Search

57 Background: Delivering cancer care by high-functioning multidisciplinary teams promises to address care fragmentation and complexity, which threaten care quality, impact patient outcomes, and strain the oncology workforce. We assessed whether the 4R Oncology model (Trosman et al 2021) for team-based interdependent care delivery and patient self-management impacted team functioning at Kaiser Permanente Northern California (KPNC), a large community-based health system. Methods: We deployed the 4R intervention in breast and lung cancers at 4 KPNC centers. The intervention encompassed team development and care delivery optimizations enabling teamwork. 4R Care Sequences – novel patient-facing care plans outlining timing and sequence of care – informed team formation, activities and functioning. We assessed intervention along 4 characteristics of high-functioning teams (Vogel JOP 2016). Results: 4R facilitated development of a high-functioning team along all 4 characteristics. (1) We formed an internally and externally recognized multidisciplinary team of 24 specialties who assumed team responsibilities for relevant care. (2) All participants committed to a shared goal of delivering interdependent care at the optimal time and sequence based on Care Sequences. (3) The team conducted 40 optimizations to enable effective interdependent care: 22 in breast, 7 in lung, and 11 in both cancers (Table). The optimizations impacted 6 care domains at 4 points in care continuum. Half of optimizations entailed low effort; 70% resulted in improved process efficiency. (4) An ongoing teamwork adaptation process was established. Conclusions: 4R is an effective and feasible approach to fostering high-functioning teams, which may contribute to improvement of multidisciplinary care delivery and support viability of the oncology workforce. Our intervention and taxonomy of results inform other institutions motivated to strengthen teamwork and improve delivery of complex interdependent care.[Table: see text]

54 Background: Advance directives (ADs) are an important part of life care planning in patients with cancer. There is a lack of effective interventions to increase AD rates in breast cancer patients prior to surgery. In this quality improvement project, we implemented an intervention for breast cancer patients receiving care in an integrated healthcare delivery system. 4R (Right Info / Right Care / Right Patient / Right Time) is a novel care planning and delivery model that enables the patient and oncology care team to manage complex time-sensitive care using a multi-modality 4R Care Sequence plan, coupled with follow-up workflows. Methods: We studied two groups of patients with newly diagnosed non-metastatic breast cancer who attended a multidisciplinary clinic and underwent definitive surgery at one facility. The Usual Care (UC) cohort received care from 10/1/19 to 9/30/20. The 4R Intervention (4R) cohort received care from 10/1/20 to 9/30/21 using a 4R Care Sequence plan that included AD completion prior to surgery; those without an AD were referred for follow-up to a health educator to discuss AD completion. Bivariate analyses were used to compare the UC and 4R cohorts on demographics, NCCN thermometer distress scores, and AD completion rates. Results: Characteristics of age, gender, race/ethnicity, needing interpreter, Elixhauser Comorbidity Index, NCCN distress scores > 4, surgery type, grade, ER/PR/HER-2 status were similar in the UC (N = 140) and 4R cohorts (N = 141). AD completion prior to surgery was significantly higher for the 4R vs. UC cohort, both overall (15% vs 74%, p

Malignant peripheral nerve sheath tumors (MPNSTs) comprise a rare, aggressive subtype of soft tissue sarcoma. While surgery is the mainstay of therapy for this disease, the role of neoadjuvant therapy remains undefined.This study reviewed patients 16 years of age and older who underwent surgical treatment for MPNST between 1974 and 2012 at the authors' institution. Univariate and multivariate analyses were performed of clinicopathologic and treatment variables predictive of disease-specific survival (DSS) and disease-free survival.Eighty-eight patients with primary localized MPNST underwent surgical treatment between 1974 and 2012 at our institution. Of these, 38 (43%) underwent neoadjuvant chemotherapy and had tissue available for analysis. Neoadjuvant radiation was given to 25 patients (68%). The median follow-up time for survivors was 12.5 years (range, 4 to 27 y). Nine patients (23%) had underlying MPNST. With a cutoff of ≥90% pathologic necrosis and/or fibrosis defining response, we identified 14 responders (36%). On univariate analysis, patient age, tumor size, and pathologic response were significantly associated with DSS (P=0.015, 0.011, and 0.030, respectively).Although the impact of neoadjuvant chemotherapy on the outcome of primary localized MPNST patients continues to be debated, this study shows that a pathologic response to therapy is associated with a significant improvement in DSS. The challenge moving forward is to determine upfront which patients will be "responders" to standard systemic therapy and which patients should be considered for newer investigational agents as part of a clinical trial.

e13511 Background: Advance directives (ADs) are an important part of life care planning in patients with cancer. There is a lack of effective interventions that increase AD rates in breast cancer patients prior to surgery. In this quality improvement project, we implemented a 4R Oncology intervention in a community-based cancer center within an integrated health care system. 4R (Right Info / Care / Patient / Time) is a novel care planning and delivery model, which enables patients and care teams to manage complex time-sensitive care with a multi-modality 4R Care Sequence plan, coupled with follow-up workflows. Methods: Patients with newly diagnosed non-metastatic breast cancer who attended a multidisciplinary clinic and underwent definitive surgery at one facility were included in the study. Patients received usual care from 10/1/19 to 9/30/20 (usual care cohort). From 10/1/20 to 9/30/21 (intervention cohort), patients were provided a 4R Care Sequence, which included AD completion prior to surgery, and those without AD were referred for follow-up with a health educator to discuss AD completion. Demographics, NCCN thermometer distress scores, and AD completion rates were compared between the usual care and intervention cohorts using descriptive statistics. Results: Characteristics of age, gender, race/ethnicity, language interpreter usage, Elixhauser Comorbidity Index, NCCN distress scores > 4, surgery type, tumor grade, ER/PR/HER-2 status were similar between the usual care (N=140) and intervention cohorts (N=141). The intervention improved AD completion rates in a time-sensitive fashion prior to surgery between usual care and intervention cohorts, both in total (15% vs 74%, p

BACKGROUND The current study was conducted to examine the association between ipsilateral breast tumor recurrence (IBTR) and the timing of radiotherapy (RT) in women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery (BCS). METHODS Women with DCIS who were treated with BCS and RT from 1980 through 2010 were identified from a prospectively maintained database. IBTR rates, measured from the time of RT completion, were compared between those who initiated RT ≤8 weeks, >8 to 12 weeks, and >12 weeks after the completion of surgery. The association between RT timing and IBTR was evaluated by Kaplan-Meier and log-rank analyses; Cox modeling was used for multivariable analysis. RESULTS A total of 1323 women met the inclusion criteria. The median follow-up was 6.6 years, with 311 patients followed for ≥10 years. A total of 126 IBTR events occurred. Patients were categorized by RT timing: 806 patients (61%) with timing of ≤8 weeks, 386 patients (29%) with timing of >8 to 12 weeks, and 131 patients (10%) with timing >12 weeks. The 5-year and 10-year IBTR rates were 5.8% and 13.0%, respectively, for RT starting ≤8 weeks after surgery; 3.8% and 7.6%, respectively, for RT starting >8 to 12 weeks after surgery; and 8.8% and 23.0%, respectively, for an RT delay >12 weeks after surgery (P = .004). On multivariable analysis, menopause (hazard ratio [HR], 0.54; P = .0009) and endocrine therapy (HR, 0.45; P = .002) were found to be protective against IBTR, whereas a delay in RT >12 weeks compared with ≤8 weeks was associated with a higher risk of IBTR (HR, 1.92; P = .014). There was no difference in IBTR noted between RT initiation at ≤8 weeks and initiation at >8 to 12 weeks after BCS (P = .3). CONCLUSIONS A delay in RT >12 weeks is associated with a significantly higher risk of IBTR in women undergoing BCS for DCIS. Efforts should be made to avoid delays in starting RT to minimize the risk of disease recurrence. Cancer 2018;124:46-54. © 2017 American Cancer Society.

6555 Background: Male breast cancer (MBC) accounts for approximately 1% of all breast cancers. Racial disparities have not been examined in MBC. Methods: Within a large, integrated health delivery system, all adult female and male patients who were diagnosed with breast cancer from 01-01-2010 to 12-31-2018 were examined. Bivariate analysis was performed to examine clinical and demographic factors associated with breast cancer-related mortality. We conducted more detailed chart review in the MBC-only group (data period 01-01-2010 to 12-31-2019) to assess the mean time to treatment (from diagnosis to surgery, surgery to chemotherapy, and surgery to radiation) stratified by race using bivariate (t-test, one way ANOVA) analyses. Results: 32,848 female breast cancer and 226 MBC patients were evaluated; MBC patients represented 0.63% of all breast cancer patients. Between males and females, there was no statistically significant difference in race, with an overall distribution of 62% White, 19% Asian, 8% Black, and 11% Hispanic. To our knowledge, this is the largest and most racially diverse sample of MBC patients to date. MBC patients at diagnosis were significantly older (p

Malignant peripheral nerve sheath tumor (MPNST) is the sixth most common type of soft tissue sarcoma. Most MPNSTs arise in association with a peripheral nerve or preexisting neurofibroma. Neurofibromatosis type is the most important risk factor for MPNST. Tumor size and fludeoxyglucose F 18 avidity are among the most helpful parameters to distinguish MPNST from a benign peripheral nerve sheath tumor. The histopathologic diagnosis is predominantly a diagnosis of light microscopy. Immunohistochemical stains are most helpful to distinguish high-grade MPNST from its histologic mimics. Current surgical management of high-grade MPNST is similar to that of other high-grade soft tissue sarcomas.

The current study was conducted to examine the association between ipsilateral breast tumor recurrence (IBTR) and the timing of radiotherapy (RT) in women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery (BCS).Women with DCIS who were treated with BCS and RT from 1980 through 2010 were identified from a prospectively maintained database. IBTR rates, measured from the time of RT completion, were compared between those who initiated RT ≤8 weeks,8 to 12 weeks, and12 weeks after the completion of surgery. The association between RT timing and IBTR was evaluated by Kaplan-Meier and log-rank analyses; Cox modeling was used for multivariable analysis.A total of 1323 women met the inclusion criteria. The median follow-up was 6.6 years, with 311 patients followed for ≥10 years. A total of 126 IBTR events occurred. Patients were categorized by RT timing: 806 patients (61%) with timing of ≤8 weeks, 386 patients (29%) with timing of8 to 12 weeks, and 131 patients (10%) with timing12 weeks. The 5-year and 10-year IBTR rates were 5.8% and 13.0%, respectively, for RT starting ≤8 weeks after surgery; 3.8% and 7.6%, respectively, for RT starting8 to 12 weeks after surgery; and 8.8% and 23.0%, respectively, for an RT delay12 weeks after surgery (P = .004). On multivariable analysis, menopause (hazard ratio [HR], 0.54; P = .0009) and endocrine therapy (HR, 0.45; P = .002) were found to be protective against IBTR, whereas a delay in RT12 weeks compared with ≤8 weeks was associated with a higher risk of IBTR (HR, 1.92; P = .014). There was no difference in IBTR noted between RT initiation at ≤8 weeks and initiation at8 to 12 weeks after BCS (P = .3).A delay in RT12 weeks is associated with a significantly higher risk of IBTR in women undergoing BCS for DCIS. Efforts should be made to avoid delays in starting RT to minimize the risk of disease recurrence. Cancer 2018;124:46-54. © 2017 American Cancer Society.

Purpose Integration of numerous prognostic variables not included in the conventional staging of retroperitoneal soft tissue sarcomas (RPS) is essential in providing effective treatment. The purpose of this study was to build a specific nomogram for predicting postoperative overall survival (OS) and disease-free survival (DFS) in patients with primary RPS. Patients and Methods Data registered in three institutional prospective sarcoma databases were used. We included patients with primary localized RPS resected between 1999 and 2009. Univariate (Kaplan and Meier plots) and multivariate (Cox model) analyses were carried out. The a priori chosen prognostic covariates were age, tumor size, grade, histologic subtype, multifocality, quality of surgery, and radiation therapy. External validation was performed by applying the nomograms to the patients of an external cohort. The model's discriminative ability was estimated by means of the bootstrap-corrected Harrell C statistic. Results In all, 523 patients were identified at the three institutions (developing set). At a median follow-up of 45 months (interquartile range, 22 to 72 months), 171 deaths were recorded. Five- and 7-year OS rates were 56.8% (95% CI, 51.4% to 62.6%) and 46.7% (95% CI, 39.9% to 54.6%. Two hundred twenty-one patients had disease recurrence. Five- and 7-year DFS rates were 39.4% (95% CI, 34.5% to 45.0%) and 35.7% (95% CI, 30.3% to 42.1%). The validation set consisted of 135 patients who were identified at the fourth institution for external validation. The bootstrap-corrected Harrell C statistics for OS and DFS were 0.74 and 0.71 in the developing set and 0.68 and 0.69 in the validating set. Conclusion These nomograms accurately predict OS and DFS. They should be used for patient counseling in clinical practice and stratification in clinical trials.

// Elizabeth Shurell 1, * , Arun S. Singh 2, 7, * , Joseph G. Crompton 1 , Sarah Jensen 2 , Yunfeng Li 3 , Sarah Dry 3, 7 , Scott Nelson 3, 7 , Bartosz Chmielowski 2, 7 , Nicholas Bernthal 4, 7 , Noah Federman 2, 7 , Paul Tumeh 5, 7 , Fritz C. Eilber 1, 6, 7 1 Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA 90095, USA 2 Department of Hematology/Oncology, University of California, Los Angeles, CA 90095, USA 3 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA 4 Department of Orthopaedic Surgery, University of California, Los Angeles, CA 90095, USA 5 Department of Dermatology, University of California, Los Angeles, CA 90095, USA 6 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA 7 UCLA JCCC Sarcoma Program, University of California, Los Angeles, CA 90095, USA * indicates co-first authors Correspondence to: Fritz C. Eilber, email: fceilber@mednet.ucla.edu Keywords: immune microenvironment, MPNST, PD-L1, CD8, sarcoma Received: June 29, 2016 Accepted: August 16, 2016 Published: August 31, 2016 ABSTRACT Background: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with few treatment options. Tumor immune state has not been characterized in MPNST, and is important in determining response to immune checkpoint blockade. Our aim was to evaluate the expression of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and presence of CD8+ tumor infiltrating lymphocytes (TILs) in MPNST, and correlate these findings with clinical behavior and outcome. Results: PD-L1 staining of at least 1% was seen in 0/20 nerves, 2/68 benign lesions and 9/53 MPNST. Two of 68 benign lesions and 7/53 (13%) MPNST had at least 5% PD-L1 staining. CD8 staining of at least 5% was seen in 1/20 (5%) nerves, 45/68 (66%) benign lesions and 30/53 (57%) MPNST. PD-L1 was statistically more prevalent in MPNST than both nerves and benign lesions (p=0.049 and p=0.008, respectively). Expression of PD-1 was absent in all tissue specimens. There was no correlation of PD-L1 or CD8 expression with disease state (primary versus metastatic) or patient survival. Methods: A comprehensive PNST tissue microarray was created from 141 surgical specimens including primary, recurrent, and metastatic MPNST (n=53), neurofibromas (n=57), schwannoma (n=11), and normal nerve (n=20). Cores were stained in triplicate for PD-L1, PD-1, and CD8, and expression compared between tumor types. These data were then examined for survival correlates in 35 patients with primary MPNST. Conclusions: MPNST is characterized by low PD-L1 and absent PD-1 expression with significant CD8+ TIL presence. MPNST immune microenvironment does not correlate with patient outcome.

// Elizabeth Shurell 1, * , Maria E. Vergara-Lluri 2, * , Yunfeng Li 3 , Joseph G. Crompton 1 , Arun Singh 4 , Nicholas Bernthal 5 , Hong Wu 3 , Fritz C. Eilber 1 , Sarah M. Dry 2 1 Division of Surgical Oncology, University of California, Los Angeles, CA 90095, USA 2 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA 3 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA 4 Department of Hematology/Oncology, University of California, Los Angeles, CA 90095, USA 5 Department of Orthopaedic Surgery, University of California, Los Angeles, CA 90095, USA * Co-first author Correspondence to: Fritz C. Eilber, email: fceilber@mednet.ucla.edu Keywords: NY-ESO-1, sarcoma, MPNST, liposarcoma, immunotherapy Received: July 28, 2016 Accepted: September 09, 2016 Published: September 17, 2016 ABSTRACT Background: Immunotherapy targeting cancer-testis antigen NY-ESO-1 shows promise for tumors with poor response to chemoradiation. Malignant peripheral nerve sheath tumors (MPNSTs) and liposarcomas (LPS) are chemoresistant and have few effective treatment options. Materials Methods: Using a comprehensive tissue microarray (TMA) of both benign and malignant tumors in primary, recurrent, and metastatic samples, we examined NY-ESO-1 expression in peripheral nerve sheath tumor (PNST) and adipocytic tumors. The PNST TMA included 42 MPNSTs (spontaneous n = 26, NF1-associated n = 16), 35 neurofibromas (spontaneous n = 22, NF-1 associated n = 13), 11 schwannomas, and 18 normal nerves. The LPS TMA included 48 well-differentiated/dedifferentiated (WD/DD) LPS, 13 myxoid/round cell LPS, 3 pleomorphic LPS, 8 lipomas, 1 myelolipoma, and 3 normal adipocytic tissue samples. Stained in triplicate, NY-ESO-1 intensity and density were scored. Results: NY-ESO-1 expression was exclusive to malignant tumors. 100% of myxoid/round cell LPS demonstrated NY-ESO-1 expression, while only 6% of WD/DD LPS showed protein expression, one of which was WD LPS. Of MPNST, 4/26 (15%) spontaneous and 2/16 (12%) NF1-associated MPNSTs demonstrated NY-ESO-1 expression. Strong NY-ESO-1 expression was observed in myxoid/round cell and dedifferentiated LPS, and MPNST in primary, neoadjuvant, and metastatic settings. Conclusions: We found higher prevalence of NY-ESO-1 expression in MPNSTs than previously reported, highlighting a subset of MPNST patients who may benefit from immunotherapy. This study expands our understanding of NY-ESO-1 in WD/DD LPS and is the first demonstration of staining in a WD LPS and metastatic/recurrent myxoid/round cell LPS. These results suggest immunotherapy targeting NY-ESO-1 may benefit patients with aggressive tumors resistant to conventional therapy.

Phyllodes tumors of the breast are rare fibroepithelial tumors that are characterized as benign, borderline, or malignant based on cellular characteristics such as stromal overgrowth and number of mitoses. Currently, there is a lack of consensus on risk factors and management of patients with phyllodes tumors, which has led to variation in treatment patterns as well as patient outcomes across many institutions. This study seeks to understand the clinicopathologic features, risk factors for local and metastatic recurrence, and clinical outcomes of patients with phyllodes tumors to better define optimal treatment patterns.

Background Gender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied. Methods Forty-three mGFAP-Cre+;Pten loxp/+;LSL-K-ras G12D/+ mice were observed for tumor development and evaluated for gender disparity in age of MPNST onset. Patient data from the prospectively collected UCLA sarcoma database (1974–2011, n = 113 MPNST patients) and 39 published studies on MPNST patients (n = 916) were analyzed for age of onset differences between sexes and between NF-1 and spontaneous MPNST patients. Results Our murine model showed gender-based differences in MPNST onset, with males developing MPNST significantly earlier than females (142 vs. 162 days, p = 0.015). In the UCLA patient population, males also developed MPNST earlier than females (median age 35 vs. 39.5 years, p = 0.048). Patients with NF-1-associated MPNST had significantly earlier age of onset compared to spontaneous MPNST (median age 33 vs. 39 years, p = 0.007). However, expanded analysis of 916 published MPNST cases revealed no significant age difference in MPNST onset between males and females. Similar to the UCLA dataset, patients with NF-1 developed MPNST at a significantly younger age than spontaneous MPNST patients (p Conclusions Although our preclinical model and single-institution patient cohort show gender dimorphism in MPNST onset, no significant gender disparity was detected in the larger MPNST patient meta-dataset. NF-1 patients develop MPNST 13 years earlier than patients with spontaneous MPNST, with little geographical variance.

Tumor-targeting Salmonella enterica serovar Typhimurium A1-R (Salmonella A1-R) had strong efficacy on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. GFP-expressing Salmonella A1-R highly and selectively colonized the PDOX melanoma and significantly suppressed tumor growth (p = 0. 021). The combination of Salmonella A1-R and cisplatinum (CDDP), both at low-dose, also significantly suppressed the growth of the melanoma PDOX (P = 0. 001). Salmonella A1-R has future clinical potential for combination chemotherapy with CDDP of melanoma, a highly-recalcitrant cancer.

Malignant peripheral nerve sheath tumors (MPNST) compose a fraction of all soft tissue sarcomas, but are life-threatening and present difficult diagnostic and therapeutic challenges. Benign peripheral nerve sheath tumors, including schwannomas or neurofibromas, can often be managed conservatively unless symptomatic. MPNSTs require aggressive multimodality treatment (surgery, radiation therapy, ± chemotherapy). MPNSTs can arise from pre-existing neurofibromas in patients with neurofibromatosis type 1 (NF1) or can develop sporadically in the general population. Peripheral nerve sheath tumors are often pathologically heterogeneous or in difficult anatomic locations often making needle biopsy unreliable or unfeasible. Current standard imaging of these tumors rely on computed tomography (CT) or magnetic resonance imaging (MRI), both of which characterize size and local invasiveness, but do not provide reliable insight into the presence of malignant transformation. Clinical manifestations of malignant transformation classically rely on reported symptoms of new neurological deficits, rapid increase in size, change in palpated density from soft to hard, and unremitting pain. Investigations into the glycolytic phenotype of peripheral nerve sheath tumors with [18F] 2-Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) have been performed to identify potential areas of malignant degeneration. Lower tumor FDG uptake has proven to correlate with benign peripheral nerve sheath tumors, which can be distinguished from the high FDG uptake of its malignant counterpart, MPNST. Clinicians may employ this imaging modality to help identify MPNSTs, guide biopsies, direct therapies, measure response to treatment, and survey for tumor recurrence.

10555 Background: MPNST is an aggressive soft tissue sarcoma often arising from preexisting neurofibromas (NF). Our previous study using murine models demonstrated that PTEN loss and PI3K/AKT/mTOR pathway upregulation is a potential mechanism of malignant transformation. The goal of this study is to determine whether a similar mechanism also drives human MPNST development. Methods: A tissue microarray was created from 144 surgical specimens (MPNST n=58, NF n=51, schwannoma n=11, and normal nerve n=24). Cores were stained in triplicate for PTEN and PI3K pathway-associated markers (PTEN, P-AKT, P-S6, GLUT1, SKP-2), other previously identified alterations (p53, p16, P-ERK and c-Myc) as well as tumor grade biomarkers Ki-67 and cleaved caspase 3. Density, intensity and subcellular localization of each marker were quantified and compared using linear regression and survival analysis was performed using Cox proportional hazards modeling. Results: Consistent with our mouse model study, P-S6, GLUT1 and SKP-2, downstream surrogate markers for PI3K pathway, are upregulated in MPNST compared to benign NF (p=0.002, p=0.000, p=0.016, respectively). Upregulated GLUT1 is notable as we have shown that FDG imaging can be used to stratify MPNST lesions from benign. In the 34 primary MPNST patients, PTEN protein expression correlated with improved disease specific survival (DSS) and disease free survival (DFS) (p=0.066 and p=0.014, respectively). In this cohort, large size (p=0.085), low PTEN (p=0.066), and low c-MYC (p=0.001) were associated with poor DSS. Large size (p=0.074), low PTEN (p=0.023), skp2 (p=0.097), p-AKT (p=0.086), and c-MYC (p=0.001) all correlated with poor DFS. NF-1 patients and spontaneous patients had different expression patterns associated with survival. NF-1 patients had improved DSS with high p53 (p=0.044) and smaller size (p=0.013), whereas spontaneous patients showed improved DSS only with increased c-MYC (p=0.008). Conclusions: PTEN loss and PI3K/AKT/mTOR pathway activation are important in MPNST development/prognosis and serves as a potential therapeutic target.

10000 Background: To build a specific nomogram for predicting postoperative overall survival (OS) in primary retroperitoneal soft tissue sarcoma (RPS). A few single institutions attempts are already available, but due to the rarity of the disease they are based on limited number of cases with inherent limitations. In an attempt to improve the predictive capability of such a prognostic model we utilized series from 3 major sarcoma centers. Methods: We included patients with primary localized RPS resected with curative intent between 1999 and 2009 at 3 institutions (1 European and 2 North Americans). Univariable (Kaplan Meier plots) and multivariable (Cox model) analyses were carried out. Prognostic covariates were: Age (modeled as continuous covariate using 3 knot restricted cubic spline transformation); Tumor size (modeled as continuous covariate using 3 knot restricted cubic spline transformation); Grade (I,II,III); Histological subtype (Leiomyosarcoma, DD Liposarcoma, WD Liposarcoma, MPNST, Pleomorphic Sa, SFT, Other); Multifocality (no,yes); Quality of surgery (macroscopically complete, incomplete); radiation therapy (RT, done/not done). A backward selection procedure, based on the Akaike Information Criterion (AIC), was applied to select the Cox model covariates. The model discriminative ability was estimated by means of bootstrap-corrected Harrel C statistic. Results: 526 patients were identified. At a median follow-up of 45 months (interquartile range: 22‑72 months) 174 deaths were recorded. 5-yr and 7yr OS (95% confidence interval) were 56.4% (51.1,62.2%) and 50.1% (44.1,57.0%). The backward selection procedure by AIC criterion lead to exclude RT from the covariates set. All other covariates proved to be statistically significant in the final multivariable Cox model. The Bootstrap-corrected Harrell C statistic was 0.74. Of interest, size of the tumor and age of the patient had a bimodal contribution to the risk of death and the combination of histological subtype and grade proved significant. Conclusions: A new multi-institution RPS specific nomogram is now available for prognostication in the clinic and patient selection in clinical trials.

Liposarcoma is a type of soft tissue sarcoma that exhibits poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, which emphasizes the need for better understanding of this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. All xenografts recapitulated morphological and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability was directly correlated with disease-specific survival of liposarcoma patients. Thus, the ability for the tumor of a patient to engraft may help identify those patients who will benefit from more aggressive treatment regimens. Gene expression analyses highlighted the association between xenograftability and a unique gene expression signature, including down-regulated PTEN tumor-suppressor gene expression and a progenitor-like phenotype. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multikinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. These human xenograft models may facilitate liposarcoma research and accelerate the generation of readily translatable preclinical data that could ultimately influence patient care.