Recurrent Sarcoma Research Articles

Elimination of extensive cranioorbitofacial defect after removal of myxofibrosarcoma (G2) with replacement of the hard palate and the alveolar process on the left: clinical case

The study objective is to present the experience of performing extensive cranioorbital resection with subsequent arthroplasty of the hard palate and the dentition of the alveolar process of the maxilla. Materials and methods . In 2018, in the Department of Microsurgery of the P.A. Hertzen Moscow Oncology Research Institute, extensive cranioorbital surgery for recurrent sarcoma of the upper jaw was performed, after the treatment in other clinics. The extensive intervention included the exposure of the dura and the single-stage reconstruction of tissue defect, bone defect of the skull base by using the displaced aponeurotic flap of scalp and microsurgical reconstruction of the soft tissues of the face and mouth left free of the gastro-omental flap. In the early postoperative period, the patient underwent endoprosthesis replacement of the hard palate and alveolar process with a dentition. Results . Extensive intervention with resection of the structures cranioorbital zone and the skull base with a single-stage reconstruction with free gastro-omental flap with subsequent arthroplasty of the hard palate and the alveolar process dental arch allowed to rehabilitate the patient.

Immunotherapy for advanced lung cancer combined with surgery for mediastinal myxofibrosarcoma: a case report

BackgroundIt is unclear whether simultaneous primary neoplasm resection and immunotherapy for advanced lung cancer is safe. We report a case of an elderly man with advanced lung cancer and myxofibrosarcoma.Case presentationThe advanced lung cancer was treated with pembrolizumab, and partial response was achieved in 3 months. However, the mediastinal cyst enlarged rapidly. We resected the mediastinal tumor and diagnosed it as myxofibrosarcoma. The postoperative course was uneventful. Immunotherapy was resumed after the operation without any adverse effects. No recurrence of mediastinal sarcoma or progression of lung cancer was found until the patient died in an accident 8 months after surgery.ConclusionSurgery for mediastinal sarcoma could be performed safely in combination with immunotherapy for advanced lung cancer.

A case report of the recurrence of a rare cardiac low-grade fibromyxoid sarcoma and mortality

A case report of the recurrence of a rare cardiac low-grade fibromyxoid sarcoma and mortality

Recurrent distal epithelioid sarcoma with post-auricular metastatic nodule in a young adult female

Recurrent distal epithelioid sarcoma with post-auricular metastatic nodule in a young adult female

Intraoperative radiation therapy for the treatment of recurrent retroperitoneal and pelvic tumors: a single-institution analysis

BackgroundPatients with recurrent retroperitoneal and pelvic region tumors often require multimodal therapies. Intraoperative radiation therapy (IORT) can deliver high-dose radiation to tumor beds, even if first-line external beam radiation therapy (EBRT) was administered. We evaluated local control (LC) and survival in patients receiving IORT for recurrent tumors.MethodsWe retrospectively analyzed 41 patients with isolated pelvic or retroperitoneal recurrences of colorectal, gynecological, or retroperitoneal primary tumors. Following salvage surgery, all patients underwent tumor bed IORT via electron beam or high dose rate brachytherapy. Isolated IORT (median dose: 15 Gy) was administered to patients who had received first-line EBRT; other patients received IORT (median dose 12 Gy) plus EBRT. Local (LF), regional (RF), and distant failures (DF) were evaluated, and the Kaplan–Meier method and log-rank test were used to evaluate and compare overall survival (OS) from the date of IORT.ResultsForty-one patients underwent 44 treatments, including 27 (61.3%) isolated IORT and 17 (38.7%) IORT and EBRT combination regimens. The median follow-up was 8.1 years (range: 4.4–11.7 years), and the 2, 5, and 8 year overall LC rates were 87.9, 64.0, and 49.8%, respectively. Regarding resection status, the respective 2, 5, and 8 year LC rates were 90, 76, and 76% for R0 resection and 75, 25, and 0% for R1 resection (p < 0.001). The 2, 5, and 8 year OS rates were 68, 43, and 26%, respectively. OS was better among patients with LC (p < 0.001). Twenty-four patients (58.5%) experienced a DF, and the 5 year OS rates for the patients with and without DF were 36 and 52%, respectively (p = 0.04).In a multivariate analysis, LF (p = 0,012) and recurrent retroperitoneal sarcoma (p = 0,014) were identified as significant predictors of worse OS. Thirteen patients (31%) developed clinically treatable complications related to IORT.ConclusionsMany patients achieve long-term OS and LC without significant morbidity after salvage surgery and IORT, especially in case of clear margins.

Epididymis myeloid sarcoma recurrence in acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: report of one case and review of literature

目的 探讨行异基因造血干细胞移植（allo-HSCT）的白血病患者以髓系肉瘤（MS）复发的临床病理特点、鉴别诊断及治疗方法。 方法 分析连云港市第一人民医院收治的1例急性髓系白血病（AML）行allo-HSCT 9年后发生左侧附睾MS患者的临床、实验室及病理学资料，并复习相关文献。 结果 该男性患者2004年2月经细胞形态学、免疫学、细胞遗传学和分子生物学（MICM）诊断为AML-M5b，经DA、HA方案诱导缓解；2004年5月行同胞全相合allo-HSCT；2013年7月发现左侧阴囊肿块，手术病理示左侧附睾MS，表达LCA、CD34、CD68、CD99；经化疗、供者淋巴细胞输注（DLI）后生存时间>32个月。 结论 MS是白血病造血干细胞移植后复发形式之一，多数在1~2年内发生，具有AML-M2/M5好发倾向，可选择手术、化疗、局部放疗、DLI以及二次移植等治疗方法，预后不良。

Initial Clinical Experience with Uni-Directional LDR Brachytherapy in the Treatment of Retroperitoneal Sarcoma

Retroperitoneal sarcomas (RPS)s constitute 10%-15% of patients diagnosed with soft tissue sarcomas. Despite advances in cancer care and aggressive management, the 5-year overall survival rate is 47%-67%. The crude cumulative incidence of local recurrence (LR) is 26%. A previous trial combining preoperative external beam radiation therapy with post-operative brachytherapy found substantial toxicity and treatment related death. This report demonstrates the utility of unidirectional LDR brachytherapy for treatment of RPS. In this study, the unidirectional device employed is a permanent, Pd-103 brachytherapy device designed to be implanted during surgical resection for the treatment of anticipated positive or close surgical margins. The device consists of a plane of sources with an unidirectional gold shield backing to protect normal tissues yet direct radiation to the target margin(s). The sources are embedded in a bio-absorbable matrix membrane that may be cut to size to allow for conformal targeting of the surgical tumor bed. At surgery, patients were assessed and determined to have close or positive margins. The prescribed LDR brachytherapy dose averaged 34.7 Gy (range: 20 – 60 Gy) and covered an average area of 6060 mm2 (∼58 sources). Pd-103 has a half-life of 16.99 days and delivers therapeutic radiation dose over several weeks. The device was attached with sutures and tacks. Seven RPS patients have been implanted with the CivaSheet at 4 medical centers. Six patients had recurrent sarcoma in the retroperitoneum or pelvic side wall. One patient had locally advanced leiomyosarcoma with no previous treatment. Three patients had prior EBRT at first diagnosis (45 – 57.5 Gy). Five patients received neoadjuvant EBRT (35 – 57.5 Gy) prior to surgery plus brachytherapy. The patients tolerated the implant well with no complications following surgery. There have been 0 reports of source movement in RPS patients. At median 15 months (8-24 months) follow-up, 0/7 patients have demonstrated local recurrence as defined as the targeted field of brachytherapy radiation. One patient (1/7) recurred outside of the surgical field and subsequent brachytherapy radiation. There were 0 reported incidences of acute or late radiation toxicity despite the surrounding organs at risk, inclusive of the small intestine, ureter and kidneys. Unidirectional, planar Pd-103 LDR brachytherapy has demonstrated a 100% local recurrence free survival with no acute or late-term toxicities at a median of 15 months in our patient cohort. Application of uni-directional, planar Pd-103 LDR brachytherapy technology is very safe and easy, and should be considered to escalate dose or retreat to the high risk margins of RPS after resection.

MRI surveillance for local recurrence in extremity soft tissue sarcoma

IntroductionThe role of MRI in surveillance for local recurrence (LR) remains uncertain in extremity soft tissue sarcoma (STS). The aims of this study were 1) to examine the usefulness of MRI in detecting LR, 2) to identify the characteristics of LR detected by MRI, and 3) to examine whether MRI surveillance is associated with oncologic outcome. Materials and Methods477 patients who had regular surveillance for LR after surgery for extremity STS were reviewed. Surveillance was performed by routine MRI in 325 patients or other imaging modalities in 152 patients. ResultsThe rate of MRI-detected LR, defined as clinically undetectable LR identified on MRI, was 10.5% in the MRI surveillance cohort. The detection rates of MRI-detected LR were significantly higher in the patients with high risk of LR. MRI-detected LRs were more commonly located in the thigh or buttock (p = 0.005), were smaller (p = 0.001) and had LRs without mass formation (p = 0.007) than non-MRI-detected LRs. On Kaplan-Meier analysis, patients with MRI-detected LR tended to have better post-LR survival (p = 0.104). ConclusionRoutine MRI surveillance can detect a significant number of clinically undetectable LRs in extremity STS especially for LRs in the thigh or buttock, small LRs or LRs without mass formation.

Magnetic resonance imaging features for the differential diagnosis of local recurrence of bone sarcoma after prosthesis replacement

ObjectiveTo explore the imaging features of local recurrences (LRs) based on magnetic resonance imaging (MRI) after oncological orthopaedic surgery with prosthesis reconstruction. MethodsA total of 78 cases totalling 157 scans were retrospectively reviewed. Patients with nodule/mass-like signals were retrospectively classified into LR, infectious pseudotumour, and asymptomatic pseudotumour according to clinicopathological data. LRs were histologically confirmed, and the patients without recurrences were followed up for at least 2 years. Mass size distribution and radiological characteristics were analysed for differential diagnosis of the LR versus pseudotumour. ResultsThirty-three of 78 cases were positive with nodule/mass-like signal findings on the post-operative MRI images. By analysing the size distribution, we found that masses >2.1 cm (14) were almost attributable (98% specificity) to LRs and mostly (84.6%) timely treated. Contrarily, masses ≤2.1 cm (19) are challenging for differential diagnosis of LRs versus pseudotumour and were undertreated in five of the nine LR cases. MRI characteristics of masses ≤2.1 cm were found to be highly heterogeneous, with solid appearance, adjacent infiltration, and less peritumour oedema being significant indicators for LRs (P＜0.05). Receiver operating characteristic curve showed area under curve of 0.93 for this predictive model. ConclusionsFor the post-operative MRI surveillance of oncological orthopaedic surgery with prosthesis reconstruction, a mass larger than 2.1 cm was highly specific for recurrence. When a mass was smaller than 2.1 cm, more solid property, more adjacent tissue infiltration, and less muscular oedema indicated recurrence rather than a benign mass. The translational potential of this articleThere has been very little data associated with the post-operative magnetic resonance imaging features indicating recurrence in patients with malignant bone sarcoma after prosthesis replacement. This study could help develop diagnostic features of magnetic resonance imaging for differentiating recurrence from benign changes in these patients after prosthesis replacement.

Wound Complications After Multimodal Treatment of Soft Tissue Sarcomas

Background: Surgical removal of the tumor remains the only 1 radical treatment of patients with soft tissue sarcomas of the extremities. However, the parameters of total and disease-free survival after this type of treatment cannot be considered satisfactory. Currently the active search and introduction into clinical practice of additional impact methods that can improve the immediate and long-term results of treatment of such patients is being conducted. Aim: To evaluate the risk of the wound process complications after surgical treatment of soft tissue sarcomas using endovascular embolization and cryosurgery. Methods: We have assessed the quantity and quality of postoperative complications of wound process in 199 patients with soft tissue sarcomas and their recurrences. The study group consisted of 53 patients, who underwent radical surgery with selective preoperative endovascular embolization and intraoperative cryosurgery. The control group consisted of 146 patients who had radical surgery without any additional methods. Preoperative embolization and cryosurgery on the wound bed after tumor removal was used to prevent local recurrence of soft tissue sarcomas. Preoperative angiography with selective embolization of vessels feeding the tumor was performed 1-1.5 hours before the main surgical treatment. Cryosurgery was carried out by the method of “Olympic rings” with 3 minutes duration. The temperature of exposure was −186°C. In the course of cryosurgery we adhere to the principle of “quick freezing - an independent slow thawing”. All postoperative wounds tightly sutured with silicone drains by Redon, if necessary. Results: Complications of wound healing have been diagnosed in 15 (28.3%) patients of the main group and in 34 (23.3%) control group patients. Inflammatory-suppurative complications were observed in the remaining 8 (15.1%) patients of the main group and in 18 (12.3%) control group patients ( P &gt; 0.05). Long lymphorrhea was observed in 6 (11.3%) patients of the main group and 11 (7.5%) control group patients. Bleeding in the postoperative period was observed in 1 (1.9%) case of main group patients and in 5 (3.4%) cases of control group. Conclusion: The additional using of selective preoperative endovascular embolization and cryosurgery is safe and does not worsen immediate results of surgical treatment of soft tissue sarcomas.

Abstract A24: Tumor immune profiling suggests synovial sarcoma but not desmoplastic small round cell tumor may respond to cancer immunotherapies

Abstract Background: Desmoplastic small round cell tumor (DSRCT) and synovial sarcoma are rare cancers, mainly affecting older children and young adults, with very poor survival rates. Other than surgery for localized disease, conventional treatments such as chemotherapy and radiotherapy have not had significant impacts on outcomes. Whether immunotherapeutic approaches may be useful for these diseases is unknown. Results from other cancer subtypes indicate that knowledge of the expression of relevant immunologic molecules and intratumoral immune cell infiltrates may be predictive of prognosis and therapeutic response. Objective: To characterize the immune profiles of human DSRCT and synovial sarcoma tumors. Methods: This study was approved by the Nationwide Children’s Hospital Institutional Review Board. Using tissue microarrays of 9 DSRCT and 12 synovial sarcoma tumor samples, we detected tumoral HLA–A/B/C, beta-2-microglobulin (B2M), and PD-L1 expression, and quantified tumor-infiltrating lymphocytes expressing CD4, CD8, CD56, CD45RO, or FOXP3 by immunohistochemistry. We used staining intensity on a scale of 0-3 (absent= 0, weak= 1, moderate = 2, strong = 3) and percentage of tumor stained to determine HLA, B2M, and PD-L1 scores (range 0-300). We calculated the cytotoxic T lymphocyte (CTL) Target score as HLA score x B2M score/100 (range 0-900). All data were summarized descriptively and statistical comparisons were made using Mann-Whitney tests. Results: We found DSRCT diagnostic samples had higher HLA, CTL Target, and PD-L1 scores compared to recurrent samples (15, 17, and 16.7 versus 0, 0, and 3.3, respectively). We observed fewer CD8+ and CD45RO+ cells in relapsed samples compared to those obtained at diagnosis (35.3 versus 1.3/mm2 and 14.6 versus 4.7/mm2, respectively). We found no significant difference in CD56+ cell numbers (0.8 versus 0.7/mm2) at diagnosis or relapse. In synovial sarcomas, HLA and CTL Target scores decreased from diagnosis to recurrence (100 and 133.3 versus 81.7 and 78.3, respectively), while PD-L1 scores increased (10 versus 21.7). FOXP3+ cell numbers remained stable, while the numbers of CD56+ and CD45RO+ cells increased from diagnosis to recurrence (0 versus 0.6/mm2, 0.4 versus 2.6/mm2, 8.7 versus 13.1/mm2, respectively). Comparing synovial sarcoma to DSRCT, the HLA and CTL Target scores were statistically significantly different (95.8 versus 3.3, p = 0.0192; 98.3 versus 0, p= 0.0235, respectively). Conclusions: We found lower HLA scores, resulting in decreased CTL Target scores, in recurrent DSRCT and synovial sarcoma tumors compared with diagnostic samples. These results suggest that up-front, rather than second-line, CTL-based immunotherapeutic strategies may be beneficial, and that these tumors may evade antitumor immunity by downregulating HLA I. Low PD-L1 scores in both tumor types indicate potential lack of response to PD-1/PD-L1 axis immune checkpoint blockade. The low HLA scores and consistent presence of CD56+ cells in DSRCT samples suggest that NK cell-based immunotherapeutic modalities may be beneficial for these patients, though this conclusion is limited by the small sample size. We hypothesize that synovial sarcoma is more likely than DSRCT to benefit from CTL-based immunotherapies. However, we found wide heterogeneity in both tumor types, suggesting the need to develop and validate predictive biomarkers for individual patients. Citation Format: Mary Frances Wedekind, Kellie Haworth, Michael Arnold, Joseph Stanek, Timothy Cripe. Tumor immune profiling suggests synovial sarcoma but not desmoplastic small round cell tumor may respond to cancer immunotherapies [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A24.

Abstract B16: Evaluation of LDH inhibition as a treatment strategy in Ewing sarcoma

Abstract Long-term outcomes for patients with relapsed, recurrent, or metastatic Ewing sarcoma (ES) remain poor despite advances in multimodal chemotherapy and local tumor control. The discovery of new targets and novel therapies is therefore critical to improving care for these patients. Recent insights into the metabolic landscape of ES have revealed that the EWS/FLI1 fusion oncoprotein regulates metabolic pathways in this disease, including shifting glucose consumption away from oxidative metabolism and towards glycolysis, a pathway that relies on LDH. Targeting this increased dependence on glycolysis presents an opportunity to inhibit the growth of ES cells through a novel therapeutic approach, while potentially limiting the toxicity delivered to normal cells. We therefore sought to evaluate the activity of NCGC-737 and NCGC-006, two novel LDHA/B inhibitors identified and validated as part of the Experimental Therapeutics Program of the National Cancer Institute (NCI-NExT), in ES. For in vitro studies, proliferation of ES cells lines was assessed after inhibition of LDHA/B by each agent using IncuCyte and MTS assays. Protein expression of phospho- and total LDH was evaluated by Western blot. LDH activity was assessed using the pyruvate-dependent oxidation of NADH. NAD/NADH levels were determined using NAD/NADH-Glo. Analysis of glycolytic profiles was performed using the Agilent Extracellular Flux Analyzer. For in vivo studies, female SCID mice underwent orthotopic injection of ES cells from established cell lines. When tumors reached a desired size, mice were randomized and then treated on a variety of dosing schedules. Toxicity assessments included evaluation of overall appearance, weekly weights, blood sampling, and full necropsies on selected mice. Tumors were measured twice per week for assessment of efficacy. Tumors were harvested at midpoints and at study endpoint for assessments of drug level, target inhibition, and biology. ES cell lines displayed varying sensitivity to NCGC-737 and NCGC-006, with IC-50 values ranging from 50 nM to 500 nM. While protein expression of phospho-LDH, total LDH-A, and total LDH-B were not correlated with sensitivity to either agent, glycolytic profiles were predictive of sensitivity. Cell lines that underwent a greater reduction in glycolytic capacity (the change in ECAR measured before and after oligomycin treatment) after LDHA/B inhibition experienced a greater antiproliferative effect, while cell lines that were able to maintain glycolytic capacity despite LDHA/B inhibition exhibited less of an effect on growth. In vivo studies to describe the toxicity of these agents demonstrated that hemolysis was the primary dose-limiting toxicity, and was dose dependent. Additional toxicity studies of specific tissues are ongoing and will be reported. Preliminary in vivo studies to optimize dosing regimen established that compared to oral dosing, intravenous dosing resulted in higher and more consistent tumor drug levels and improved target inhibition, with up to 93% of intratumoral LDH activity inhibited. Efficacy studies are ongoing and will be reported. Preclinical data suggest that inhibition of LDHA/B may represent a potentially novel therapeutic strategy in the treatment of ES. Citation Format: Christine M. Heske, Anna E. Gibson, Josh T. Baumgart, Choh Yeung, Sameer H. Issaq, A Mendoza, Michelle S. Johnson, Guiseppe L. Squadrito, Lillian Culp, Victor M. Darley-Usmar, Len M. Neckers. Evaluation of LDH inhibition as a treatment strategy in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B16.

Pulmonary metastasectomy: analysis of survival and prognostic factors in 243 patients.

Pulmonary metastases are a sign of advanced malignant disease. Interdisciplinary management of metastatic cancer mandates the consideration of all treatment options, and in selected patients pulmonary metastasectomy can be performed with curative intent. This study aims to analyze the prognostic factors associated with survival and optimize the selection of surgical candidates. The sarcoma subset analysis aims to examine the role of multiple repeat resections for pulmonary metastatic recurrence. A total of 243 patients were analyzed in this retrospective cohort study. Overall survival was estimated using Kaplan-Meier analysis. Univariate analyses with log-rank tests and multivariate analysis with Cox proportional hazards model were undertaken to determine the independent prognostic factors for survival. Multivariate analyses identified germ cell cancer (P = 0.01) and a disease-free interval of >36 months (P = 0.006) as significant independent prognostic factors for improved survival, whilst synchronous metastases (P = 0.04), multiple metastases (P = 0.005) and incomplete resection (P < 0.001) were identified as significantly poor prognostic factors. Subset analyses identified that ≥2 repeat resections within the sarcoma cohort was associated with an increased median survival of 63.5 months (P = 0.04). In selected patients, pulmonary metastasectomy can be performed with curative intent and have associated long-term survival benefits. Patients presenting with recurrent sarcoma pulmonary metastases should be considered for repeat metastasectomy.

Outcomes of Elderly Patients Undergoing Curative Resection for Retroperitoneal Sarcomas: Analysis From the US Sarcoma Collaborative

BackgroundThe postoperative outcomes of elderly patients undergoing resection of retroperitoneal sarcomas (RPS) have not been widely studied. MethodsPatients undergoing surgical resection for primary or recurrent RPS between 2000 and 2015 at participating US Sarcoma Collaborative institutions were identified. Patient demographics, perioperative morbidity, mortality, length of stay, discharge to home, disease-specific survival, and disease-free survival were compared between elderly (≥70 y, n = 171) and nonelderly (<70 y, n = 494) patients. ResultsThere was no difference in perioperative morbidity (total and major complications elderly versus nonelderly: 39% versus 35%; P = 0.401 and 18% versus 17%; P = 0.646, respectively) or mortality between elderly and nonelderly patients with each group experiencing a 1% 30-d mortality rate. Length of stay and 30-d readmission rates were similar (elderly versus nonelderly; 7 d interquartile range [IQR: 5-9] versus 6 d [IQR: 4-9], P = 0.528 and 11% versus 12%, P = 0.667). Elderly patients were more likely to be discharged to a skilled nursing or rehabilitation facility (elderly versus nonelderly; 19% versus 7%, P < 0.001). There was no difference in 3-y disease-free survival between the elderly and nonelderly patients (41% versus 43%, P = 0.65); however, elderly patients had a lower 3-y disease-specific survival (60% versus 76%, P < 0.001). In elderly patients, the presence of multiple comorbidities and high-grade tumors were most predictive of outcomes. ConclusionsAdvanced age was not associated with an increased risk of perioperative morbidity and mortality following resection of RPS in this multi-institutional review. Although short-term oncologic outcomes were similar in both groups, the risk of death after sarcoma recurrence was higher in elderly patients and may be related to comorbidity burden and tumor histology.

Prognostic significance of microscopic tumor extension in local recurrence of myxofibrosarcoma and undifferentiated pleomorphic sarcoma.

Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) frequently display infiltrative growth into the adjacent normal soft tissue. In this study, we aimed to determine whether the microscopic extension into surrounding normal tissue can influence the local recurrence of MFS and UPS. A total of 42 cases (22 MFS and 20 UPS) were examined. The length of the microscopic extension was measured from the edge of the main tumor mass to the end of infiltration. The length of 5.5 mm was selected as the optimal cut-off value that could predict local recurrence using the receiver operating characteristic (ROC) curve and Youden index. Longer length of microscopic extension was significantly correlated with the status of resection margin (P = 0.032). The group with longer length of microscopic extension (>5.5 mm) had significantly worse recurrence-free survival than the group with shorter length of microscopic extension (≤5.5 mm) (P = 0.000). Multivariate analysis revealed that the length of microscopic extension was independent predictors of recurrence-free survival (P = 0.018). In conclusion, microscopic extensions at the edge of the main mass into the surrounding normal tissue were observed in most MFS and UPS patients, and the length of microscopic extension was associated with local recurrence.

Human mesenchymal stromal cells do not promote recurrence of soft tissue sarcomas in mouse xenografts after radiation and surgery

Background. Mesenchymal stromal cells (MSCs) promote wound healing, including after radiotherapy (RT) and surgery. The use of MSCs in regenerative medicine in the context of malignancy, such as to enhance wound healing post-RT/surgery in patients with soft tissue sarcomas (STSs), requires safety validation. The aim of this study was to determine the effects of human MSCs on STS growth in vitro and local recurrence and metastasis in vivo. Methods. Human primary STS and HT-1080 fibrosarcoma lines were transduced to express luciferase/eGFP (enhanced green fluorescent protein). Sarcoma cells were co-cultured or co-injected with bone marrow–derived MSCs for growth studies. Xenograft tumor models were established with STS lines in NOD/SCID/γcnull mice. To emulate a clinical scenario, subcutaneous tumors were treated with RT/surgery prior to MSC injection into the tumor bed. Local and distant tumor recurrence was studied using histology and bioluminescence imaging. Results. MSCs did not promote STS proliferation upon co-culture in vitro, which was consistent among MSCs from different donors. Co-injection of MSCs with sarcoma cells in mice exhibited no significant tumor-stimulating effect, compared with control mice injected with sarcoma cells alone. MSC administration after RT/surgery had no effect on local recurrence or metastasis of STS. Discussion. These studies are important for the establishment of a safety profile for MSC administration in patients with STS. Our data suggest that MSCs are safe in STS management after standard of care RT/surgery, which can be further investigated in early-phase clinical trials to also determine the efficacy of MSCs in reducing morbidity and to mitigate wound complications in these patients.

Abstract 3178: Up-regulation of GLI1 expression in drug resistant rhabdomyosarcoma (RMS) and Ewing sarcoma (EWS) cell lines

Abstract Outcome for pediatric patients with recurrent sarcomas remains poor. Therefore, understanding mechanisms that lead to drug resistance and ways to overcome drug resistance therapeutically are essential. Recent reports have suggested a role for the Hedgehog signaling pathway and its downstream mediator GLI1 in acquisition of a multidrug resistance phenotype in esophageal adenocarcinoma, glioblastoma, and myeloid leukemia. Since GLI1 is expressed in the majority of RMS and EWS cases, we hypothesized that GLI1 up-regulation occurs as cells become drug resistant in vitro and in vivo. We established vincristine (VCR) resistant RMS cell lines (Embryonal RMS: RD, Ruch-2; Alveolar RMS: Rh30, Rh41) by serial exposure to increasing concentrations of VCR. Drug-resistance was defined as an IC50 of ≥30 fold of the baseline that was established using parental cells. In addition, we obtained EWS cell lines, representing untreated cases (CHLA-9 and TC-32) and cases following recurrence (CHLA-258 and TC-71). We used an 86-gene cancer drug resistance PCR array (Qiagen), to characterize gene expression differences between the parental vs. VCR-resistant RMS cells lines and between the untreated and recurrent EWS cell lines. GLI1 expression was significantly increased (p≤0.05) in VCR-resistant alveolar RMS cell lines (Rh30 [2.3 fold], and Rh41 [10.3 fold]) compared with parental cells. Expression of 2 additional genes (MDR1 [13,307 fold in Rh30 and 1,755 fold in Rh41 cells] and MVP [2.4 fold in Rh30 and 8.8 fold in Rh41]) was also significantly up-regulated in these cells. Gel mobility shifts showed interaction of GLI1 with the MVP promoter, and cotransfection assays showed that GLI1 up-regulates reporter gene expression through the MVP promoter. GLI1 expression was significantly up-regulated in Ruch-2 embryonal RMS cells (2 fold). We also showed higher GLI1 expression in recurrent EWS cell lines (TC-71 [3.4 fold] and CHLA-258 [4.8 fold]) compared with untreated CHLA-9 cells. Expression of 1 additional gene (androgen receptor [11.1 fold in CHLA-258 cells and 274.6 fold in TC-71 cells]) was also significantly up-regulated in CHLA-258 and TC-71 cells. Treatment of VCR-resistant UKF Rhb-1 RMS cells with VCR together with either GANT61 or Cpd#33 (GLI1 inhibitors) significantly decreased cell viability by MTT assay at doses that did not reduce cell viability individually. Our results suggest that GLI1 up-regulation contributes to development of drug-resistance in RMS and EWS and that GLI1-inhibitors may reduce multidrug resistance. Citation Format: Joon Won Yoon, Iris Smith, Sumeed Manzoor, Marilyn Lamm, Philip Iannaccone, David Walterhouse. Up-regulation of GLI1 expression in drug resistant rhabdomyosarcoma (RMS) and Ewing sarcoma (EWS) cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3178.

DNA-cytometric characteristics of recurrent soft tissue sarcomas

Aim. To determine the content of deoxyribonucleic acid (DNA) and distribution of cells in mitotic phases in patients with recurrent soft tissue sarcomas for the assessment of malignancy of the process. Methods. Tumor tissues of patients with recurrent soft tissue sarcomas were studied. Research methods included histological, DNA-cytometric and statistical methods. Results. Proliferative activity and proliferative index of recurrent sarcomas differed depending on the tumor grade and stage. Differences in the number of diploid, aneuploid and polyploid cells were determined in each group and between the groups depending on the cell cycle phases. Cell cycle parameters were as following: 100% of G1 (well-differentiated) cancer were diploid, as well as 33.3% of G2 (moderately differentiated) and 15% of G3 (poorly differentiated) tumors. Aneuploid tumors prevailed in G2 and G3, the ratio of which was 66.7 and 85%, respectively. The analysis of kinetic parameters of the cell cycle allowed establishing a decrease in the number of cells in G1/G0 phase of the cell cycle from G1 to G3, which was accompanied by a statistically significant increase in the proportion of cells in S-phase (p ˂0.05). Conclusion. The DNA-cytometric study of cell cycle parameters showed high biological potential of recurrent soft tissue sarcomas, which was determined by two indices - the proportion of cells in G2+M-phase and the cell loss factor; 100% of well-differentiated (G1) tumors, 33.3% of moderately differentiated (G2) and 15% of poorly differentiated (G3) tumors were diploid; aneuploid tumors prevailed in G2 and G3.

Out of Borders for Radical Gynecologic Surgery

Abstract Advances in several medical disciplines have resulted in greatly improved outcome and reduced morbidity and mortality in the management of complex gynecologic tumors. Early reports of central pelvic exenteration were discouraging and associated with high mortality (28%) and major complications (100%). Preoperative medical assessment, expert anesthesia, and postoperative intensive care have reduced perioperative mortality to less than 5%. For patients with recurrent cervical and endometrial cancer, who already had surgery, and for a minority of primary or recurrent sarcomas without distance metastases, the contemporaneous surgery offers a chance by bone extended resections.

Local recurrence of soft-tissue sarcoma: issues in imaging surveillance strategy.

Soft-tissue sarcomas pose diagnostic and therapeutic challenges to physicians, owing to the large number of subtypes, aggressive tumor biology, lack of consensus on management, and controversy surrounding interval and duration of surveillance scans. Advances in multidisciplinary management have improved the care of sarcoma patients, but controversy remains regarding strategies for surveillance following definitive local control. This review provides an updated, comprehensive overview of the current understanding of the risk of local recurrence of soft-tissue sarcoma, by examining the literature based on features such as histological type and grade, tumor size, and resection margin status, with the aim of helping clinicians, surgeons, and radiologists to develop a tailored approach to local imaging surveillance.