A Phase I Study of Binimetinib (MEK162) Combined with Pexidartinib (PLX3397) in Patients with Advanced Gastrointestinal Stromal Tumor.

LESSONS LEARNED: The combination of pexidartinib and binimetinib was safe and tolerable and demonstrated encouraging signs of efficacy in two patients with advanced gastrointestinal stromal tumor (GIST) refractory to tyrosine kinase inhibitors (TKIs).Molecular profiling of GISTs at diagnosis and upon progression may provide insight into the mechanisms of response or resistance to targeted therapies.Additional trials are needed to further explore combined KIT and MEK inhibition in treatment-naïve and TKI-refractory patients with advanced GIST. BACKGROUND: Nearly all patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Dual inhibition of KIT and MAPK pathways has synergistic antitumor activity in preclinical GIST models. METHODS: This was an investigator-initiated, phase I, dose escalation study of the MEK inhibitor binimetinib combined with pexidartinib, a potent inhibitor of CSF1R, KIT, and FLT3, in patients with advanced or metastatic GIST who progressed on imatinib. The primary endpoint was phase II dose determination; secondary endpoints included safety, tolerability, and efficacy. An expansion cohort to further evaluate safety and efficacy was planned. RESULTS: Two patients were treated at dose level one (binimetinib 30 mg b.i.d. and pexidartinib 400 mg every morning and 200 mg every evening), after which the study was terminated by the manufacturer. No dose-limiting toxicities (DLTs) were reported, and treatment was well tolerated. The only grade ≥3 treatment-emergent adverse event (TEAE) was asymptomatic elevated creatine phosphokinase (CPK). Both patients had a best response of stable disease (SD) by RECIST. Progression-free survival (PFS) and overall survival (OS) were 6.1 and 14.6 months, respectively, in one patient with five prior lines of therapy. The second patient with NF1-mutant GIST had a 27% decrease in tumor burden by RECIST and remains on study after 19 months of treatment. CONCLUSION: Pexidartinib combined with binimetinib was tolerable, and meaningful clinical activity was observed in two imatinib-refractory patients.

Size and Location are the Most Important Risk Factors for Malignant Behavior in Resected Solitary Fibrous Tumors.

PURPOSE: While previously thought to be clinically indolent, recent data suggest significant late metastatic capacity of solitary fibrous tumors (SFTs). We define prognostic factors for recurrence and disease-specific death (DSD) in resected primary SFTs. METHODS: Resected primary SFTs from 1982 to 2015 were identified from a prospective, single institutional database. Risk factors for local (LR) and distant recurrence (DR), and DSD were assessed using competing risk analysis. RESULTS: A total of 219 patients with median follow-up of 6.1 (0.1-22) years were included. Five- and 10-year cumulative DSD was 9 and 11%, respectively. Size greater than the median 8 cm, gender, location, and complete gross resection were significantly associated with DSD (p < 0.05). Five- and 10-year cumulative risk (CR) of LR was 4 and 7%, whereas 5- and 10-year CR of DR was 13 and 16%, respectively. LR was associated with location (p = 0.02) and tumor size (p = 0.02), and DR was associated with size (p < 0.01). Histopathologic classification did not predict long-term behavior with both malignant and benign tumors demonstrating capacity for DR and associated death. Tumors in the thoracic cavity and abdomen/retroperitoneum presented the greatest risk of DR (16 and 27% 10-year CR). On multivariate analysis, size ≥ 8 cm (hazard ratio 2.89, p = 0.05) and tumor location in chest or abdominal/retroperitoneal cavity (hazard ratio 2.68, p = 0.01) significantly impacted DSD. CONCLUSIONS: Recurrence is highly associated with DSD and events occur as late as 16 years after initial presentation, including in patients with initially considered benign tumors. Patients with large (≥ 8 cm) tumors in the chest or abdominal/retroperitoneal cavity are at greatest risk.

Imaging and clinicopathologic features of esophageal gastrointestinal stromal tumors.

OBJECTIVE: The purpose of this article is to describe the imaging and clinicopathologic characteristics of esophageal gastrointestinal stromal tumors (GISTs) and to emphasize the features that differentiate esophageal GISTs from esophageal leiomyomas. MATERIALS AND METHODS: A pathology database search identified all surgically resected or biopsied esophageal GISTs, esophageal leiomyomas, and esophageal leiomyosarcomas from 1994 to 2012. Esophageal GISTs were included only if imaging studies (including CT, fluoroscopic, or (18)F-FDG PET/CT scans) and clinical data were available. RESULTS: Nineteen esophageal mesenchymal tumors were identified, including eight esophageal GISTs (42%), 10 esophageal leiomyomas (53%), and one esophageal leiomyosarcoma (5%). Four patients (50%) with esophageal GIST had symptoms, including dysphagia in three (38%), cough in one (13%), and chest pain in one (13%). One esophageal GIST appeared on barium study as a smooth submucosal mass. All esophageal GISTs appeared on CT as well-marginated predominantly distal lesions, isoattenuating to muscle, that moderately enhanced after IV contrast agent administration. Compared with esophageal leiomyomas, esophageal GISTs tended to be more distal, larger, and more heterogeneous and showed greater IV enhancement on CT. All esophageal GISTs showed marked avidity (mean maximum standardized uptake value, 16) on PET scans. All esophageal GISTs were positive for c-KIT (a cell-surface transmembrane tyrosine kinase also known as CD117) and CD34. On histopathology, six esophageal GISTs (75%) were of the spindle pattern and two (25%) were of a mixed spindle and epithelioid pattern. Five esophageal GISTs had exon 11 mutations (with imatinib sensitivity). Clinical outcome correlated with treatment strategy (resection plus adjuvant therapy or resection alone) rather than risk stratification. CONCLUSION: Esophageal GISTs are unusual but clinically important mesenchymal neoplasms. Although esophageal GISTs and esophageal leiomyomas had overlapping imaging features, esophageal GISTs tended to be more distal, larger, more heterogeneous, and more enhancing on CT and were markedly FDG avid on PET. Given their malignant potential, esophageal GISTs should be included in the differential diagnosis of intramural esophageal neoplasms.

mRNA and protein levels of FUS, EWSR1, and TAF15 are upregulated in liposarcoma.

Translocations or mutations of FUS, EWSR1, and TAF15 (FET) result in distinct genetic diseases. N-terminal translocations of any FET protein to a series of transcription factors yields chimeric proteins that contribute to sarcomagenesis, whereas mutations in the conserved COOH-terminal domain of wild-type FUS were recently shown to cause familial amyotrophic lateral sclerosis. We thus investigated whether the loss of one FUS allele by translocation in liposarcoma may be followed by mutations in either the remaining FUS allele or the paralogous EWSR1. Furthermore, we investigated the strength of the FET promoters and their contributions to sarcomagenesis given the proteins' frequent involvement in oncogenic translocations. We sequenced the respective genomic regions of both FUS and EWSR1 in 96 liposarcoma samples. Additionally, we determined FET transcript and protein levels in several liposarcoma cell lines. We did not observe sequence variations in either FUS or EWSR1. However, protein copy numbers reached an impressive 0.9 and 5.5 Mio of FUS and EWSR1 per tumor cell, respectively. Compared with adipose-derived stem cells, FUS and EWSR1 protein expression levels were elevated on average 28.6-fold and 7.3-fold, respectively. TAF15 mRNA levels were elevated on average 3.9-fold, although with a larger variation between samples. Interestingly, elevated TAF15 mRNA levels did not translate to strongly elevated protein levels, consistent with its infrequent occurrence as translocation partner in tumors. These results suggest that the powerful promoters of FET genes are predominantly responsible for the oncogenic effect of transcription factor translocations in sarcomas.

Long-term results with resection of radiation-induced soft tissue sarcomas.

INTRODUCTION: Radiation therapy is increasingly used as adjuvant treatment of many childhood and adult malignancies. Radiation-induced sarcoma is a well recognized if uncommon event. The objective of this study is to determine the prevalence and long-term outcome for patients who develop radiation-induced sarcomas. METHODS: From July 1982 to December 2001, 4884 adult patients with sarcoma were admitted and treated at our institution and recorded in a prospective database. There were 123 (2.5%) patients who had radiation-induced soft tissue sarcomas. Survival was determined by Kaplan-Meier analysis. Patient, tumor, and treatment characteristics were tested for their prognostic significance by log rank and the Cox proportional hazards model. RESULTS: The median interval between radiation and development of sarcoma was 103 (6 to 534) months. In 114 patients with radiation-induced sarcoma who underwent curative resection, the 5-year actuarial survival was 41%, with a median survival of 48 months at a median follow-up of 36 months for survivors. The most common malignancy for which radiation was used was breast cancer (29%), followed by lymphoma (16%) and prostate cancer (15%). Malignant fibrous histiocytoma (23%) was the most common histologic diagnosis, followed by fibrosarcoma (15%) and angiosarcoma (15%). High-grade tumors (n = 85; 79%), age > 60 years (n = 61; 50%), and gross positive resection margin (n = 36; 32%) were predictive of poor sarcoma-specific survival on univariate and multivariate analysis. CONCLUSIONS: The increasing utilization of adjuvant radiation therapy, especially for early-stage breast cancer mandates long-term follow-up to detect radiation-induced sarcoma. Surgical resection remains the primary therapy, but 5-year survival remains approximately 40%.

Localized extremity soft tissue sarcoma: improved knowledge with unchanged survival over time.

PURPOSE: The objective of this study was to define whether survival of patients with extremity soft tissue sarcoma (STS), stratified for known risk factors, has improved over the last 20 years. PATIENTS AND METHODS: From January 1982 to December 2001, 1,706 patients with primary and recurrent STS of the extremities were treated at our institution and were prospectively followed. From this cohort, we selected 1,261 patients who underwent complete macroscopic resection and had one of the following histopathologies: fibrosarcoma, liposarcoma, leiomyosarcoma, malignant fibrous histiocytoma, or synovial sarcoma. Median follow-up was 55 months. Patient, tumor, and treatment factors were analyzed as prognostic factors. RESULTS: The 5-year disease-specific actuarial survival was 79% (78% for patients treated from 1982 to 1986, 79% for patients treated from 1986 to 1991, 79% for patients treated from 1992 to 1996, and 85% for patients treated from 1997 to 2001; P = not significant). For high-risk patients (high-grade, > 10 cm, deep tumors; n = 247), 5-year disease-specific survival was 51% (50% for patients treated from 1982 to 1986, 45% for patients treated from 1986 to 1991, 52% for patients treated from 1992 to 1996, and 61% for patients treated from 1997 to 2001; P = not significant). Tumor depth, size, grade, microscopic margin status, patient age, presentation status (primary tumor versus local recurrence), location (proximal versus distal), and certain histopathologic subtypes were significant prognostic factors for disease-specific survival on multivariate analysis; however, time period of treatment was not. CONCLUSION: Prognosis of patients with extremity STS, stratified for known risk factors, has not improved over the last 20 years, indicating that current therapy has reached the limits of efficacy.

Conventional hemangiopericytoma: modern analysis of outcome.

BACKGROUND: Hemangiopericytoma (HPC) is a rare vascular tumor, and pathologic distinction from synovial sarcoma and solitary fibrous tumor is a significant problem due to shared histologic features. In the current report the authors defined the clinical behavior and prognosis for patients with HPC. METHODS: Between July 1982 and February 1998, 62 patients with a diagnosis of primary, recurrent, or metastatic HPC were identified from a prospectively maintained database. The pathology of all cases for which material was available (57 cases) was re-reviewed for histologic confirmation of the HPC diagnosis. Using strict pathologic criteria, including immunohistochemistry and electron microscopy, tumors from 25 of 57 patients qualified for the diagnosis of conventional hemangiopericytoma; those tumors formed the basis of the current report. Survival was determined by the Kaplan-Meier method. RESULTS: At the time of initial presentation, 19 patients had primary tumors, 3 had locally recurrent disease, and 3 had metastatic disease. The most frequent anatomic sites for HPC were the extremities, the pelvis, and the head and neck, accounting for 80% of the total cases. The median followup (n = 25) was 49 months (range, 1 to 160 months). The two and five year overall survival rates (n = 25) were 93% and 86% respectively. The disease-specific survival was 86% at last followup. Patients undergoing complete resection (n = 16) showed a 100% median survival at 60 months. CONCLUSIONS: At present, complete tumor resection for patients with conventional HPC is recommended. However, considering the favorable outcome in this disease, the authors caution against performing operations that may potentially cause loss of function or are limb threatening.