Publications by authors named "Scott H Okuno"

70 Publications

Teaching NeuroImages: Brain and Skin Involvement in Erdheim-Chester Disease.

Neurology 2021 03 9;96(11):e1590-e1592. Epub 2020 Nov 9.

From the Departments of Neurology (A.B., D.D., W.O.T.), Pathology (K.L.R.), and Medicine (R.S.G.), Division of Hematology/Oncology, Mayo Clinic, Rochester, MN; and the Department of Medicine, Division of Dermatology (J.M.P.), and Medical Oncology (S.H.O.), Mayo Clinic Health System, Eau Claire, WI.

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http://dx.doi.org/10.1212/WNL.0000000000011159DOI Listing
March 2021

A Case Series of Long-Term Surgical Outcomes of Primary Pulmonary Artery Sarcomas With Opportunities for 3D-Printed Models in Surgical Planning.

Innovations (Phila) 2021 Jan-Feb;16(1):94-100. Epub 2020 Oct 20.

12346 Division of General Thoracic Surgery, Mayo Clinic, Rochester, MN, USA.

There are limited data regarding the surgical management of primary pulmonary artery sarcomas (PPAS) because of their rarity and complicated diagnostic history. The objective of this study was to analyze our institution's long-term surgical management outcomes for PPAS in the absence of a care pathway. From May 1997 to June 2013, 8 patients (mean age 60.6 ± 11.8 years; range, 40-73 years; 5 women and 3 men) underwent surgical intervention for PPAS at our institution. The most common computed tomography finding was a luminal filling defect obstructing the pulmonary artery (PA), without evidence of extraluminal extension. Three patients underwent debulking/pulmonary endarterectomy alone and 5 patients underwent a more radical resection with PA patch angioplasty, PA resection and reconstruction, pulmonary valve replacement, and unilateral pneumonectomy. The mean postoperative survival in this series was 3.8 ± 3.6 years (range, 1-11.9 years), with 2 radical surgical resection patients alive at 4.9 and 11.9 years, respectively. For those patients with incomplete resection, 3-dimensional (3D) models were created to demonstrate the advantage of a preoperative guide for a more complete resection and what it would entail. Six patients had local recurrences with mean disease-free interval of 14 ± 10.9 months (range, 2 months-2.5 years), and 2 patients with re-resections had an overall postoperative survival of 2.8 and 11.9 years, respectively. In our small cohort of PPAS, patients treated with radical surgical resection had better survival. The small number of PPAS cases in this series makes proving this association unlikely but warrants consideration.
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http://dx.doi.org/10.1177/1556984520960716DOI Listing
October 2020

Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial.

Lancet Oncol 2020 08 20;21(8):1110-1122. Epub 2020 Jul 20.

Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA.

Background: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone.

Methods: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867.

Findings: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3-1·6) in the pazopanib group and 1 year (0·3-1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5-55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related.

Interpretation: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up.

Funding: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.
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http://dx.doi.org/10.1016/S1470-2045(20)30325-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745646PMC
August 2020

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Regorafenib Versus Placebo in Advanced/Metastatic, Treatment-Refractory Liposarcoma: Results from the SARC024 Study.

Oncologist 2020 11 20;25(11):e1655-e1662. Epub 2020 Aug 20.

Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Lessons Learned: The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist.

Background: Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients.

Methods: Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3 weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1.

Results: Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92-3.67) months for regorafenib versus 2.07 (95% CI, 1.64-3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16-23.48) months for regorafenib and 4.89 (95% CI, 3.02-9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31-1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib.

Conclusion: Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.
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http://dx.doi.org/10.1634/theoncologist.2020-0679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648334PMC
November 2020

Results of a Randomized, Double-Blinded, Placebo-Controlled, Phase 2.5 Study of Saracatinib (AZD0530), in Patients with Recurrent Osteosarcoma Localized to the Lung.

Sarcoma 2020 30;2020:7935475. Epub 2020 Apr 30.

Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California Children's Hospital Los Angeles, 4650 Sunset Blvd Mail Stop 57, Los Angeles, CA 90027, USA.

Purpose: Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. . Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles.

Results: Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (=0.47). Median OS was not reached in either arm.

Conclusions: Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.
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http://dx.doi.org/10.1155/2020/7935475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211262PMC
April 2020

Clinical outcomes of patients with advanced synovial sarcoma or myxoid/round cell liposarcoma treated at major cancer centers in the United States.

Cancer Med 2020 07 6;9(13):4593-4602. Epub 2020 May 6.

Mayo Clinic, Jacksonville, FL, USA.

Background: Outcomes data regarding advanced synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are limited, consisting primarily of retrospective series and post hoc analyses of clinical trials.

Methods: In this multi-center retrospective study, data were abstracted from the medical records of 350 patients from nine sarcoma centers throughout the United States and combined into a registry. Patients with advanced/unresectable or metastatic SS (n = 249) or MRCL (n = 101) who received first-line systemic anticancer therapy and had records of tumor imaging were included. Overall survival (OS), time to next treatment, time to distant metastasis, and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox regression.

Results: At start of first-line systemic anticancer therapy, 92.4% of patients with SS and 91.1% of patients with MRCL had metastatic lesions. However, 74.7% of patients with SS and 72.3% of patients with MRCL had ≥2 lines of systemic therapy. Median OS and median PFS from first-line therapy for SS was 24.7 months (95% CI, 20.9-29.4) and 7.5 months, respectively (95% CI, 6.4-8.4). Median OS and median PFS from start of first-line therapy for MRCL was 29.9 months (95% CI, 27-44.6) and 8.9 months (95% CI 4.5-12.0).

Conclusions: To the best of our knowledge, this is the largest retrospective study of patients with SS and MRCL. It provides an analysis of real-world clinical outcomes among patients treated at major sarcoma cancer centers and could inform treatment decisions and design of clinical trials. In general, the survival outcomes for this selected population appear more favorable than in published literature.
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http://dx.doi.org/10.1002/cam4.3039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333839PMC
July 2020

Assessment of Familiarity With Work-up Guidelines for Bone and Soft Tissue Sarcoma Among Primary Care Practitioners in Minnesota.

Mayo Clin Proc Innov Qual Outcomes 2020 Apr 18;4(2):143-149. Epub 2020 Mar 18.

Mayo Clinic Alix School of Medicine, Rochester, MN.

Objective: To assess familiarity with sarcoma guidelines among primary care practitioners (PCPs) in Minnesota.

Participants And Methods: Surveys were distributed at 2 educational conferences held in Minnesota on April 16-17, 2015, and October 24, 2015. The PCPs were asked a series of questions about their current practice, past experience with sarcoma, and familiarity with sarcoma guidelines. They were then given a series of case presentations and asked to indicate if they would pursue a sarcoma work-up given the information provided.

Results: The study group included 80 physicians and 32 nurse practitioners (NPs). Over their careers (median, 14 years), physicians reported seeing a mean of 2.2 cases of soft tissue sarcoma and 0.7 cases of bone sarcoma. The NPs reported seeing a mean of 0.7 and 0.2 cases, respectfully, over their careers (median, 8 years). Both physicians and NPs reported low familiarity with sarcoma guidelines. When challenged with case presentations for which urgent referral to a sarcoma specialist is recommended, more than 50% of PCPs did not indicate that they would refer patients. The PCPs who had previous experience with soft tissue sarcoma and bone sarcoma estimated that only 17% and 23% of their patients, respectively, were diagnosed within 1 month of presentation. The most reported reason for a delayed diagnosis was the PCP advising the patient to "watch and wait."

Conclusion: Minnesota PCPs have seen very few cases of sarcoma and report low familiarity with sarcoma guidelines. When challenged with case presentations, PCPs made decisions inconsistent with established guidelines. This study supports ongoing efforts to increase sarcoma awareness.
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http://dx.doi.org/10.1016/j.mayocpiqo.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140016PMC
April 2020

Targeting Refractory Sarcomas and Malignant Peripheral Nerve Sheath Tumors in a Phase I/II Study of Sirolimus in Combination with Ganetespib (SARC023).

Sarcoma 2020 30;2020:5784876. Epub 2020 Jan 30.

Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, USA.

Purpose: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas. Combining Hsp90 inhibitors to enhance endoplasmic reticulum stress with mTOR inhibition results in dramatic MPNST shrinkage in a genetically engineered MPNST mouse model. Ganetespib is an injectable potent small molecule inhibitor of Hsp90. Sirolimus is an oral mTOR inhibitor. We sought to determine the safety, tolerability, and recommended dose of ganetespib and sirolimus in patients with refractory sarcomas and assess clinical benefits in patients with unresectable/refractory MPNSTs. . In this multi-institutional, open-label, phase 1/2 study of ganetespib and sirolimus, patients ≥16 years with histologically confirmed refractory sarcoma (phase 1) or MPNST (phase 2) were eligible. A conventional 3 + 3 dose escalation design was used for phase 1. Pharmacokinetic and pharmacodynamic measures were evaluated. Primary objectives of phase 2 were to determine the clinical benefit rate (CBR) of this combination in MPNSTs. Patient-reported outcomes assessed pain.

Results: Twenty patients were enrolled (10 per phase). Toxicities were manageable; most frequent non-DLTs were diarrhea, elevated liver transaminases, and fatigue. The recommended dose of ganetespib was 200 mg/m intravenously on days 1, 8, and 15 with sirolimus 4 mg orally once daily with day 1 loading dose of 12 mg. In phase 1, one patient with leiomyosarcoma achieved a sustained partial response. In phase 2, no responses were observed. The median number of cycles treated was 2 (1-4). Patients did not meet the criteria for clinical benefit as defined per protocol. Pain ratings decreased or were stable.

Conclusion: Despite promising preclinical rationale and tolerability of the combination therapy, no responses were observed, and the study did not meet parameters for further evaluation in MPNSTs. This trial was registered with (NCT02008877).
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http://dx.doi.org/10.1155/2020/5784876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013290PMC
January 2020

Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab.

Clin Cancer Res 2020 03 3;26(6):1258-1266. Epub 2020 Jan 3.

Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment.

Patients And Methods: Pretreatment ( = 78) and 8-week on-treatment ( = 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti-PD-1 response.

Results: Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8 CD3 PD-1) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher densities of effector memory cytotoxic T cells and regulatory T cells compared with non-responders. In addition, higher density of cytotoxic tumor-infiltrating T cells at baseline correlated with a better progression-free survival (PFS).

Conclusions: We show that quantitative assessments of CD8 CD3 PD-1 T cells, percentage of TAMs expressing PD-L1, and other T-cell densities correlate with sarcoma response to pembrolizumab and improved PFS. Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti-PD-1 therapy in specific advanced sarcomas. Efforts to confirm the activity of pembrolizumab in an expansion cohort of patients with UPS/DDLPS are underway.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731262PMC
March 2020

Phase 1 trial of Vismodegib and Erlotinib combination in metastatic pancreatic cancer.

Pancreatology 2020 Jan 21;20(1):101-109. Epub 2019 Nov 21.

Schulze Center for Novel Therapeutics, Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background/objectives: Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients.

Methods: Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers.

Results: Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2-7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels.

Conclusions: Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.
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http://dx.doi.org/10.1016/j.pan.2019.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195700PMC
January 2020

Targeting Sporadic and Neurofibromatosis Type 1 (NF1) Related Refractory Malignant Peripheral Nerve Sheath Tumors (MPNST) in a Phase II Study of Everolimus in Combination with Bevacizumab (SARC016).

Sarcoma 2019 24;2019:7656747. Epub 2019 Jul 24.

Cincinnati Children's Hospital, 3333 Burnet Ave, Cincinnati, OH 45229, USA.

Purpose: There are no known effective medical treatments for refractory MPNST. Inactivation of the NF1 tumor suppressor in MPNST results in upregulation of mTOR (mammalian target of rapamycin) signaling and angiogenesis, which contributes to disease progression. We conducted a phase II study for patients (pts) with refractory MPNST combining everolimus (10 mg PO once daily) with bevacizumab (10 mg/kg IV every 2 weeks) to determine the clinical benefit rate (CBR) (complete response, partial response (PR), or stable disease (SD) ≥ 4 months).

Patients And Methods: Patients ≥18 years old with chemotherapy refractory sporadic or NF1 MPNST were eligible. Tumor response was assessed after every 2 cycles (the WHO criteria). A two-stage design targeting a 25% CBR was used: if ≥ 1/15 pts in stage 1 responded, enrollment would be expanded by 10 pts, and if ≥ 4/25 patients had clinical benefit, the combination would be considered active.

Results: Twenty-five pts, 17 with NF1 and 8 with sporadic MPNST, enrolled. One of 15 pts in stage 1 had clinical benefit. Of 10 additional pts enrolled, 2 had clinical benefit. The median number of completed cycles was 3 (range 1-16). Adverse events were similar to those known for this combination.

Conclusion: With a CBR of 12% (3/25), the combination of everolimus and bevacizumab did not reach the study's target response rate and is not considered active in refractory MPNST.
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http://dx.doi.org/10.1155/2019/7656747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681622PMC
July 2019

Oncolytic Measles Virotherapy and Opposition to Measles Vaccination.

Mayo Clin Proc 2019 09 22;94(9):1834-1839. Epub 2019 Jun 22.

Department of Molecular Medicine, Mayo Clinic, Rochester, MN.

Recent measles epidemics in US and European cities where vaccination coverage has declined are providing a harsh reminder for the need to maintain protective levels of immunity across the entire population. Vaccine uptake rates have been declining in large part because of public misinformation regarding a possible association between measles vaccination and autism for which there is no scientific basis. The purpose of this article is to address a new misinformed antivaccination argument-that measles immunity is undesirable because measles virus is protective against cancer. Having worked for many years to develop engineered measles viruses as anticancer therapies, we have concluded (1) that measles is not protective against cancer and (2) that its potential utility as a cancer therapy will be enhanced, not diminished, by prior vaccination.
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http://dx.doi.org/10.1016/j.mayocp.2019.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800178PMC
September 2019

Evaluating the Role of Adjuvant Radiotherapy in the Management of Sacral and Vertebral Chordoma: Results from a National Database.

World Neurosurg 2019 Jul 14;127:e1137-e1144. Epub 2019 Apr 14.

Department of Neurologic Surgery, Mayo Clinic Neuro-Informatics Laboratory, Mayo Clinic, Rochester, Minnesota, USA; Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Background: Chordomas are slow-growing but locally invasive tumors. The standard of care consists of surgical resection and radiotherapy (RT) when complete resection is not possible. The reported data has reached equivocal results regarding the effect of adding RT to increase patient survival. We investigated the effect of adjuvant RT on patient survival.

Methods: The National Cancer Database was queried for patients with a diagnosis of sacral and vertebral column chordoma from 2004 to 2010. The primary outcome was overall survival, which was assessed using Kaplan-Meier plots. Cox proportional hazards were performed to evaluate the effect of each treatment modality on survival after adjusting for an array of patient demographics, facility type, and tumor characteristics.

Results: The data from 282 patients with chordoma were analyzed; 209 patients (74.1%) had undergone gross total resection (GTR) alone. The median follow-up period for the GTR alone and GTR plus RT groups was 63.4 and 67.6 months, respectively. The mean survival was comparable between patients receiving GTR alone and those receiving adjuvant RT, for both sacral (7.7 and 6.9 years, respectively; P = 0.56) and vertebral chordoma (8.8 and 6.2 years, respectively; P = 0.59). Using Cox proportional hazards, we found that compared with GTR alone, GTR plus adjuvant RT did not add any significant survival benefit, for patients with either sacral chordoma (hazard ratio, 0.55; P = 0.43) or vertebral chordoma (hazard ratio, 7.29; P = 0.23).

Conclusion: Using data from a large national cancer registry, we found that the available evidence is not enough to suggest that the addition of RT offers a survival benefit for patients with sacral and spinal chordoma after GTR. Given the non-negligible complications associated with RT, the balance of benefits and risks must be considered during preoperative tailoring of the treatment decisions.
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http://dx.doi.org/10.1016/j.wneu.2019.04.070DOI Listing
July 2019

Inhibition of STAT3 blocks protein synthesis and tumor metastasis in osteosarcoma cells.

J Exp Clin Cancer Res 2018 Oct 4;37(1):244. Epub 2018 Oct 4.

Department of Orthopedic Surgery, 2-69 Medical Sciences, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

Background: Osteosarcoma is the most common bone cancer. Despite advances, molecular mechanisms associated with osteosarcoma have not been fully understood. Hence, an effective treatment for osteosarcoma has yet to be developed. Even though signal transducer and activator of transcription3 (STAT3) has been implicated, its role in pathogenesis of osteosarcoma is not fully determined. In this study, we investigated the antitumor effect of napabucasin (NP) (BBI608), an inhibitor of STAT3 on osteosarcoma in vitro and in vivo and studied the underlying molecular mechanism.

Methods: Cell viability, colony formation, apoptosis, tumor growth and metastasis assays were performed to examine the effect of NP on osteosarcoma in vitro and in vivo. Real-time RT-PCR, western analysis, immunofluorescence and reporter assays were used to monitor the expression and activity of proteins and underlying molecular pathways. Protein synthesis, co-immunoprecipitation and CAP binding assays were carried out to understand NP-mediated mechanism of actions in osteosarcoma cells.

Results: Our results show that NP treatment decreases cell viability and induces apoptosis in several osteosarcoma cell lines. NP treatment suppresses both expression and phosphorylation of STAT3 in addition to blocking STAT3-mediated transcription and downstream target proteins in osteosarcoma cells. Furthermore, NP inhibits protein synthesis through regulation of the eukaryotic initiation factor 4E (eIF4E) and eIF4E-binding protein 1 (4E-BP1). NP also inhibits the progression of osteosarcoma tumors and metastasis in vivo in an orthotopic tibial model of osteosarcoma.

Conclusions: Taken together, our investigation reveals that NP acts through a novel mechanism and inhibits osteosarcoma growth and metastasis, and could be investigated clinically for treating osteosarcoma patients alone or in combination with other drugs.
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http://dx.doi.org/10.1186/s13046-018-0914-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172747PMC
October 2018

Clinicopathologic features and outcomes of gastrointestinal stromal tumors arising from the esophagus and gastroesophageal junction.

J Gastrointest Oncol 2018 Aug;9(4):718-727

Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.

Background: Our aim was to characterize the clinicopathological features and outcomes of gastrointestinal stromal tumors (GISTs) arising from the esophagus and gastroesophageal junction (GEJ) and describe the survival of patients treated at our institution as well as from a national hospital-based registry.

Methods: Twenty-eight cases were identified using the Mayo Clinic Cancer Registry from 1997 to 2016, and 1,010 cases from the National Cancer Database (NCDB) between 2004 and 2014, with analysis of TNM staging, histopathological features, mitotic index, immunohistochemical studies, and KIT mutational analysis.

Results: At Mayo Clinic, the tumors ranged in size from 0.3-13 cm (mean 5.40 cm). IHC results were: CD117 () in 100% (23/23 cases) and DOG1 in 100% (6/6), followed by CD34 (85.7%, 12/14), smooth muscle actin (27.8%, 5/18), desmin (18.2%, 2/11), and S-100 protein (13.3%, 2/15). Mutational analysis (performed in 10 cases) showed exon 11 mutations in 8 cases; mutation was not identified in 2 cases (presumed wild-type). Two-thirds of patients underwent surgery, of which 70% had an esophagectomy. Fourteen patients received adjuvant imatinib mesylate. Five patients had liver metastases at the time of diagnosis; none had lymph node metastases. A total of 38.9% of cases had recurrent or metastatic disease. Complete clinical follow-up was available for 10 patients (median follow-up duration 31.5 months; range, 10-145 months): one (male) had a local recurrence at the anastomotic site and one (female) suffered a liver metastasis; the others were either disease-free or had stable disease at the time of last follow-up. There was a significant association seen among metastatic disease and mitotic count >5/50 high-powered field (HPF) (P=0.016), with median mitotic rate 90/50 HPF (range, 7-500) for metastatic tumors versus 6/50 HPF (range, 0-100) for non-metastatic tumors. For metastatic disease, median tumor size was 7.3 cm (range, 1-66 cm) compared to 4.8 cm (range, 0.02-71 cm) for non-metastatic disease, which was also statistically significant (P≤0.0001). Two hundred and fifty-eight NCDB cases were risk stratified using the Joensuu criteria. Among 89 low risk category tumors, only 2 (2.2%) were ultimately metastatic. A total of 10.9% (15/138) of high risk category tumors were metastatic. The median overall survival (OS) from the time of diagnosis for the Mayo Clinic cohort was 129.5 months (95% CI, 55.7-not reached), with 5-year OS 85.7%. Median OS for the NCDB cohort was 135.95 months (95% CI, 104.08-not reached) with 5-year OS 68.2%. Superior OS was seen in females (HR 0.67, 95% CI, 0.49-0.89, P=0.006).

Conclusions: Among esophageal and GEJ GISTs, metastatic disease was associated with increased mitotic count and increased tumor size. Men were found to have inferior OS. The Joensuu risk criteria were validated for risk stratification of esophageal and GEJ GISTs.
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http://dx.doi.org/10.21037/jgo.2018.04.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087867PMC
August 2018

Decreased local and systemic levels of sFRP3 protein in osteosarcoma patients.

Gene 2018 Oct 19;674:1-7. Epub 2018 Jun 19.

Dept. of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA. Electronic address:

Osteosarcoma is a malignant bone tumor that occurs mainly in children and adolescents. Because Wnt signaling has been implicated in the pathogenesis of osteosarcoma, we have investigated the circulating and local levels of the Wnt antagonist protein, Secreted Frizzled Related Protein (sFRP) 3, in osteosarcoma patients. Enzyme linked immunosorbent assay (ELISA) analysis of 67 osteosarcoma and age-matched non-diseased control sera showed that sFPR3 protein levels were significantly lower in osteosarcoma than in normal. Analysis of tumor and adjacent normal tissues (9 pairs) from osteosarcoma patients showed a decrease in sFRP3 expression in 5 out of 9 tumor samples compared to normal tissues. Furthermore, immunohistochemical analysis of tissue microarray revealed a significant decrease in sFRP3 levels in tumor compared to normal bone. RNA sequencing analysis in osteosarcoma cells shows suppression of sFRP3 and concomitant expression of multiple Wnt family members mediating canonical or non-canonical Wnt signaling. Taken together, our findings show that the systemic and local levels of sFRP3 protein are downregulated in osteosarcoma and sFRP3 levels could be explored further in the diagnosis and the care of osteosarcoma patients.
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http://dx.doi.org/10.1016/j.gene.2018.06.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086756PMC
October 2018

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial.

Lancet Oncol 2017 11 4;18(11):1493-1501. Epub 2017 Oct 4.

University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed pembrolizumab, an anti-PD-1 antibody, for safety and activity in patients with advanced soft-tissue sarcoma or bone sarcoma.

Methods: In this two-cohort, single-arm, open-label, phase 2 study, we enrolled patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years or older to enrol; patients with bone sarcoma could enrol if they were aged 12 years or older. Patients had histological evidence of metastatic or surgically unresectable locally advanced sarcoma, had received up to three previous lines of systemic anticancer therapy, had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors version 1.1, and had at least one lesion accessible for biopsy. All patients were treated with 200 mg intravenous pembrolizumab every 3 weeks. The primary endpoint was investigator-assessed objective response. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the activity analysis. Accrual is ongoing in some disease cohorts. This trial is registered with ClinicalTrials.gov, number NCT02301039.

Findings: Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). Median follow-up was 17·8 months (IQR 12·3-19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had an objective response, including four (40%) of ten patients with undifferentiated pleomorphic sarcoma, two (20%) of ten patients with liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients with bone sarcoma had an objective response, including one (5%) of 22 patients with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of the 13 patients with Ewing's sarcoma had an objective response. The most frequent grade 3 or worse adverse events were anaemia (six [14%]), decreased lymphocyte count (five [12%]), prolonged activated partial thromboplastin time (four [10%]), and decreased platelet count (three [7%]) in the bone sarcoma group, and anaemia, decreased lymphocyte count, and prolonged activated partial thromboplastin time in the soft-tissue sarcoma group (three [7%] each). Nine (11%) patients (five [12%] in the bone sarcoma group and four [10%] in the soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), five of whom had immune-related SAEs, including two with adrenal insufficiency, two with pneumonitis, and one with nephritis.

Interpretation: The primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment to expanded cohorts of those subtypes is ongoing to confirm and characterise the activity of pembrolizumab.

Funding: Merck, SARC, Sarcoma Foundation of America, QuadW Foundation, Pittsburgh Cure Sarcoma, and Ewan McGregor.
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http://dx.doi.org/10.1016/S1470-2045(17)30624-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939029PMC
November 2017

Olaratumab for the treatment of advanced soft tissue sarcoma.

Expert Rev Anticancer Ther 2017 10 8;17(10):883-887. Epub 2017 Sep 8.

a Department of Oncology , Mayo Clinic , Rochester , MN USA.

Introduction: Olaratumab, a human monoclonal antibody against platelet derived growth factor receptor alpha (PDGFR- α), is the first drug that in combination with doxorubicin for the treatment of patients with advanced/metastatic soft tissue sarcoma (STS) that has showed an improved overall survival compared to doxorubicin alone. These initial results are exciting and have the potential to change the landscape of treatment for patients with STS. Areas covered: This article reviews the development of olaratumab for oncology use by reviewing articles in PubMed for 'platelet derived growth factor' and 'receptor' and 'soft tissue sarcoma'. We provide an overview of the published studies to date for olaratumab and specifically the use in soft tissue sarcoma. Expert commentary: Olaratumab is a well-tolerated drug that, when combined with doxorubicin, has shown an improved overall survival compared to doxorubicin alone and the phase III confirmatory study is eagerly awaited.
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http://dx.doi.org/10.1080/14737140.2017.1374857DOI Listing
October 2017

Characteristics and long-term outcomes of head and neck squamous cell carcinoma after solid organ transplantation.

Oral Oncol 2017 09 17;72:104-109. Epub 2017 Jul 17.

Division of Medical Oncology, Mayo Clinic, Rochester, MN, United States.

Introduction: Immunosuppression after solid organ transplant prevents graft rejection, but leads to increased incidence of various malignancies including head and neck squamous cell carcinoma (HNSCC). Outcomes of patients with post-transplant HNSCC are unknown.

Materials And Methods: We retrospectively identified patients who developed HNSCC after solid organ transplant between 1995 and 2010. Adults with pathology-proven HNSCC and adequate follow up were included. Median overall survival and progression free survival were analyzed using the Kaplan-Meier method. The prognostic effect of variables was studied with Cox proportional hazards models.

Results: Thirty-three patients met study inclusion criteria. The median time to diagnosis of HNSCC after transplant was 5.9years. The primary site was oral cavity in 15 patients, oropharynx in 10, larynx in 3, hypopharynx in 2, parotid in 2 and unknown in 1 patient. Eighty-eight percent underwent upfront surgical resection. Of those, sixty-six percent received adjuvant therapy. Six percent of patients had definitive chemoradiation. Treatment was well tolerated and did not lead to graft rejection. The 5-year overall survival rate was 45% and 37% for localized and locally advanced disease respectively. Seventy-five percent of patients with oropharyngeal tumors were HPV-positive and they had better outcomes (5-year overall survival rate of 67%). In multivariate analysis, age ≥60years was a negative predictor of survival (HR 2.7; 95% CI, 1.1-6.5; P=0.03).

Conclusions: Patients with post-transplant HNSCC have relatively poor survival and high risk of locoregional and distant recurrence. HPV- positive oropharyngeal tumors continue to have better outcomes in this population.
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http://dx.doi.org/10.1016/j.oraloncology.2017.07.010DOI Listing
September 2017

Extraskeletal Osteosarcoma: Outcomes and the Role of Chemotherapy.

Am J Clin Oncol 2018 09;41(9):832-837

Division of Medical Oncology.

Objectives: Extraskeletal osteosarcoma (EO) is a malignant neoplasm that produces osteoid, bone, and chondroid material without direct attachment to bone or periosteum. Surgical resection is the mainstay of treatment; the role of chemotherapy is not well defined. Therefore, we evaluated the impact of chemotherapy in the survival of patients with EO.

Methods: All EO patients seen at Mayo Clinic between 1990 and 2014 were assessed. Forty-three patients were included after all archived pathology slides were reviewed to confirm the diagnosis of EO.

Results: Of 43 patients, 37 patients had localized disease and 6 patients had metastatic disease at diagnosis. Chemotherapy was used in 73% and 75% of patients, respectively. Chemotherapy was predominantly anthracycline based, and included platinum in 22 patients (84%).Median overall survival (OS) and progression-free survival (PFS) were 50 months (95% confidence interval, 25-99), and 21 months (95% confidence interval, 13-not reached), respectively. There was a trend towards longer OS and PFS in patients who received chemotherapy. Those who received platinum-based therapy had remarkably prolonged OS (median, 182 vs. 18 mo; 5-year, 61% vs. 0%; P=0.01) and PFS (median, not reached vs. 10 mo; 5-year, 56% vs. 0%; P=0.005). Baseline characteristics were similar in the platinum and nonplatinum group.In patients who received chemotherapy, relapse/recurrence rate was lower in the platinum-based group (41%) as opposed to the nonplatinum-based group (100%; P=0.02). In the neoadjuvant setting, the overall response rate of platinum-containing regimens was 27%.

Conclusions: Our results suggest a clinical benefit when platinum-based chemotherapy is incorporated in the management of patients with EO. We plan to validate this further with an expanded multicenter analysis.
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http://dx.doi.org/10.1097/COC.0000000000000397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732098PMC
September 2018

Hyperbaric Oxygen as Radiation Sensitizer for Locally Advanced Squamous Cell Carcinoma of the Oropharynx: A Phase 1 Dose-Escalation Study.

Int J Radiat Oncol Biol Phys 2017 03 15;97(3):481-486. Epub 2016 Nov 15.

Baromedical Research Foundation, Columbia, South Carolina.

Purpose: To explore, in a dose-escalation study, the feasibility of hyperbaric oxygen (HBO) treatments immediately before intensity modulated radiation therapy in conjunction with cisplatinum chemotherapy for squamous cell carcinoma of the head and neck (SCCHN).

Methods And Materials: Eligible patients presented with SCCHN (stage III-IV [M0]), life expectancy >6 months, and Karnofsky performance status ≥70. Enrollees received intensity modulated radiation therapy, 70 Gy in 35 fractions over 7 weeks with weekly cisplatinum. Patients received HBO-100% oxygen, 2.4 atmospheres absolute (ATA) for 30 minutes-twice per week initially. Subsequent patients were escalated to 3 and then 5 times per week. Intensity modulated radiation therapy began within 15 minutes after HBO. Patients were followed for 2 years after RT with quality-of-life questionnaires (Performance Status Scale-Head and Neck Cancer and the Functional Assessment of Cancer Therapy-Head and Neck Cancer) and for 5+ years for local recurrence, distant metastases, disease-specific survival, and overall survival.

Results: Twelve subjects enrolled from 3 centers. Two withdrew during radiation therapy and 1 within 14 weeks after radiation therapy. The remaining 9 had primary oropharyngeal disease and were stage IVA (7) or IVB (2). No dose-limiting toxicities were observed with daily HBO. Two patients (22%) required pressure equalization tubes. The average time between HBO and radiation therapy was 8.5 minutes, with 2 of 231 administrations delivered beyond 15 minutes (0.5%). Per-protocol analysis showed a clinical complete response in 7 and a pathologic complete response without tumor in salvage neck dissections in 2. With minimum follow-up of 61 months, per-protocol 5-year overall survival was 100%, local recurrence 0%, and distant metastases 11%. Patient-reported outcomes for quality of life (Functional Assessment of Cancer Therapy-Head and Neck Cancer) were comparable to published results for chemoradiotherapy without HBO.

Conclusions: While acknowledging the study's small size and early attrition of 3 patients, our in-depth review of the acquired data indicates the feasibility of combining HBO with chemoradiation.
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http://dx.doi.org/10.1016/j.ijrobp.2016.10.048DOI Listing
March 2017

A proof-of-concept trial of protein kinase C iota inhibition with auranofin for the paclitaxel-induced acute pain syndrome.

Support Care Cancer 2017 03 12;25(3):833-838. Epub 2016 Nov 12.

Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.

Purpose: Paclitaxel causes the paclitaxel-induced acute pain (PIAP) syndrome. Based on preclinical data, we hypothesized that the protein kinase C (PKC) iota inhibitor, auranofin (a gold salt used for other pain conditions), palliates this pain.

Methods: In a randomized, double-blinded manner, patients who had suffered this syndrome were assigned a one-time dose of auranofin 6 mg orally on day #2 of the chemotherapy cycle (post-paclitaxel) versus placebo. Patients completed the Brief Pain Inventory and a pain diary on days 2 through 8 and at the end of the cycle. The primary endpoint was pain scores, as calculated by area under the curve, in response to "Please rate your pain by circling the one number that best describes your pain at its worse in the last 24 hours."

Results: Thirty patients were enrolled. For the primary endpoint, mean area under the curve of 55 units (standard deviation 19) and 61 units (standard deviation 22) were observed in auranofin-treated and placebo-exposed patients, respectively (p = 0.44). On day 8 and at the end of the cycle, pain scores in auranofin-treated patients were more favorable, although differences were not statistically significant.

Conclusions: In the dose schedule studied, auranofin did not palliate the PIAP syndrome, but delayed beneficial trends suggest further study for this indication.
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http://dx.doi.org/10.1007/s00520-016-3467-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5269609PMC
March 2017

Systemic therapy for recurrent or metastatic salivary gland malignancies.

Cancers Head Neck 2016 1;1:11. Epub 2016 Sep 1.

Division of Medical Oncology, Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 USA.

Salivary gland carcinomas are notoriously resistant to therapy and no standard of care exists. Due to the rarity of these malignancies, various histologies, and wide ranging clinical behavior it has been difficult to standardize systemic therapy. We have reviewed clinical prospective studies in the last 15 years with salivary gland malignancies involving cytotoxic chemotherapy and biologic agents including targeted therapies such as anti-HER-2, anti-EGFR therapies, and therapies directed at c-kit. Although the results of most trials are modest at best, there has been an increase in studies for salivary cancer in recent years and there are several promising treatment approaches in evolution. Every effort should be made to treat salivary gland malignancies under a clinical protocol and/or at a large multidisciplinary practice with clinicians experienced in treating these malignancies.
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http://dx.doi.org/10.1186/s41199-016-0011-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460835PMC
September 2016

Myoepithelioma of Soft Tissues: A Single Institution Retrospective Case Series.

Am J Clin Oncol 2018 04;41(4):357-361

Departments of Medical Oncology.

Background: Myoepithelioma of the soft tissues is a rare entity and little is known about how best to manage locally recurrent and high-grade disease. Here, we retrospectively examined outcomes of surgery, chemotherapy, and radiation therapy (RT) for treatment of low-grade and high-grade myoepithelioma of soft tissues.

Methods: We reviewed 20 cases of myoepithelioma of soft tissues seen at Mayo Clinic between 1994 and 2014. The effect of histologic grade and therapies received on relapse and survival were assessed.

Results: We identified 13 patients with low-grade disease and 7 patients with high-grade disease. We found that low-grade disease was frequently effectively managed with surgical resection alone, whereas high-grade disease frequently metastasized and was often fatal. The 5-year event-free survival was 88% (confidence interval, 46%-98%) for low-grade disease versus 36% (confidence interval, 7%-75%; P=0.04) for high-grade disease. The relapse rate in low-grade disease was 29% at 5 years versus 64% (P=0.04) in high-grade disease. No significant responses to chemotherapy were noted, however, excellent responses to perioperative RT were seen.

Conclusions: Surgery continues as the primary modality of treatment for myoepithelioma of soft tissues. Our study did not show a clear benefit of chemotherapy in the metastatic disease setting, but supports the use of perioperative RT in the management of high-grade disease; further investigation is warranted.
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http://dx.doi.org/10.1097/COC.0000000000000292DOI Listing
April 2018

S0502: A SWOG Phase III Randomized Study of Imatinib, With or Without Bevacizumab, in Patients With Untreated Metastatic or Unresectable Gastrointestinal Stromal Tumors.

Oncologist 2015 Dec 17;20(12):1353-4. Epub 2015 Nov 17.

Oregon Health & Science University, Portland, Oregon, USA.

Lessons Learned: Despite having significant rationale, S0502 failed to accrue for a number of reasons.Vetting a trial first, with scientific experts and funding agencies, does not guarantee success, especially when dealing with a rare tumor and/or one with an existing highly effective therapy.In the present case, adding an intravenous drug to an oral medication as part of a regimen expected to be continued for many years likely decreased patient (and physician) convenience and, thus, interest in the study.

Background: Imatinib mesylate, a potent inhibitor of the KIT and PDGFR tyrosine kinases, is highly effective in the treatment of advanced gastrointestinal stromal tumors (GISTs). However, most imatinib-treated tumors eventually become resistant, accounting for a median progression-free survival of 19-23 months. Expression of vascular endothelial growth factor (VEGF) correlates with poor prognosis in GIST; bevacizumab, a monoclonal antibody against VEGF, is effective in a variety of solid tumors. We postulated combination therapy with imatinib plus bevacizumab would benefit patients with advanced GIST, particularly those reliant on VEGFA-dependent angiogenesis.

Methods: Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial, S0502. At registration, patients were randomly assigned to either imatinib 400 mg (standard) or 800 mg (patients with exon 9 KIT mutations), or imatinib plus bevacizumab, 7.5 mg/kg i.v. every 3 weeks. Patients were treated to progression, symptomatic deterioration, unacceptable toxicity, treatment delay greater than 4 weeks, or patient choice to withdraw from the study. The primary objective was to determine whether the addition of bevacizumab to imatinib would improve progression-free survival (PFS) in first-line treatment of incurable GIST.

Results: S0502 opened on April 15, 2008. As of fall 2009, only 12 patients from at least 178 eligible SWOG centers plus those participating through Cancer Trials Support Unit had been entered in the study. Despite an aggressive promotion scheme involving the other cooperative groups and a major GIST patient advocacy group, accrual remained slow. The trial was closed on October 1, 2009, having accrued only 2% of the 572 patients planned. No scientific conclusions were forthcoming because of the small number of patients entered in the study. Two patients of the 6 in the combination arm reported grade 3 toxicities, 1 with proteinuria and 1 with fatigue, upper gastrointestinal hemorrhage, and anemia.

Conclusion: No conclusions may be drawn from this trial and, thus, the combination of imatinib plus bevacizumab cannot be recommended for use.
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http://dx.doi.org/10.1634/theoncologist.2015-0295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679092PMC
December 2015

Clinicopathologic characteristics and survival for adult renal sarcoma: A population-based study.

Urol Oncol 2015 Dec 28;33(12):505.e15-20. Epub 2015 Aug 28.

Department of Urology, Mayo Clinic, Rochester, MN. Electronic address:

Introduction: To analyze the association of clinicopathologic characteristics and treatment modality with survival among adult patients with renal sarcoma.

Methods: We identified 489 adults diagnosed with renal sarcoma from the Surveillance, Epidemiology and End Results registry between 1973 and 2011. Cancer-specific survival was estimated using the Kaplan-Meier method and was compared between groups with log rank and Cox models.

Results: Median age at diagnosis was 61 years, while median tumor size was 11 cm. Tumor histology was leiomyosarcoma in 175, liposarcoma in 100, other subtypes in 129, and unknown in 85 cases. Tumor stage at diagnosis was nonmetastatic in 322 (67%) and metastatic in 167 (33%) cases. Treatment of nonmetastatic disease was surgical resection in 171 patients, radiation in 24, both in 35, neither in 18, and unknown in 74 cases. Treatment of metastatic disease was surgery in 39 patients, radiation in 27, both in 11, neither in 42, and unknown in 48. For nonmetastatic and metastatic disease, 5-year cancer-specific survival rates were 58% and 16%, respectively. On multivariable analysis, surgery was associated with decreased cancer-specific mortality among both patients with nonmetastatic disease (hazard ratio = 0.34; 95% CI: 0.14-0.85) and those with metastatic disease (hazard ratio = 0.38; 95% CI: 0.18-0.77). Age, race, tumor size, and tumor grade were independently associated with cancer death in nonmetastatic disease, whereas race and tumor histology remained associated with mortality in metastatic disease (all P < 0.05).

Conclusion: Although metastatic renal sarcoma has an ominous prognosis, durable survival may be achieved for localized tumors. Although we recognize the potential for selection bias, our results suggest an association between surgical resection and decreased mortality for both nonmetastatic and metastatic renal sarcoma.
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http://dx.doi.org/10.1016/j.urolonc.2015.07.022DOI Listing
December 2015

Clinical Activity of Pazopanib in Metastatic Extraosseous Ewing Sarcoma.

Rare Tumors 2015 May 21;7(2):5992. Epub 2015 May 21.

Mount Sinai Medical Center , New York, NY, USA.

We report a response to pazopanib in a 69-year-old man with heavily pre-treated metastatic extraosseous Ewing sarcoma in addition to molecular profiling of his tumor. To our knowledge, this case is the earliest to demonstrate activity of an oral multi-targeted kinase inhibitor in Ewing sarcoma. This case provides rationale for adding a Ewing sarcoma arm to SARC024, a phase II study of regorafenib, another multi-targeted kinase inhibitor, in patients with liposarcoma, osteosarcoma and Ewing and Ewing-like sarcomas (NCT02048371). This national multi-institutional study is ongoing.
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http://dx.doi.org/10.4081/rt.2015.5992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508650PMC
May 2015

Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma.

J Clin Oncol 2014 Oct 2;32(29):3299-306. Epub 2014 Sep 2.

Sant P. Chawla, Sarcoma Oncology Center, Santa Monica; Andrew E. Hendifar, Cedars Sinai Medical Center, Los Angeles; Stew Kroll, Threshold Pharmaceuticals, South San Francisco; Kristen N. Ganjoo, Stanford University Medical Center, Stanford, CA; Lee D. Cranmer, University of Arizona Cancer Center, Tucson, AZ; Brian A. Van Tine and Douglas R. Adkins, Washington University in St Louis, St Louis, MO; Damon R. Reed, Moffitt Cancer Center and Research Institute, Tampa, FL; Scott H. Okuno, Mayo Clinic, Rochester, MN; and James E. Butrynski, Dana-Farber Cancer Institute, Boston, MA.

Purpose: TH-302, a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard, is preferentially activated in hypoxic conditions. This phase II study investigated TH-302 in combination with doxorubicin, followed by single-agent TH-302 maintenance therapy in patients with first-line advanced soft tissue sarcoma (STS) to assess progression-free survival (PFS), response rate, overall survival, safety, and tolerability.

Patients And Methods: In this open-label phase II study, TH-302 300 mg/m(2) was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m(2) on day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302.

Results: Ninety-one patients initiated TH-302 plus doxorubicin induction treatment. The PFS rate at 6 months (primary efficacy measure) was 58% (95% CI, 46% to 68%). Median PFS was 6.5 months (95% CI, 5.8 to 7.7 months); median overall survival was 21.5 months (95% CI, 16.0 to 26.2 months). Best tumor responses were complete response (n = 2 [2%]) and partial response (n = 30 [34%]). During TH-302 maintenance (n = 48), five patients improved from stable disease to partial response, and one patient improved from partial to complete response. The most common adverse events during induction were fatigue, nausea, and skin and/or mucosal toxicities as well as anemia, thrombocytopenia, and neutropenia. These were less severe and less frequent during maintenance. There was no evidence of TH-302-related hepatic, renal, or cardiac toxicity.

Conclusion: PFS, overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced STS. A phase III study of TH-302 is ongoing (NCT01440088).
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http://dx.doi.org/10.1200/JCO.2013.54.3660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588714PMC
October 2014

Adjuvant chemoradiation therapy with high-dose versus weekly cisplatin for resected, locally-advanced HPV/p16-positive and negative head and neck squamous cell carcinoma.

Oral Oncol 2014 Apr 24;50(4):311-8. Epub 2014 Jan 24.

Division of Medical Oncology, Mayo Clinic, Rochester, MN, United States. Electronic address:

Objectives: Standard treatment for patients with poor-risk, resected head and neck squamous cell carcinoma (HNSCC) is adjuvant radiation therapy combined with high-dose cisplatin. Many patients are treated with weekly cisplatin; it is not known whether weekly and high-dose cisplatin are equivalent. This study compares the outcomes of patients with locally-advanced HPV-negative HNSCC and HPV/p16-positive oropharynx HNSCC treated with adjuvant chemoradiation therapy with either high-dose or weekly cisplatin.

Materials And Methods: Retrospective review of patients with Stage III/IV HNSCC who had surgery followed by adjuvant chemoradiation therapy at Mayo Clinic, Rochester. HPV and/or p16 status was available for all oropharynx patients.

Results: 104 Patients (51 high-dose, 53 weekly) were analyzed. The 3-year overall survival was 84% and 75% for patients who received high dose and weekly cisplatin, respectively (p=0.30). The 3-year recurrence free survival was 71% and 74% in the high dose and weekly cisplatin group, respectively (p=0.95). Patients with HPV/p16-positive oropharynx cancer who received adjuvant chemoradiation therapy with high-dose and weekly cisplatin had three-year overall survival rates of 91% and 86% (p=0.56), and 3-year recurrence free survival of 84% and 82% (p=0.93). Extracapsular extension did not affect prognosis in either group.

Conclusions: No significant survival difference was seen between patients with locally advanced HNSCC treated with adjuvant chemoradiation therapy with high-dose or weekly cisplatin, although there was a trend for improved survival with high-dose cisplatin. Weekly cisplatin in the adjuvant setting may be a better treatment for patients with HPV-positive oropharynx cancer to preserve survival and minimize toxicity.
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http://dx.doi.org/10.1016/j.oraloncology.2014.01.001DOI Listing
April 2014

Adult ewing sarcoma: survival and local control outcomes in 102 patients with localized disease.

Sarcoma 2013 11;2013:681425. Epub 2013 Jun 11.

Mayo Medical School, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

Objectives. To assess the clinical features and local control (LC) outcomes in adult patients with localized Ewing Sarcoma (ES). Methods. The records of 102 ES patients with localized disease ≥18 years of age seen from 1977 to 2007 were reviewed. Factors relevant to prognosis, survival, and LC were analyzed. Results. The 5-year overall survival (OS) and event-free survival (EFS) were 60% and 52%, respectively, for the entire cohort. Treatment era (1977-1992 versus 1993-2007) remained an independent prognostic factor for OS on multivariate analysis, with improved outcomes observed in the 1993-2007 era (P = 0.02). The 5-year OS and EFS for the 1993-2007 era were 73% and 60%, respectively. Ifosfamide and etoposide based chemotherapy and surgery were more routinely used in the 1993-2007 era (P < 0.01). The 5-year local failure rate (LFR) was 14%, with a 5-year LFR of 18% for surgery, 33% for radiation, and 0% for combined surgery and radiation in the 1993-2007 era (P = 0.17). Conclusion. Modern survival outcomes for adults with localized ES are similar to multi-institutional results in children. This improvement over time is associated with treatment intensification with chemotherapy and increased use of surgery. Aggressive LC (combined surgery and radiation) may improve outcomes in poor prognosis patients.
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http://dx.doi.org/10.1155/2013/681425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693164PMC
July 2013