Poor Histologic Response Research Articles

Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed

BackgroundMajor goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H + −rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma.MethodMG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre-treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin.ResultsPreclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients.ConclusionThis study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy.

Prognostic Value of Histological Response to Chemotherapy in Osteosarcoma Patients Receiving Tumor-Bearing Frozen Autograft

BackgroundA variety of surgical procedures are now available for tissue reconstruction after osteosarcoma excision, and an important prognostic factor is the evaluation of response to chemotherapy using histology. Although tumor-bearing autografts are useful tools for reconstruction, re-use of the primary tumor may make it difficult to assess the histological response to chemotherapy, since the entire tumor cannot be analyzed. Here, we analyzed the prognostic value of the histological response in the patients who received frozen tumor-bearing autografts for reconstruction.MethodRetrospective analysis of the medical records of 51 patients with high-grade osteosarcoma of the extremities was performed. All patients received reconstruction using frozen tumor-bearing autografts. Tumor necrosis was evaluated in extraskeletal masses and cancellous bone.ResultsFive-year overall survival of patients with good and poor response to chemotherapy was 82.9% and 46.4%, respectively (P = 0.044), and 5-year event-free survival was 57.7% and 36.0%, respectively (P = 0.329). Multivariate analysis revealed that a poor histological response to chemotherapy was a significant prognostic factor for overall survival (P = 0.033).ConclusionHistological response is an important and reliable prognostic factor in patients undergoing reconstruction using frozen tumor-bearing autografts.

Association of genetic polymorphisms in the folate pathway with efficacy and toxicity of methotrexate in pediatric osteosarcoma.

10051 Background: Osteosarcoma is the most common childhood malignant bone tumor. Methotrexate (MTX), one of the main drugs used for osteosarcoma, is a representative folic acid antagonist. Genetic polymorphisms in folate pathway genes are expected to influence the response and toxicity of high-dose MTX therapy. However, there are scarce data available regarding associations between genetic polymorphisms and pediatric osteosarcoma. This study evaluated the effect of common genetic polymorphisms in the folate metabolic pathway on overall survival, event-free survival and histological response to neoadjuvant chemotherapy including high-dose MTX. In addition, whether these genetic polymorphisms affect the concentrations of MTX and toxicity after high-dose MTX therapy for osteosarcoma was investigated. Methods: Blood and tissue samples from 48 osteosarcoma patients who had completed chemotherapy were obtained, and the following polymorphisms were analyzed; RFC1 80G>A, DHFR 829C>T, MTHFR 677C>T, MTHFR 1298A>C, AMPD1 34C>T, ATIC 347C>G, and ITPA 94C>A. Associations between candidate polymorphisms and survival, histological response (tumor necrosis rate) and MTX level and toxicity after high-dose MTX therapy were analyzed. Results: Event-free survival significantly decreased in DHFR 829 CC homozygote (P=0.045). Variant carriers of MTHFR 677C>T had tendency towards poor histological response (P=0.078). MTX concentration was significantly associated with RFC1 80G>A polymorphism (P=0.027). Liver toxicity after high-dose MTX was associated with ATIC 347C>G (P=0.043) and tended to increase in carriers of MTHFR 677C>T (P=0.069). Severe stomatitis was associated with RFC1 80G>A (P=0.012). Conclusions: This study has demonstrated that several genetic polymorphisms in folate pathway can significantly influence therapeutic response, clinical outcome and MTX level and toxicity after high-dose MTX therapy in osteosarcoma patients. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of patients with osteosarcoma, aiding the development of tailored therapeutic approaches.

Histopathological regression grading matches excellently with local and regional spread after neoadjuvant therapy of rectal cancer

Histopathological regression grading has been shown to predict outcome in chemoradiated rectal cancer. Lymph node spread is still considered the most important single prognostic parameter. Therefore, we investigated the association of regression grading with tumor spread in a single center retrospective cohort.102 consecutive patients who had undergone neoadjuvant therapy for rectal adenocarcinoma were included. Surgery was performed, including total mesorectal excision. Pathological examination included UICC staging and Dworak's five-tier tumor regression grading.Histological complete response was achieved in 16.7% of cases. Dworak's regression grading and a simplified two tier scheme both correlated excellently with ypT, ypN and UICC stage. However, cases with poor histological response were strongly represented in ypN0.Tumor regression grading is a reliable method for assessment of response to neoadjuvant therapy, but the optimal cut-off for separating good and poor response remains to be established based on clinical outcome.

Prognostic factors in primary nonmetastatic Ewing sarcoma of the rib in children and young adults

BackgroundThe rarity of Ewing sarcoma of rib has resulted in paucity of data, particularly on the prognostic factors and pattern of relapses. We analyzed the recurrences in patients with primary nonmetastatic Ewing sarcoma of the rib and examined prognostic factors of poor outcome. MethodsFrom January 2004 to January 2011, 37 patients were treated. After induction chemotherapy, complete (from costal cartilage to vertebra) or partial excision of involved rib with or without adjacent ribs was performed. Postoperative radiotherapy was administered for positive margins, poor response to chemotherapy, and large primary tumors with significant soft tissue component at presentation. ResultsDisease relapsed in 16 patients: at the local site (n = 5), both local and distant (n = 2), and distant site only (n = 9). The projected 5-year cause-specific, relapse-free survival and local control were 50%, 44%, and 72%. Poor response to chemotherapy (>5% residual tumor) and resection of adjacent lung parenchyma (a surrogate for tumor extension) were adverse prognostic factors for relapse-free survival in multivariate analysis. ConclusionRelapses occurred more often at distant sites and had a poor outcome. In this study, poor histologic response to chemotherapy (P = .04) and the infiltration of adjacent lung parenchyma (P = .01) are adverse prognostic factors.

18F-FDG PET SUVmax as an indicator of histopathologic response after neoadjuvant chemotherapy in extremity osteosarcoma

This study evaluated the usefulness of the maximum standardized uptake value (SUVmax) as a measure of histologic response to neoadjuvant chemotherapy in patients with extremity osteosarcoma. The correlation between [(18) F]FDG PET SUVmax values and histologic response to preoperative chemotherapy was also assessed prospectively using PET/MRI. A total of 26 consecutive patients with high-grade osteosarcoma were prospectively enrolled. All patients underwent parallel PET and MRI scans before and after neoadjuvant chemotherapy. Using the PET and MRI images and pathologic mapping, we assessed the percentage necrosis by histology at the highest metabolic activity point in the tumors. This was defined as the minimum histologic response. The predictive values of SUVmax before (SUV1) and after (SUV2) chemotherapy and the SUV change ratio were determined. Correlations were also investigated among SUV2, minimum histologic response and histologic response. Histologically, 13 patients were classified as good responders and 13 as poor responders. Patients with an SUV2 of >5 showed a poor histologic response. A significant correlation was found between SUV2 and histologic response (Spearman's rho -0.642; P < 0.001), and SUV2 and histologic response were both found to be significantly correlated with minimum histologic response (Spearman's rho -0.515 and 0.911; P = 0.007 and P < 0.001, respectively). A SUVmax of more than 5 after neoadjuvant chemotherapy identified the majority of histologic nonresponders (sensitivity 61.3%, PPV 88.9%). Tumor necrosis at the point of maximum metabolic activity was found to be significantly correlated with the histologic response of entire resected specimen.

Prognostic factors and clinical outcome of patients with Ewing’s sarcoma family of tumors in adults: multicentric study of the Anatolian Society of Medical Oncology

The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with Ewing sarcoma family of tumors (ESFT). Data of patients with ESFTs followed up at different cancer centers in Turkey between 2001 and 2010 were retrospectively analyzed. The median age of 114 patients was 26 years (range 14-66). The median follow-up was 20 months (range 1-118 months). Tumor size was between 1.5 and 14 cm (median 8 cm). Eighty-six percent of patients had localized disease at presentation, and 14 % had metastatic disease. Local therapy was surgery alone in 31 % of patients, surgery combined with radiotherapy in 41 % and radiotherapy alone in 18 %. Approximately 70 % of patients were treated with vincristine, doxorubicin, cyclophosphamide and actinomycin-D, alternating with ifosfamide and etoposide every 3 weeks. In patients with localized disease at presentation, the 5-year disease-free survival and overall survival were 60 and 65 %, respectively. At univariate analysis, patients with tumor size ≥ 8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size ≤ 8 cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. ESFTs are aggressive tumors with a high incidence of local recurrence and distant metastasis. Multimodality treatment consisting of adequate surgical resection, aggressive chemotherapy (VAC alternating with IE) and radiotherapy is recommended for patients with ESFTs.

Neoadjuvant chemotherapy evaluation by MRI volumetry in rectal cancer followed by chemoradiation and total mesorectal excision: Initial experience

To evaluate rectal cancer volumetry in predicting initial neoadjuvant chemotherapy response. Sixteen consecutive patients who underwent neoadjuvant chemotherapy (CX) before chemoradiotherapy (CRT) and surgery were enrolled in this retrospective study. Tumor volume was evaluated at the first magnetic resonance imaging (MRI), after CX and after CRT. Tumor volume regression (TVR) and downstaging were compared with histological results according to Tumor Regression Grade (TRG) to assess CX and CRT response, respectively. The mean tumor volume was 132 cm(3) ± 166 before and 56 cm(3) ± 71 after CX. TVR after CX was significantly different between patients with poor histologic response (TRG1/2) and those with good histologic response (TRG3/4) (P = 0.001). An optimal cutoff of TVR >68% (area under the curve [AUC]: 0.9, 95% confidence interval [CI]: 0.65-0.98, P = 0.0001) to predict good histology response after CX was assessed by receiver operating characteristic curve. According to previous data and this study, we defined 70% as the best cutoff values according to sensitivity (86%), specificity (100%) of TVR for predicting good histology response. In contradistinction, MRI downstaging was associated with TRG only after CRT (P = 0.04). Our pilot study showed that MRI volumetry can predict early histological response after CX and before CRT. MRI volumetry could help the clinician to distinguish early responders in order to aid appropriate individually tailored therapies.

Management of Bone Tumours in Paediatric Oncology

The management of bone tumours in paediatric oncology requires careful multidisciplinary planning due to the need for multimodal therapy approaches. The non-specific symptoms often lead to a delayed definitive diagnosis of a bone tumour. Imaging procedures are of major importance for an individualised and optimised treatment planning. They have to be carried out before any surgery, including biopsies. The introduction of multi-agent chemotherapy has led to a significant improvement in survival rates in patients suffering from Ewing's sarcomas and osteosarcomas. However, local therapy still remains indispensable in order to achieve long-term survival. For osteosarcoma, surgery remains the only adequate local therapy modality. Radiotherapy may be considered if surgery is not feasible. In these cases, high radiation doses need to be applied. The choice for local therapy modality is not as clear in patients with Ewing's sarcoma. Today, surgery is often preferred if a wide or at least marginal resection can be carried out. Additional radiotherapy is advised in patients with marginal/intralesional resection or poor histological response to induction chemotherapy. Definitive radiotherapy is recommended for inoperable lesions. In the future, new radiotherapy approaches, such as intensity-modulated radiotherapy or proton therapy, may yield better results with minor risks of late effects.

Predictive factors of positive circumferential resection margin after radiochemotherapy for rectal cancer: The French randomised trial ACCORD12/0405 PRODIGE 2

Circumferential resection margin (CRM) appears as a new powerful prognostic factor of survival after surgery for rectal cancer. We aimed to evaluate predictive factors of positive CRM following preoperative radiochemotherapy in a French trial.Patients with rectal cancer were randomised in long course preoperative radiotherapy 45Gy plus capecitabine versus 50Gy plus capecitabine and oxaliplatin. Mesorectal excision was performed 6weeks after treatment. Impact of clinical, pathological and surgical variables on positive CRM (⩽1mm) were analysed by multivariate analysis.Of 565 randomised patients, CRM was recorded in 390 cases and was positive in 8% (30/390). Patients with 50Gy plus capecitabine and oxaliplatin had a 6% rate of positive CRM while those treated by 45Gy plus capecitabine had a 10% rate (p=0.128). Three independent predictive factors of positive CRM were identified: abdominoperineal resection (APR) (odds ratio OR=3.24; p=0.004), vascular tumour invasion (OR=2.78; p=0.026) and poor histological response (modified Dworak 0–2) (OR=9.01; p=0.003).Significant predictive factors of positive CRM are related to type of surgery, especially APR, and poor histological prognostic factors. Intensification of neoadjuvant radiochemotherapy does not seem to have a major role in this study.

EWS/FLI1 Regulates EYA3 in Ewing Sarcoma via Modulation of miRNA-708, Resulting in Increased Cell Survival and Chemoresistance

Ewing sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients whose tumors have a poor histologic response to initial chemotherapy have a poor overall prognosis. Therefore, it is important to identify molecules involved in resistance to chemotherapy. Herein, we show that the DNA repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell-of-origin of Ewing sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor. We further show that EWS/FLI1 mediates upregulation of EYA3 via repression of miR-708, a miRNA that targets the EYA3 3'-untranslated region, rather than by binding the EYA3 promoter directly. Importantly, we show that high levels of EYA3 significantly correlate with low levels of miR-708 in Ewing sarcoma samples, suggesting that this miR-mediated mechanism of EYA3 regulation holds true in human cancers. Because EYA proteins are important for cell survival during development, we examine, and show, that loss of EYA3 decreases survival of Ewing sarcoma cells. Most importantly, knockdown of EYA3 in Ewing sarcoma cells leads to sensitization to DNA-damaging chemotherapeutics used in the treatment of Ewing sarcoma, and as expected, after chemotherapeutic treatment, EYA3 knockdown cells repair DNA damage less effectively than their control counterparts. These studies identify EYA3 as a novel mediator of chemoresistance in Ewing sarcoma and define the molecular mechanisms of both EYA3 overexpression and of EYA3-mediated chemoresistance.

Playing Bad Cards Properly: Challenges to Improving Cure Rates in Rhabdomyosarcoma

“Success . . . comes not from having the right cards, but from playing bad ones properly.” —Joshua Dool. At least two thirds of children and adolescents with intermediateand higher-risk nonmetastatic rhabdomyosarcoma can be cured with multidisciplinary therapy. Although a reasonably good outcome, it clearly is not good enough. The total burden of therapy is high, with substantial acute and chronic toxicity. The best established therapy is a three-drug chemotherapy combination using vincristine, dactinomycin, and an alkylator (either cyclophosphamide or ifosfamide) and local control measures that cause substantial morbidity, particularly in our youngest patients. The therapy approach and anticipated outcome have not substantially changed in the last two decades. Oberlin et al report in Journal of Clinical Oncology the results of the MMT95 trial, a well-designed prospective, randomized study comparing intensified six-drug therapy versus standard three-drug chemotherapy in nonmetastatic rhabdomyosarcoma and other chemosensitive childhood soft tissue sarcomas. Intensification of chemotherapy provided no survival advantage, no reduction in the intensity of local therapy, and added toxicity—certainly not the answer for which these investigators had hoped. Why have we been unable to make any recent progress in treating rhabdomyosarcoma? Successful clinical trials must be well designed. Most advances in pediatric oncology have used prospective, randomized comparative study designs. However, good trial design certainly does not guarantee success. The two most recently completed intermediate-risk rhabdomyosarcoma studies conducted by the Intergroup Rhabdomyosarcoma Study (IRS) Group (IRS-IV comparing vincristine, dactinomycin, and cyclophosphamide [VAC]; vincristine, dactinomycin, and ifosfamide; and vincristine, ifosfamide, and etoposide) and the Children’s Oncology Group (COG; D9803 comparing VAC v VAC plus topotecan and cyclophosphamide) were well designed and appropriately powered and evaluated agents with substantial clinical activity, yet they failed to show any improvement in the experimental arms. The MMT95 (Malignant Mesenchymal Tumor 1995) study prospectively randomly assigned patients to receive threeor six-drug therapy, with a switch to the six-drug combination in patients who had disease progression, less than 50% imaging response, or poor histologic response. This design decreased the number of patients who received either only threeor only six-drug therapy. In addition, a relatively high number of eligible patients were not randomly assigned (149 of 606; 25%). However, these flaws, while decreasing the statistical power of this study, are relatively minor and do not seem to have affected the final negative results. Selection of the right patient population is a key component of sound clinical trial design. The MMT95 study enrolled higher-risk patients with rhabdomyosarcoma with both embryonal and alveolar histologies. These two histologies are biologically distinct, yet all cooperative group trials in higher-risk rhabdomyosarcoma have included both histologies, with few data to suggest substantial differences in treatment response for the different histologic entities. In addition, the MMT95 study enrolled 72 patients with chemotherapy-sensitive nonrhabdomyosarcoma soft tissue sarcomas. Soft tissue primitive neuroectodermal tumors (27 patients enrolled onto MMT95) share morphologic, immunohistochemical, and genetic features with Ewing tumors arising in bone, are classified by WHO inclusively as Ewing sarcoma/primitive neuroectodermal tumor, and are currently treated in studies of the Ewing family of tumors. COG trials previously enrolled patients with undifferentiated sarcomas together with rhabdomyosarcomas, but these patients were recently treated on a study for other nonrhabdomyosarcoma soft tissue sarcomas (COG ARST0332: Risk-based treatment for nonrhabdomyosarcoma soft tissue sarcomas in patients under30yearsofage).Ratesofmetastasis inMMT95werehigher inthese patient subsets (P .03); the number of patients enrolled with these histologies was insufficient to provide insights into the impact of more intensive therapy. Cure rates have improved in some childhood cancers with the optimization of chemotherapy schedules and doses. Decades of empiric adjustments using a modest number of active chemotherapy

Neoadjuvant Chemotherapy With Methotrexate, Cisplatin, and Doxorubicin With or Without Ifosfamide in Nonmetastatic Osteosarcoma of the Extremity: An Italian Sarcoma Group Trial ISG/OS-1

We compared two chemotherapy regimens that included methotrexate (MTX), cisplatin (CDP), and doxorubicin (ADM) with or without ifosfamide (IFO) in patients with nonmetastatic osteosarcoma of the extremity. Patients age ≤ 40 years randomly received regimens with the same cumulative doses of drugs (ADM 420 mg/m(2), MTX 120 g/m(2), CDP 600 mg/m(2), and IFO 30 g/m(2)) but with different durations (arm A, 44 weeks; arm B, 34 weeks). IFO was given postoperatively when pathologic response to MTX-CDP-ADM was poor (arm A) or given in the primary phase of chemotherapy with MTX-CDP-ADM (arm B). End points of the study included pathologic response to preoperative chemotherapy, toxicity, and survival. Given the feasibility of accrual, the statistical plan only permitted detection of a 15% difference in 5-year overall survival (OS). From April 2001 to December 2006, 246 patients were enrolled. Two hundred thirty patients (94%) underwent limb salvage surgery (arm A, 92%; arm B, 96%; P = .5). Chemotherapy-induced necrosis was good in 45% of patients (48% in arm A, 42% in arm B; P = .3). Four patients died of treatment-related toxicity (arm A, n = 1; arm B, n = 3). A significantly higher incidence of hematologic toxicity was reported in arm B. With a median follow-up of 66 months (range, 1 to 104 months), 5-year OS and event-free survival (EFS) rates were not significantly different between arm A and arm B, with OS being 73% (95% CI, 65% to 81%) in arm A and 74% (95% CI, 66% to 82%) in arm B and EFS being 64% (95% CI, 56% to 73%) in arm A and 55% (95% CI, 46% to 64%) in arm B. IFO added to MTX, CDP, and ADM from the preoperative phase does not improve the good responder rate and increases hematologic toxicity. IFO should only be considered in patients who have a poor histologic response to MTX, CDP, and ADM.

Risk adapted chemotherapy for localised Ewing’s sarcoma of bone: The French EW93 study

Aim of the studyTo determine whether a risk factor adapted chemotherapy would improve the outcome of non-metastatic bone Ewing’s sarcoma. MethodsStandard risk tumours (SR, good histological response to chemotherapy or small unresected tumours) received the previous EW88 chemotherapy. Ifosfamide/etoposide (IE) were introduced after 3 courses of cyclophosphamide/doxorubicine when tumour regression was <50% or during consolidation therapy for the intermediate risk tumours (IR, intermediate histological response 5–30% residual cells or large unresected tumours >100ml). High risk tumours (HR, histological poor response >30% residual cells or clinical poor response <50% for unresectable tumours), received IE prior high dose busulfan/melphalan with stem cell rescue. ResultsFrom 1993 to 1999, 214 patients were enrolled. 5y-EFS and OS were 60% (95% confidence interval (CI), 53–66) and 69% (95% CI, 63–75), respectively. 116 (54%), 46 (21%), 48 (22%) patients were considered as SR, IR and HR of relapse, respectively. No advantage to IE was observed in the IR group. As compared to previous study, tumour with poor histological response to induction chemotherapy seemed to benefit from the consolidation strategy including busulfan/melphalan: EFS were 45% (95% CI, 30–60) and 20% (95% CI, 7–43) for EW93 and EW88, respectively. Despite a risk-adapted strategy, histological response to chemotherapy remains the main prognostic factor in resected tumours, while initial tumour volume is the main prognostic factor for unresected tumours. ConclusionThese results showing a potential benefit of a consolidation strategy including busulfan/melphalan as compared to conventional chemotherapy needed confirmation by a randomised trial and were one of the bases of the ongoing EuroEwing99.

Extraskeletal Ewing's Sarcoma Family of Tumors in Adults: Prognostic Factors and Clinical Outcome

The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with extraskeletal Ewing's sarcoma. Data of patients with extraskeletal Ewing's sarcoma followed up at our center between 1997 and 2010 were retrospectively analyzed. The median age of 27 patients was 24 years (range, 16-54 years). The median follow-up was 31.8 months (range, 6-144 months). Tumor size was between 1.5 and 14 cm (median: 8 cm). Eighty-five percent of patients had localized disease at presentation and 15% had metastatic disease. Local therapy was surgery alone in 16% of patients, surgery combined with radiotherapy in 42% and radiotherapy alone in 27%. All patients were treated with vincristine, doxorubicin, cyclophosphamide and actinomycin-D, alternating with ifosfamide and etoposide every 3 weeks. In patients with localized disease at presentation, the 5-year event-free survival and overall survival were 59.7 and 64.5%, respectively. At univariate analysis, patients with tumor size ≥ 8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size 8 ≥ cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. Prognostic factors were similar to primary osseous Ewing's sarcomas. Adequate surgical resection, aggressive chemotherapy (vincristine, doxorubicin, cyclophosphamide and actinomycin-D alternating with ifosfamide and etoposide) and radiotherapy if indicated are the recommended therapy for patients with extraskeletal Ewing's sarcoma.

A preliminary investigation of Beta-hCG expression in patients with osteosarcoma

There are eight reported cases in the literature of osteosarcomas secreting β-hCG. Our primary aim was to investigate the rate of β-hCG expression in osteosarcoma and attempt to understand the characteristics of osteosarcomas that secrete β-hCG. We reviewed 37histopathology slides (14 biopsies and 23 surgical specimens) from 32 patients with osteosarcoma. The slides were retrospectively stained for β-hCG expression. Patient and tumour characteristics, including age, gender, tumour location, subtype, proportion of necrosis, presence of metastases and recurrence were recorded. A total of five of the 32tumours were found to be positive for β-hCG expression (one strongly and four weakly). This incidence of this expression was found in tumours with poor histological response to neoadjuvant chemotherapy. The use of β-hCG expression as a diagnostic, prognostic or follow-up marker is questionable and needs further investigation with a larger sample size.

Outcome for adolescent and young adult patients with osteosarcoma

There are conflicting data regarding age as a prognostic factor in osteosarcoma. The authors conducted a study evaluating the impact of age on prognosis in children and young adults with osteosarcoma enrolled on North American cooperative group trials. Patients with high-grade osteosarcoma of any site enrolled on North American cooperative group trials CCG-7943, POG-9754, INT-0133, and AOST0121 were included in this study. Primary tumor site, age, sex, ethnicity, histologic response, and presence of metastatic disease at diagnosis were evaluated for their impact on overall survival (OS) and event-free survival (EFS). A total of 1054 patients were eligible and had complete data available for the study. Age was not significantly associated with any other presenting covariate analyzed except sex. Age 18 or older was associated with a statistically significant poorer EFS (P = .019) and OS (P = .043). The 10-year EFS and OS in patients <10, 10 to 17, and ≥18 years old were 55%, 55%, 37% and 68%, 60%, 41%, respectively. The poorer EFS in patients ≥18 years old was because of an increased rate of relapse. Presence of metastatic disease at diagnosis, poor histologic response, and pelvic tumor site were also associated with a poorer prognosis. In multivariate analysis, age continued to be associated with poorer EFS (P = .019) and OS (P = .049). In osteosarcoma, age 18 to 30 years is associated with a statistically significant poorer outcome because of an increased rate of relapse. Poorer outcome in adolescent and young adult patients is not explained by tumor location, histologic response, or metastatic disease at presentation.

Bone Sarcomas: From Biology to Targeted Therapies

Primary malignant bone tumours, osteosarcomas, and Ewing sarcomas are rare diseases which occur mainly in adolescents and young adults. With the current therapies, some patients remain very difficult to treat, such as tumour with poor histological response to preoperative CT (or large initial tumour volume for Ewing sarcomas not operated), patients with multiple metastases at or those who relapsed. In order to develop new therapies against these rare tumours, we need to unveil the key driving factors and molecular abnormalities behind the malignant characteristics and to broaden our understanding of the phenomena sustaining the metastatic phenotype and treatment resistance in these tumours. In this paper, starting with the biology of these tumours, we will discuss potential therapeutic targets aimed at increasing local tumour control, limiting metastatic spread, and finally improving patient survival.

Multilevel en bloc spondylectomy in malignant tumours of the spine: a technical note

BackgroundSingle level en bloc spondylectomy has become a standardised surgical procedure among spinal tumour surgeons. Multilevel spondylectomies, however, remain a challenge due to the complex nature of the procedure.MethodsFifteen multilevel en bloc spondylectomies were performed between 1998 and 2010 in patients with primary tumours of the spine in two spine centres. In all but two cases, a combined posterior and anterior technique was applied. There were four 2-level, eight 3-level, one 4-level, one 5-level and one 6-level spondylectomies.ResultsAfter an average follow-up of 39 months three patients had died of the disease, one patient was alive with disease and 11 patients had no evidence of disease. In total, five resections were intralesional, all five patients had had previous piecemeal resection. In the remaining cases, wide (n=4) or marginal (n=6) resection was accomplished. In total, there were five revisions in three patients, mainly due to local recurrence. One patient in a 6-level spondylectomy sustained an irreversible ischemic paraplegia. In two patients with a four and/or five level spondylectomy there was a transient paraparesis that recovered to Frankel D in both cases.ConclusionsMultilevel en bloc spondylectomy is technically feasible and enables wide or marginal resection of malignant lesions of the spine in most cases with an acceptable morbidity. Resection of four levels or more is associated with an increased neurological risk. Previous intralesional surgery resulting in intralesional resection, local recurrence and poor histologic response are associated with a poor prognosis.

Abstract B78: A novel EWS/Fli1 target gene, Eya3, is upregulated in Ewing's sarcoma to mediate chemoresistance.

Abstract Ewing's sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients' whose tumors have a poor histological response to initial chemotherapy have a poor overall prognosis. Importantly, childhood cancer survivors are faced with long-term chemotherapy-associated toxicities many years after they have been cured of their primary disease. Therefore, targeting molecules involved in resistance to chemotherapy should benefit patients with resistant disease and allow lower doses of toxic chemotherapies to be used in treatment regimens, thus improving outcomes for children suffering from Ewing's sarcoma on multiple fronts. The vast majority of Ewing's sarcomas harbor a characteristic translocation, t(11;22), encoding the EWS/Fli1 fusion protein. We have identified the DNA-repair protein and transcriptional cofactor, Eya3, as a downstream target of EWS/Fli1. Eya3 is highly expressed in Ewing's sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell of origin of Ewing's sarcoma. We demonstrate that EWS/Fli1 mediates upregulation of Eya3 via repression of miR-145 and miR-708, microRNAs that target the Eya3 3'UTR. Furthermore, replacement of miR-145 and miR-708 in a Ewing's sarcoma cell line decreases Eya3 levels. It was recently shown that Eya3 promotes DNA repair by dephosphorylating a critical tyrosine residue on H2AX in response to DNA damage, resulting in the recruitment of DNA repair factors to the sites of DNA damage. Thus we tested whether knockdown of Eya3 in Ewing's sarcoma cells would decrease cell survival and sensitize cells to DNA-damaging chemotherapeutics used in the treatment of Ewing's sarcoma: etoposide and doxorubicin. Indeed, Eya3 knockdown led to increased cell death and sensitization to chemotherapy, and, as expected, Eya3 knockdown cells contained more DNA damage following treatment with etoposide than their control counterparts. These data strongly suggest that Eya3 mediates chemoresistance in Ewing's sarcoma through its ability to enhance DNA repair. Because Eya3 mediates DNA repair and survival via its intrinsic phosphatase activity, and because the phosphatase activity of Eya is also known to play a role in metastasis of other cancers, we have begun to develop inhibitors targeting the Eya phosphatase activity and to demonstrate their efficacy both in vitro and in cell culture. In closing, Eya phosphatase inhibitors or synthetic mimics of the microRNAs targeting Eya3 have the potential to improve outcomes for Ewing's sarcoma patients by improving therapeutic efficacy and decreasing associated toxicities of conventional chemotherapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B78.