3 [1.6; 3.2] p=1.10-6). DBCLD1 has been found associated with poor prognosis in small cell lung cancer (Han 2014). These 2 SNPs were not significantly associated with OS (p=1.10-5 and 2.10-5), unlike SNP rs3781854 (chr 11, ELP4 gene, HR=2.5 [1.8; 3.6] p=6.10-7). Conclusions: The GWAS study showed weak signals of association with treatment efficacy in EW. Further studies are needed to validate these associations, and explore the mechanisms and clinical utility of these variants. Disclosure: All authors have declared no conflicts of interest.

Validation of a multi-modal treatment protocol for Ewing sarcoma--a report from the polish pediatric oncology group.

Ewing sarcoma (ES) is the second most common paediatric malignant bone tumor. Advances in multi-disciplinary care have resulted in significant improvement in cure rates over the last decades. However, the generalization of those results in countries traditionally excluded from large cooperative trials has yet to be demonstrated. We report the results of modern multi-disciplinary care for patients with ES in Poland. One hundred and thirty-two patients with ES were treated using modern multi-modal therapy during the period 2000-2009. Overall survival was estimated by Kaplan-Meier methods and compared using long-rank test and Cox models. Factors predictive of outcome in our setting were analyzed to identify distinct risk groups that could help identify areas for improvement. The median age at the time of diagnosis was 12.3 years. With a median follow-up of 5.0 years, the 5-year event-free survival (EFS) and OS estimates for localized disease were 54.88% and 68.29%, respectively. For patients with metastatic disease, 5-year EFS and OS estimates were 36% and 42%, respectively. There was no correlation between age and stage or site. Patients with localized, non-pelvic disease had better outcome than patients with axial tumors (71% vs. 44%, respectively, P = 0.00073). Treatment failure was associated with stage, pelvic primary, poor histological response, and type of local control. Successful treatment of ES requires optimal systemic and local therapy. We were able to replicate the results of modern multi-modal protocols. Validation of current treatment protocols in countries with more limited cancer treatment resources is required.

Systematic review of high-dose and standard-dose chemotherapies in the treatment of primary well-differentiated osteosarcoma.

The objective of this study is to evaluate whether high-dose chemotherapy is more efficacious than standard-dose chemotherapy in the treatment of primary well-differentiated osteosarcoma. The Cochrane systematic evaluation method was adopted. A database search was conducted in MEDLINE, Embase, OVID, the Cochrane Central Register of Controlled Trials database and the Chinese Biomedical Literature CD-ROM Database. The quality of the included studies was jointly evaluated by two reviewers, and homogeneous studies were included for meta-analysis. A total of five studies were included in this meta-analysis, with 1,415 subjects with primary, nonmetastatic, well-differentiated osteosarcoma in the limbs. No statistically significant differences were found between the high-dose chemotherapy group and the low-dose group in 5-year event-free survival [RR 1.04, 95 %CI (0.95, 1.13)], 5-year overall survival [RR 1.02, 95 %CI (0.95, 1.10)], local recurrence rate [RR 0.90, 95 %CI (0.59, 1.39)], proportion of subjects with good histological response [RR 0.93, 95 %CI (0.81, 1.07)], or limb salvage rate [RR 0.97, 95 %CI (0.92, 1.02)]. A statistically significant difference was observed in the 5-year event-free survival between the subjects with good histological response to preoperative chemotherapy and the subjects with poor histological response [RR 1.55, 95 %CI (1.19, 2.00), P < 0.001]. High-dose chemotherapy did not show superior efficacy to low-dose chemotherapy in the treatment of primary well-differentiated osteosarcoma. Further high-quality randomized controlled trials are needed to provide additional reliable evidence for our observation.

Outcome of surgical resection of pelvic osteosarcoma.

Background:The aim of the following study is to evaluate the morbidity, oncologic results and functional outcome in nonmetastatic patients with primary osteosarcoma of the pelvis treated with surgical resection.Materials and Methods:Twelve cases of nonmetastatic osteosarcoma of pelvis were operated as part of their multimodality treatment regime between November 2003 and May 2011. There were 5 males and 7 females with a median age of 22 years (range 8-39 years). Ten patients underwent limb sparing resections while 2 had a hindquarter amputation. All 10 cases of limb sparing surgery included resection of the acetabulum. A pseudarthrosis was carried out in 7 cases. Extracorporeal radiation therapy and reimplantation of the bone followed by fixation with plates was used in 1 case and an ischiofemoral arthrodesis was carried out in 2 cases.Results:Surgical margins were free in 11 patients. Seven patients had a poor histological response to chemotherapy while 4 patients had a good response to chemotherapy. In the patient reconstructed with radiated auto bone graft, the histological response to chemotherapy could not be assessed. Surgery related complications were seen in 8 out of 12 patients (67%). Three of these patients (25%) required additional surgical intervention for their complications. All patients were available for followup. The median followup of survivors was 56 months (range 24-102 months). Four patients (33%) developed a local recurrence. At 5 years, overall survival was 67%. Patients with a good response to chemotherapy had a better overall survival when compared with patients with a poor response to chemotherapy. The mean Musculoskeletal Tumor Society functional score was 22 (range12-27).Conclusions:Though complex and challenging, surgery provides good local control and oncologic outcomes with acceptable function in patients with osteosarcoma of the pelvis treated with appropriate surgical resection as part of their multimodality treatment.

THU0520 Interferon (IFN)-Lambda1/3, but not IFN-Alpha, is A Marker of Poor Response to Treatment in Lupus Nephritis

BackgroundLupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) affecting up to 60% of the patients. IFN-α is a central cytokine in the pathogenesis for LN, and...

Early response monitoring to neoadjuvant chemotherapy in osteosarcoma using sequential 18 F-FDG PET/CT and MRI

We evaluated the potential of sequential fluorine-18 fluorodeoxyglucose ((18) F-FDG) positron emission tomography (PET)/computed tomography (CT) and MRI (PET/MRI) after one cycle of neoadjuvant chemotherapy to predict a poor histologic response in osteosarcoma. A prospective study was conducted on 30 patients with osteosarcoma treated with two cycles of neoadjuvant chemotherapy and surgery. All patients underwent PET/MRI before, after one cycle, and after the completion of neoadjuvant chemotherapy, respectively. Imaging parameters [maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and tumor volume based on magnetic resonance (MR) images (MRV)] and their % changes were calculated on each PET/MRI data set, and histological responses were evaluated on the postsurgical specimen. A total of 17 patients (57%) exhibited a poor histologic response after two cycles of chemotherapy. Unlike the little volumetric change in MRI, PET parameters significantly decreased after one and two cycles of chemotherapy, respectively. After one cycle of chemotherapy, SUVmax, MTV, and TLG predicted the poor responders. Among these parameters, either MTV ≥ 47 mL or TLG ≥ 190 g after one cycle of chemotherapy was significantly associated with a poor histologic response on multivariate logistic regression analysis (OR 8.98, p = 0.039). The sensitivity, specificity, and accuracy of these parameters were 71%, 85% and 77%; and 71%, 85% and 77 %, respectively. The histologic response to neoadjuvant chemotherapy in osteosarcoma can be predicted accurately by FDG PET after one course of chemotherapy. Among PET parameters, MTV and TLG were independent predictors of the histologic response.

Correlation Between Fluid–Fluid Levels on Initial MRI and the Response to Chemotherapy in Stage IIB Osteosarcoma

The presence of fluid-fluid levels (FFLs) on osteosarcoma magnetic resonance imaging (MRI) is underestimated as a nonspecific finding; however, we hypothesized that FFL in conventional osteosarcoma may be indicative of chemoresistance. In 567 stage IIB osteosarcoma patients, we evaluated the following: the incidence of FFL and their correlation with other clinicopathological variables; tumor volume change after chemotherapy and survival according to the presence of FFL; and the relationship between survival and the extent of FFL. One hundred eight (19%) tumors showed FFL on initial MRI. FFL were correlated with proximal humeral location (P=0.017), osteolytic on plain radiographs (P<0.001), tumor enlargement after chemotherapy (P<0.001), and poor histological response (P=0.005). Large tumor (P<0.01), proximal tumor location (P=0.01), and presence of FFL (P<0.01) were independent predictors of poor survival. Compared to the extensive FFL (more than one third of the tumor), small foci of FFL (less than one third of the tumor) showed a high tendency for tumor enlargement after chemotherapy (P<0.001), poor histologic response (P=0.001), and worse survival (P<0.001). FFL on initial MRI could predict tumor progression after chemotherapy. Notably, tumors with small foci of FFL (less than one third of the tumor) have a high propensity for poor outcome. Patients with this finding should be considered for risk-adapted therapy.

Proximal Tumor Location and Fluid-fluid Levels on MRI Predict Resistance to Chemotherapy in Stage IIB Osteosarcoma

Primary tumor growth during neoadjuvant chemotherapy is believed to be a sign of resistance to chemotherapy (chemoresistance), and often is associated with poor histologic response, local recurrence, and poorer survival. Currently there are no proven indicators to predict poor response to chemotherapy at the time of diagnosis. We asked (1) what clinicopathologic factors present at diagnosis predict primary tumor growth during neoadjuvant chemotherapy, (2) what factors at presentation predict survival, and (3) when the factors at presentation and the treatment-related factors are considered, what factors independently correlate with survival. We studied 567 patients with Stage IIB osteosarcomas. The factors assessed included age, sex, location, pattern on plain radiographs (radiodense, radiolucent, mixed), MRI findings, pathologic subtype, initial tumor volume determined by MRI, tumor volume change after chemotherapy, surgical margin, and histologic response to preoperative chemotherapy. Logistic modeling was used to identify risk factors. Independent risk factors associated with primary tumor growth after neoadjuvant chemotherapy were proximal tumor location (p < 0.01; relative risk [RR], 2.41; 95% CI, 1.5-3.86) and fluid-fluid level on initial MRI (p < 0.01; RR, 5.56; 95% CI, 3.48-8.87). Among factors at presentation, large initial tumor volume (p < 0.01; RR, 1.58; 95% CI, 1.22-2.04), proximal tumor site (p < 0.01; RR, 1.61; 95% CI, 1.19-2.19), and presence of fluid-fluid level (p < 0.01; RR, 1.83; 95% CI, 1.37-2.5) independently predicted reduced event-free survival. When we consider the factors at presentation and treatment-related factors, large initial tumor volume (p < 0.01; RR, 1.54), tumor growth after neoadjuvant chemotherapy (p < 0.01; RR, 3.88), inadequate surgical margin (p < 0.01; RR, 2.42), and poor histologic response (p = 0.03; RR, 1.43) were independent poor prognostic factors of event-free survival. Proximal tumor location and the presence of the fluid-fluid level on initial MRI were predictors of tumor progression and poor survival in patients presenting with Stage IIB osteosarcomas. If confirmed in other studies, patients with these risk factors should be considered for trials of other treatment strategy. Level III, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.

Use of preoperative tattooing to increase lymph nodes (LNs) retrieved in patients with locally advanced rectal cancer who receive preoperative chemoradiotherapy (CRT): A randomized controlled trial.

561 Background: Retrieval of 12 or more LNs has been recommended for accurate staging of colorectal cancer. Patients with 12 or more LNs revealed better survival than those with less than 12 LNs. Preoperative tattooing has been reported to improve LNs retrieval in colorectal cancer. Preoperative CRT had been reported to decrease the number of LNs in rectal cancer. We conducted a randomized controlled study to validate whether preoperative tattooing increases the number of LNs in patients who receive preoperative CRT. Methods: Fifty patients with cStage II or III rectal cancer were randomly assigned to a group in which tattooing was performed at the time of colonoscopy one day before surgery (T group) or a group without tattooing (C group). Submucosal injection of India ink was performed into two sites at the lower tumor margin. All patients had received 40/45 Gy of radiotherapy in 20/25 fractions with concurrent oral UFT or S-1 chemotherapy. Mesorectal excision was performed 6 to 8 weeks after completion of CRT. Results: There were no significant differences in characteristics between the groups. The numbers of retrieved LNs (mean±SD) in T group and C group were 14±7 and 8±6, respectively (p &lt; 0.01). The number of patients with 12 or more LNs was greater in T group (56%) than in C group (20%) (p &lt; 0.01). The numbers of metastatic LNs were similar in both groups (0.5±1.2 and 0.5±1.4, respectively p = 0.92). In patients with poor histologic tumor regression (TRG grade 3 to 5), the number of LNs was significantly greater in T group (17±9) than in C group (6±5; p &lt; 0.01). However, in patients with good histologic response (TRG grade 1 or 2), the numbers of LNs in T group and C group were 11±5 and 9±6, respectively (p = 0.31). In T group, the numbers of LNs and metastatic LNs were significantly greater only in patients with poor histologic regression. Conclusions: Preoperative tattooing increases the number of retrieved LNs. In patients with poor histologic response following CRT, tattooing significantly increases the numbers of LNs. However, tattooing does not increase the numbers of retrieved LNs and metastatic LNs in patients with good histologic response. Clinical trial information: 11R-004.

Examination of the cutoff value of postchemotherapy increase in tumor volume as a predictor of subsequent oncologic events in stage IIB osteosarcoma

Tumor enlargement after chemotherapy is a predictor of a poor histological response, poor survival, and local recurrence. However, the cutoff point of tumor enlargement for predicting subsequent oncologic events has not been determined. We retrospectively reviewed 567 patients who were treated at our institute for stage IIB osteosarcoma. We used receiver operating characteristic (ROC) curve analysis of tumor volume increase for the prediction of subsequent metastasis or local recurrence, and calculated diagnostic indices for different cutoff values. A tumor volume increase of >15% predicted subsequent metastasis or local recurrence with a sensitivity of 64.7%, a specificity of 81.5%, a positive predictive value of 71.6%, and a negative predictive value of 76.1%. Increases in tumor volumes based on this cutoff value were able to predict subsequent oncologic events in all clinical subgroups, except in cases of rare pathologic subtypes. However, for tumors in the proximal humerus, a cutoff value of 25% had optimal predictive value. This study shows that a cutoff value of 15% for tumor volume increase is useful for predicting subsequent metastasis or local recurrence. Our results suggest that tumor enlargement after chemotherapy serves as an easily assessable clinical parameter for risk-adapted therapy.