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Undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS) are genomically complex tumors commonly diagnosed in the extremities or trunk of elderly patients. They likely represent a spectrum of disease differentiated by myxoid stroma and curvilinear vessels observed in MFS but not in UPS. Limb-sparing surgery is the standard of care although the infiltrative nature of MFS mandates wider resection margins than are necessary for UPS. UPS are conversely associated with high risks of distal recurrence, often prompting recommendations for adjuvant chemotherapy. In both histologies, anthracycline-based therapies or gemcitabine and docetaxel are used to manage advanced disease; immunotherapy may be of benefit in a subset of patients.

Normalized Tryptophan Concentrate Over Time

Purpose:Epacadostat, an indole 2,3 dioxygenase 1 (IDO1) inhibitor, proposed to shift the tumor microenvironment toward an immune-stimulated state, showed early promise in melanoma but has not been studied in sarcoma. This study combined epacadostat with pembrolizumab, which has modest activity in select sarcoma subtypes.Patients and Methods:This phase II study enrolled patients with advanced sarcoma into five cohorts including (i) undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma, (ii) liposarcoma (LPS), (iii) leiomyosarcoma (LMS), (iv) vascular sarcoma, including angiosarcoma and epithelioid hemangioendothelioma (EHE), and (v) other subtypes. Patients received epacadostat 100 mg twice daily plus pembrolizumab at 200 mg/dose every 3 weeks. The primary endpoint was best objective response rate (ORR), defined as complete response (CR) and partial response (PR), at 24 weeks by RECIST v.1.1.Results:Thirty patients were enrolled [60% male; median age 54 years (range, 24–78)]. The best ORR at 24 weeks was 3.3% [PR, n = 1 (leiomyosarcoma); two-sided 95% CI, 0.1%–17.2%]. The median PFS was 7.6 weeks (two-sided 95% CI, 6.9–26.7). Treatment was well tolerated. Grade 3 treatment-related adverse events occurred in 23% (n = 7) of patients. In paired pre- and post-treatment tumor samples, no association was found between treatment and PD-L1 or IDO1 tumor expression or IDO-pathway–related gene expression by RNA sequencing. No significant changes in serum tryptophan or kynurenine levels were observed after baseline.Conclusions:Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved.

Representativeness of study participants.

Normalized Kynurenine Concentrate Over Time

Supplementary Table S1, patient characteristics. Supplementary Table S2, genes in the signature distinguishing Cluster 1 and Cluster 2. Supplementary Table S3, genes associated with disease-specific survival. Supplementary Table S4, pathway modules identified by NetBox. Supplementary Table S5, functional annotation enrichment analysis. Supplementary Table S6, antibodies used. Supplementary Table S7, samples analyzed for ITGA10 mRNA in the comparison of primary and metastatic tissue.

Supplementary Figure Legends

Supplementary Figure S1, showing clustering of myxofibrosarcomas compared to normal tissue and showing the validation of the association of 5 genes with survival. Supplementary Figure S2, showing the effects of ITGA10 knockdown and overexpression. Supplementary Figure S3, showing the cell biology of integrin-alpha10 in myxofibrosarcoma cells. Supplementary Figure S4, showing the associations of TRIO and RICTOR amplification and overexpression with clinical outcomes. Supplementary Figure S5, showing that TRIO and RAC1 knockdown induce apoptosis in myxofibrosarcoma cells, but not in ASCs. Supplementary Figure S6, showing that RAPTOR knockdown does not induce apoptosis in myxofibrosarcoma cells. Supplementary Figure S7, showing the effects of RAC/PAK and mTOR inhibitors in myxofibrosarcoma cells and normal cells. Supplementary Figure S8, showing that mice treated with INK128 and/or EHop-016 maintain their weight.

PDF file - 281K, Model of liposarcoma initiation and progression.

PDF file - 73K, Multivariate analysis of chromosome 19q loss and clinical factors in local recurrence.

PDF file - 205K, Progression associated copy number alterations.

PDF file - 229K, Clinical characteristics of well differentiated liposarcoma samples.

PDF file - 1.4MB, Morphology of dedifferentiated liposarcoma.

PDF file - 290K, Clinical characteristics of dedifferentiated liposarcoma samples.

Purpose: Molecular events underlying progression of well-differentiated liposarcoma (WDLS) to dedifferentiated liposarcoma (DDLS) are poorly defined. This study sought to identify copy number alterations (CNA) associated with dedifferentiation of WDLS, with DDLS morphology, and with patient outcomes.Experimental Design: Fifty-five WDLS and 52 DDLS were analyzed using Agilent 244K comparative genomic hybridization and Affymetrix U133A expression arrays. CNAs were identified by RAE analysis. Thirty-nine of the DDLS specimens were categorized morphologically by a single pathologist.Results: Nine regions of CNA were identified as recurrent in DDLS but not WDLS; 79% of DDLS had at least one of these CNAs. Loss of the chromosome segment 11q23–24, the most common event, was observed only in DDLS that morphologically resembled the genomically complex sarcomas, undifferentiated pleomorphic sarcoma and myxofibrosarcoma. 11q23–24 loss was itself associated with increased genomic complexity in DDLS. Loss of 19q13, but not 11q23–24, was associated with poor prognosis. Median disease-specific survival was shorter for patients with19q13 loss (27 months) than for patients with diploid 19q13 (>90 months; P < 0.0025), and 19q13 loss was associated with local recurrence (HR, 2.86; P = 0.013). Common copy number losses were associated with transcriptional downregulation of potential tumor suppressors and adipogenesis-related genes (e.g., EI24 and CEBPA).Conclusions: Dedifferentiation of WDLS is associated with recurrent CNAs in 79% of tumors. In DDLS, loss of 11q23–24 is associated with genomic complexity and distinct morphology whereas loss of 19q13 predicts poor prognosis. CNAs in liposarcoma improve risk stratification for patients and will help identify potential tumor suppressors driving liposarcoma progression. Clin Cancer Res; 18(5); 1334–40. ©2012 AACR.

PDF file - 128K, Potential tumor suppressors in DDLS.

Supplementary Data from Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors

PDF file - 55K, Genomic complexity in 11q deleted tumors.

PDF file - 32K, Genomic complexity in well and dedifferentiated liposarcoma.

PDF file - 248K, Copy number alterations and dedifferentiated liposarcoma morphology.

Supplementary Figure from Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors

Purpose:Because the Hedgehog and Notch pathways are often overexpressed in mesenchymal malignancies, we evaluated the efficacy of concurrent inhibition of Notch and Hedgehog signaling using the gamma-secretase inhibitor (GSI) RO4929097 and the smoothened antagonist vismodegib in unresectable or metastatic sarcoma.Patients and Methods:In this investigator-initiated trial, phase Ib used standard 3+3 dose escalation in which patients first received vismodegib once daily for 21 days, followed by the combination of RO4929097 concurrently with vismodegib in 21-day cycles. In phase II, patients were randomized to RO4929097 alone or in combination with vismodegib.Results:Nine patients were treated in phase Ib with no dose-limiting toxicities. RO4929097 at 15 mg daily in combination with 150 mg daily of vismodegib was declared the recommended phase II dose. Most adverse events were grade ≤ 2. In phase II (closed early due to discontinuation of RO4929097 evaluation), 34 patients were randomized to RO4929097 alone and 33 to RO4929097 plus vismodegib. RO4929097 did not interfere with the steady-state concentration of vismodegib, while vismodegib reduced the plasma concentration of RO492909. No patients had an objective response. Neither progression-free nor overall survival differed significantly between treatment arms. Paired tumor biopsies from a subset of patients demonstrated inhibition of cleaved Notch.Conclusions:The combination of RO4929097 plus vismodegib was generally well tolerated. Although accrual to this study was not completed, vismodegib did not meaningfully enhance the clinical efficacy of RO4929097 in an unplanned analysis. GSIs and GSIs plus vismodegib can inhibit intratumoral Notch and downstream phosphorylated Akt signaling.

Supplementary Data from A Phase Ib/II Randomized Study of RO4929097, a Gamma-Secretase or Notch Inhibitor with or without Vismodegib, a Hedgehog Inhibitor, in Advanced Sarcoma

PDF file - 1MB, Integrated analysis of copy number alterations and gene expression arrays.

PDF file - 259K, Copy number alterations in well-differentiated liposarcoma.

PDF file - 431K, Copy number alterations in dedifferentiated liposarcoma.

Purpose:This phase Ib trial was designed to evaluate the safety and early efficacy signal of the combination of imatinib and binimetinib in patients with imatinib-resistant advanced gastrointestinal stromal tumors (GISTs).Patients and Methods:This trial used a standard 3 + 3 design to determine the recommended phase II dose (RP2D). Additional patients were enrolled on an expansion cohort at the RP2D enriching for succinate dehydrogenase (SDH)-deficient GISTs to explore potential efficacy.Results:The trial enrolled nine patients in the dose-escalation cohort and 14 in the dose-expansion cohort including six with SDH-deficient GISTs. Imatinib 400 mg daily with binimetinib 45 mg twice daily was established as the RP2D. Dose-limiting toxicity (DLT) was asymptomatic grade 4 creatinine phosphokinase (CPK) elevation. The most common non-DLT grade 3/4 toxicity was asymptomatic CPK elevation (69.6%). Other common ≥grade 2 toxicities included peripheral edema (17.4%), acneiform rash (21.7%), anemia (30.4%), hypophosphatemia (39.1%), and aspartate aminotransferase (AST) increase (17.4%). Two serious adverse events occurred (grade 2 dropped head syndrome and grade 3 central retinal vein occlusion). No unexpected toxicities were observed. Limited clinical activity was observed in KIT-mutant GIST. For SDH-deficient GISTs, one of five had confirmed RECIST1.1 partial response (PR). The median progression-free survival (mPFS) in patients with SDH-deficient GIST was 45.1 months [95% confidence interval (CI), 15.8–not estimable (NE)]; the median overall survival (mOS) was not reached (95% CI, 31.6 months–NE). One patient with a refractory metastatic SDH-deficient GIST had an exceptional pathologic response and durable clinical benefit.Conclusions:The combination of imatinib and binimetinib is safe with manageable toxicity and has encouraging activity in SDH-deficient but not imatinib-refractory KIT/PDGFRA-mutant GISTs. The observed clinical benefits provide a motivation for a larger trial of the combination strategy in SDH-deficient GISTs.

Purpose: Because the Hedgehog and Notch pathways are often overexpressed in mesenchymal malignancies, we evaluated the efficacy of concurrent inhibition of Notch and Hedgehog signaling using the gamma-secretase inhibitor (GSI) RO4929097 and the smoothened antagonist vismodegib in unresectable or metastatic sarcoma. Patients and Methods: In this investigator-initiated trial, phase Ib used standard 3+3 dose escalation in which patients first received vismodegib once daily for 21 days, followed by the combination of RO4929097 concurrently with vismodegib in 21-day cycles. In phase II, patients were randomized to RO4929097 alone or in combination with vismodegib. Results: Nine patients were treated in phase Ib with no dose-limiting toxicities. RO4929097 at 15 mg daily in combination with 150 mg daily of vismodegib was declared the recommended phase II dose. Most adverse events were grade ≤ 2. In phase II (closed early due to discontinuation of RO4929097 evaluation), 34 patients were randomized to RO4929097 alone and 33 to RO4929097 plus vismodegib. RO4929097 did not interfere with the steady-state concentration of vismodegib, while vismodegib reduced the plasma concentration of RO492909. No patients had an objective response. Neither progression-free nor overall survival differed significantly between treatment arms. Paired tumor biopsies from a subset of patients demonstrated inhibition of cleaved Notch. Conclusions: The combination of RO4929097 plus vismodegib was generally well tolerated. Although accrual to this study was not completed, vismodegib did not meaningfully enhance the clinical efficacy of RO4929097 in an unplanned analysis. GSIs and GSIs plus vismodegib can inhibit intratumoral Notch and downstream phosphorylated Akt signaling.

Purpose: This phase Ib trial was designed to evaluate the safety and early efficacy signal of the combination of imatinib and binimetinib in patients with imatinib-resistant advanced gastrointestinal stromal tumors (GISTs). Patients and Methods: This trial used a standard 3 + 3 design to determine the recommended phase II dose (RP2D). Additional patients were enrolled on an expansion cohort at the RP2D enriching for succinate dehydrogenase (SDH)-deficient GISTs to explore potential efficacy. Results: The trial enrolled nine patients in the dose-escalation cohort and 14 in the dose-expansion cohort including six with SDH-deficient GISTs. Imatinib 400 mg daily with binimetinib 45 mg twice daily was established as the RP2D. Dose-limiting toxicity (DLT) was asymptomatic grade 4 creatinine phosphokinase (CPK) elevation. The most common non-DLT grade 3/4 toxicity was asymptomatic CPK elevation (69.6%). Other common ≥grade 2 toxicities included peripheral edema (17.4%), acneiform rash (21.7%), anemia (30.4%), hypophosphatemia (39.1%), and aspartate aminotransferase (AST) increase (17.4%). Two serious adverse events occurred (grade 2 dropped head syndrome and grade 3 central retinal vein occlusion). No unexpected toxicities were observed. Limited clinical activity was observed in KIT-mutant GIST. For SDH-deficient GISTs, one of five had confirmed RECIST1.1 partial response (PR). The median progression-free survival (mPFS) in patients with SDH-deficient GIST was 45.1 months [95% confidence interval (CI), 15.8–not estimable (NE)]; the median overall survival (mOS) was not reached (95% CI, 31.6 months–NE). One patient with a refractory metastatic SDH-deficient GIST had an exceptional pathologic response and durable clinical benefit. Conclusions: The combination of imatinib and binimetinib is safe with manageable toxicity and has encouraging activity in SDH-deficient but not imatinib-refractory KIT/PDGFRA-mutant GISTs. The observed clinical benefits provide a motivation for a larger trial of the combination strategy in SDH-deficient GISTs.

Desmoid fibromatosis is a rare disease caused by genetic alterations that activate β-catenin. The tumors were previously treated with aggressive surgeries but do not metastasize and may regress spontaneously. For these reasons, in the absence of symptoms and when growth would not induce significant complications, active observation is considered first-line therapy. When intervention is required, surgery can be considered based on anatomy and risk of postoperative recurrence, but increasingly nonoperative therapies such as liposomal doxorubicin or sorafenib are prescribed. Cryoablation, chemoembolization, and high-intensity focused ultrasound can also be used to obtain local control in selected patients.

Desmoid tumor is considered a benign neoplasm, yet substantial morbidity can result from local invasion of structures adjacent to the tumor or from complications related to its treatment. We report two patients with extremity desmoid tumor who were each found at MRI to have an unsuspected pseudoaneurysm within their tumor after prior treatments (surgery and systemic therapy in one, surgery alone in the other). Such a pseudoaneurysm probably results from weakening of an arterial wall by adjacent desmoid tumor, as well as from local trauma. Due to the potential risk for life-threatening rupture of a pseudoaneurysm, one patient underwent surgical repair and the other, coil embolization. To our knowledge the presence of pseudoaneurysm has been reported within a few cases of abdominal desmoid tumor but not within an extremity desmoid tumor. This diagnosis has not been reported to have been made at MRI, either.

Desmoid-type fibromatosis represents a challenge in the landscape of surgical oncology, for several reasons. The tumors can be infiltrative and locally aggressive, surgery may be morbid, and patients are usually young, and thus treatment sequelae must be managed for decades. Desmoids do not have metastatic potential, therefore management strategies for desmoids have evolved to employ frontline treatments that are largely non-operative. In fact, with unpredictable and benign behavior, we now recognize that desmoids can also stabilize and regress, making active observation an option for many patients. Moreover, many medical therapies are active in the disease. We reviewed landmark studies describing contemporary issues that affect treatment recommendations for desmoid patients: prognostic factors, indication to active surveillance, role of surgical margins, postoperative radiotherapy, and the most recent expert consensus papers.

PURPOSE Dual targeting of the gastrointestinal stromal tumor (GIST) lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical efficacy. This trial was designed to test the efficacy and safety of imatinib plus binimetinib in first-line treatment of GIST. METHODS In this trial ( NCT01991379 ), treatment-naive adult patients with confirmed advanced GISTs received imatinib (400 mg once daily) plus binimetinib (30 mg twice daily), 28-day cycles. The primary end point was RECIST1.1 best objective response rate (ORR; complete response plus partial response [PR]). The study was designed to detect a 20% improvement in the ORR over imatinib alone (unacceptable rate of 45%; acceptable rate of 65%), using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1, and a planned sample size of 44 patients. Confirmed PR or complete response in > 24 patients are considered positive. Secondary end points included Choi and European Organisation for Research and Treatment of Cancer Response Rate, progression-free survival (PFS), overall survival (OS), pathologic responses, and toxicity. RESULTS Between September 15, 2014, and November 15, 2020, 29 of 42 evaluable patients with advanced GIST had confirmed RECIST1.1 PR. The best ORR was 69.0% (two-sided 95% CI, 52.9 to 82.4). Thirty-nine of 41 (95.1%) had Choi PR approximately 8 weeks. Median PFS was 29.9 months (95% CI, 24.2 to not estimable); median OS was not reached (95% CI, 50.4 to not estimable). Five of eight patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response (≥ 90% treatment effect). There were no unexpected toxicities. Grade 3 and 4 toxicity included asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%). CONCLUSION The study met the primary end point. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of GIST.

OBJECTIVE The aim of this study was to identify predictors of desmoid progression during observation. SUMMARY OF BACKGROUND DATA Untreated desmoids can grow, remain stable, or regress, but reliable predictors of behavior have not been identified. METHODS Primary or recurrent desmoid patients were identified retrospectively from an institutional database. In those managed with active observation who underwent serial magnetic resonance imaging (MRIs) with T2-weighted sequences, baseline tumor size was recorded, and 2 radiologists independently estimated the percentage of tumor volume showing hyperintense T2 signal at baseline. Associations of clinical or radiographic characteristics with progression-free survival (PFS; by RECIST) were evaluated by Cox regression and Kaplan-Meier statistics. RESULTS Among 160 patients with desmoids, 72 were managed with observation, and 37 of these had serial MRI available for review. Among these 37 patients, median age was 35 years and median tumor size was 4.7 cm; all tumors were extra-abdominal (41% in abdominal wall). Although PFS was not associated with size, site, or age, it was strongly associated with hyperintense T2 signal in ≥90% versus

To evaluate the feasibility, efficacy, and safety of doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) as an alternative local treatment for extra-abdominal desmoid tumors (DTs).Eleven adult female patients (mean age = 40.1 years) with symptomatic, progressively enlarging extra-abdominal DTs were determined ineligible for cryoablation after failing observation or systemic therapy and treated with a single session doxorubicin DEB-TACE. Six rectus sheath, one chest wall, three axilla, and one upper extremity DTs were included. The median follow-up was 155.0 ± 52.3 days. Treatment response was assessed by MRIs and maximum visual analog scale (VAS).All procedures were technically successful without immediate complications. The average size of treated DT was 161.8 ml (range: 28.3-420.0 ml). The mean doxorubicin dose was 13.3 mg/mDEB-TACE may be a safe and effective local treatment alternative in DT patients.

The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analyses analysis of 2,138 sarcomas representing 45 pathological entities. This cohort was prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations were in cell cycle control andTP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations includedTERTamplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varied between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.

Despite anatomical differences, truncal soft tissue sarcomas (STS) often are grouped with extremity sarcomas. We evaluated the clinical outcome of patients with truncal STS who underwent gross total resection (GTR) and radiation therapy (RT), with special emphasis on those treated with intensity modulated radiation therapy (IMRT). From January 1, 2001 to December 31, 2018, 64 patients received GTR and RT, where 48 patients were male, 35 patients were aged ≤ 60 years, and 48 patients had tumors ≤ 10 cm. Sixty-two tumors were high grade, 36 were in the chest wall, 7 in the abdominal wall, and 21 were paraspinal. During surgery, 7 received mesh reconstruction, and 6 received flap closure. R0 resection was achieved in 53 patients. Thirteen patients received chemotherapy. With a median follow-up of 57 months, the 5-year actuarial local control (LC) was 71%. In the IMRT subset (50/64, 78%), the 5-year LC for the chest/abdominal wall was 84%, and 69% for the paraspinal subsite. Grade 2+ radiation dermatitis was seen in 21 of 64 (33%) patients, 5 of 64 (8%) developed noninfectious wound complications, 5 of 64 (8%) developed infectious wound complications, and 1 of 64 (2%) developed grade 2 chest wall pain. No additional grade 2+ late toxicity was observed. Based on this study, achieving LC in truncal STS treated with GTR and RT remains challenging even with IMRT (5-year LC: 78%). While the use of IMRT was more promising for tumors of the chest/abdominal wall with 5-year LC of 84%, it was 69% for those located in the paraspinal subsite, indicating a need for further improvement.

Introduction: While activation of beta-catenin is associated with desmoid fibromatosis (DF), mechanisms by which this oncogene initiates tumorigenesis are unclear as are factors underlying variable biologic behavior in the disease and vulnerability to targeted therapies. This study sought to define downstream pathways dysregulated by beta-catenin that may be modulated to potentially affect patient outcome. Methods: Multiple primary DF cell lines were developed from surgical specimens, validated by Sanger sequencing, and immortalized by ectopic expression of TERT. Gene expression was assessed in DF tumors (n=45) with U133A arrays and by RNA-seq in cells. Direct targets of beta-catenin were identified by CHIP-seq. Lentiviral systems were used to deliver shRNA (or scramble control) and overexpression constructs. Cell proliferation, protein levels/phosphorylation and gene expression were assessed by CyQuant DNA quantification, immunoblot, and RT-PCR, respectively. Endothelial cell (HUVEC) tube formation was quantitated using light microscopy. Results: Gene set enrichment analysis performed on RNA-seq data comparing DF cells treated with shRNA directed against CTNNB1 showed downregulation of hypoxia-regulated genes, and unsupervised analysis clustered 45 DF tumors separately from normal mesenchymal tissue based on the expression levels of these genes. CTNNB1 knockdown (KD) was associated with reduction in HIF1A and ability of DF cells to induced endothelial tube formation in HUVEC co-cultures (71%, p Citation Format: Jia Hu, Anthony Villano, Rachael O'Connor, Yuliy Rozenberg, Alankrta Venkatesh, Mrinal Gounder, Nicholas Socci, Samuel Singer, Meera Hameed, Aimee M. Crago. Growth factor signaling and kinase inhibitors regulate oncogenesis in desmoid fibromatosis by modulating activity of the beta-catenin transcription target ABL1 [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A028.

Objective To characterize the results of surgery for gastrointestinal stromal tumor (GIST) in the pre and post-imatinib eras at a single institution and to identify current prognostic clinicopathologic factors. Background Imatinib has radically changed the management of GIST, yet the magnitude of impact on outcome across the spectrum of GIST presentation and relevance of historical prognostic factors are not well defined. Methods We retrospectively analyzed 1000 patients who underwent surgery for GIST at our institution from 1982 to 2016. Patients were stratified by presentation status as primary tumor only (PRIM), primary with synchronous metastasis (PRIM + MET), or metachronous recurrence/metastases (MET), and also imatinib era (before and after it became available). Cox proportional-hazard models and Kaplan-Meier methods were used to model and estimate overall survival (OS) and recurrence-free survival (RFS). Results OS was longer in the imatinib era compared with the pre-imatinib era in each presentation group, including in Miettinen high-risk primary tumors. Among PRIM patients from the pre-imatinib era, tumor site, size, and mitotic rate were independently associated with OS and RFS on multivariate analysis. PRIM patients in the imatinib era who received imatinib (neoadjuvant and/or adjuvant) had higher risk tumors, but after adjusting for treatment, only size >10 cm remained independently prognostic of RFS [hazard ratio (HR) 3.85, 95% confidence interval (CI) 2.00-7.40, P Conclusions Patients treated in the imatinib era had prolonged OS across all presentations. In the imatinib era, among site, size, and mitotic rate, high-risk features were associated with treatment with the drug, but only size >10 cm correlated with outcome. Imatinib should still be prescribed for patients with high-risk features.

This study was designed to compare the observed risk of femoral fracture in primary soft-tissue sarcoma (STS) of the thigh/groin treated with intensity-modulated radiation therapy (IMRT) to expected risk calculated using the Princess Margaret Hospital (PMH) nomogram.Expected femoral fracture risk was calculated by using the PMH nomogram. Cumulative risk of fracture was estimated by using Kaplan-Meier statistics. Prognostic factors were assessed with univariate and multivariate analysis using Cox's stepwise regression.Between February 2002 and December 2010, 92 consecutive eligible patients were assessed. Median follow-up was 73 months (106 months in surviving patients). IMRT was delivered preoperatively (50 Gy) in 13 (14%) patients and postoperatively in 79 (86%) patients (median dose, 63 Gy; range, 59.4-66.6 Gy). The observed crude risk of fractures was 6.5% compared with 25.6% expected risk from the nomogram; the cumulative risk of fracture using IMRT at 5 years was 6.7% (95% CI 2.8-16.0%). The median time to fracture was 23 months (range, 6.9-88.6). Significant predictors of fracture on univariate analysis were age ≥ 60 years (p = 0.03), tumor location in the anterior thigh (p = 0.008), and periosteal stripping to 20 cm (p 0.0001). On multivariate analysis, age ≥ 60 years and periosteal stripping 20 cm retained significance (p = 0.04 and p = 0.009, respectively).In this study, the cumulative risk of femur fracture in patients treated with IMRT (6.7%) is less than the expected risk using the PMH nomogram (25.6%). Established predictors of femur fracture, such as gender, tumor size, and dose of RT, seem to have less impact on fracture risk when using IMRT.

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P, There is an unmet clinical need for simple, accessible biomarkers to select patients who are more likely to respond to immune checkpoint therapy. Here the authors show that a lower neutrophil-to-lymphocyte ratio is associated with better overall and progressive-free survival, as well as higher rate of response, in a multi-cancer cohort of patients treated with immune checkpoint inhibitors.

Desmoid tumor is considered a benign neoplasm, yet substantial morbidity can result from local invasion of structures adjacent to the tumor or from complications related to its treatment. We report two patients with extremity desmoid tumor who were each found at MRI to have an unsuspected pseudoaneurysm within their tumor after prior treatments (surgery and systemic therapy in one, surgery alone in the other). Such a pseudoaneurysm probably results from weakening of an arterial wall by adjacent desmoid tumor, as well as from local trauma. Due to the potential risk for life-threatening rupture of a pseudoaneurysm, one patient underwent surgical repair and the other, coil embolization. To our knowledge the presence of pseudoaneurysm has been reported within a few cases of abdominal desmoid tumor but not within an extremity desmoid tumor. This diagnosis has not been reported to have been made at MRI, either.

Soft tissue sarcoma (STS) refers to a rare group of cancers that develop from mesenchymal cells and their progenitors. Histologic subtype, in conjunction with tumor location and size, largely defines the biologic behavior of a given lesion and the associated clinical prognosis in these cancers. The diverse characteristics of these tumors means that their treatment is similarly complex. The etiology, tumor staging and prognosis, evaluation, and treatment of STS are discussed in this review, with an aim to present an algorithm for patient evaluation and treatment while highlighting common indications for diverging from this strategy as dictated by disease subtype and location. Figures show the histologic distribution of primary STS diagnosed in the extremity and retroperitoneum and intra-abdominal compartments; disease-specific survival for primary extremity and retroperitoneal and intra-abdominal tumors stratified by histologic subtype; local recurrence in primary extremity STS stratified by histologic subtype; disease-specific survival according to American Joint Committee on Cancer (AJCC) TNGM stage; a postoperative nomogram for prediction of sarcoma-specific death at 12 years postresection for patients with STS; representative cross-sectional images of an atypical lipomatous tumor, a myxofibrosarcoma, and a desmoid tumor; a treatment algorithm for STS of the extremity; a magnetic resonance image and intraoperative photographs showing a mixoid liposarcoma of the posterior thigh; and computed tomography showing a retroperitoneal dedifferentiated liposarcoma and a photograph of the surgical bed following resection. This review contains 10 figures, 12 tables, and 49 references. Keywords: Sarcoma, soft tissue, cancer, myxofibrosarcoma, leiomyosarcoma, liposarcoma, gastrointestinal stromal tumor, rhabdomyosarcoma

PURPOSE. The aim of this study was to determine outcomes and prognostic factors for patients with primary and locally recurrent extraabdominal desmoid tumors who underwent percutaneous cryoablation, and to compare with patients treated with surgery. METHODS. Group characteristics were compared using Fisher’s exact test, and propensity score matching was performed using the nearest-neighbor approach. Kaplan–Meier and log-rank analyses were used to evaluate the variation in first local recurrence and disease control, while multivariate Cox regression was used to identify factors associated with first local recurrence. All statistical tests were two-sided and a p-value of 0.05 was considered statistically significant. RESULTS. Twenty-two cryoablation patients were matched with 33 surgical patients (n = 55). Median follow-up after cryoablation was 16.3 months versus 14.9 months after surgery. Two-year local recurrence-free survival (LRFS) was 59% after cryoablation and 71% after surgery, and median LRFS was 26.6 months after cryoablation but was not reached after surgery. Two-year disease control for all patients was 85%, however median disease control was not reached in either the cryoablation or surgery groups. There was no significant difference in LRFS or disease control between matched cryoablation and surgical patients. No local recurrences occurred after the first cryoablation in patients with zero or one of the following risk factors: tumor size > 5 cm, age ≤ 25 years, or locally recurrent disease. All patients with two or more of these risk factors recurred locally after the first cryoablation. CONCLUSION. Percutaneous cryoablation of primary and locally recurrent extra-abdominal desmoid tumors provides freedom from first local recurrence and long-term disease control comparable with surgery.