bluuebunny/crossref_metadata_2025 huggingface dataset:
Medical oncologists’ experience with returning molecular tumor profiling to patients.
Authors: Thavaneswaran Subotheni , Napier Christine , Goldstein David , Meiser Bettina , Butow Phyllis , Thomas David Morgan , Ballinger Mandy L. , Best Megan
Published: March 2020

10521

Background: Molecular tumor profiling (MTP) to guide therapy is increasingly being applied in the clinic, although how medical oncologists (MOs) manage this in clinical practice is not fully understood. Methods: An online survey explored MOs’ experience with MTP interpretation, treatment (tx) decisions, identifying resources, and communicating results to patients with cancer. MOs were identified based on their participation in the Australian Molecular Screening and Therapeutics Program. Results: 108 MOs (57% male, median years of practice, 5-9 years, 83% urban-based practice and median age range, 40-49 years) participated from June 2018 – Jan 2019. Most MOs had experience with MTP (90%), and felt it was their role to discuss results. MOs felt confident discussing the process of MTP, the probability of a ‘therapeutically actionable finding’, and results (score 70-75, range 0 least confident - 100 completely confident). However, almost two-thirds of MOs needed/wanted assistance with interpretation of results, favouring a Family Cancer Clinic (FCC) helpline, patient information sheets on MTP, and decision aids. In particular, MOs were less confident discussing germline results and their implications (median score 56) but were comfortable (median score 96) to refer to an FCC. Most MOs felt there was sufficient information on the MTP report to understand results. Some preferred to receive ‘all cancer gene variants’ (36%), others only those with clinical actionability (45%), and some only those with therapeutic actionability (19%). Most MOs (85%) wanted to know the full list of genes assayed, tx recommendations, and/or a list of relevant trials. Interestingly, MOs indicated little confidence that MTP would guide useful tx decisions (median score 51) and most reserved it for the tx-refractory setting. A minimal level of evidence supporting treatment was required by 83% of MOs prior to recommending biomarker-guided tx. Conclusions: MOs are increasingly integrating MTP into clinical practice, despite uncertainty about result validity and clinical translation, particularly regarding germline results. Understanding these potential barriers is the first step in developing clinician supports to facilitate clinical translation.
Developing an inspired leader: How to maximize human talent to maximize operating results.
Authors: Greeter Aimee
Published: March 2020

10522

Background: Healthcare is a personal industry–driven by people, for people. Developing the talent of individuals as leaders is critical to making the entire industry thrive. This session provides practical tools to develop highly competent leaders, who can then develop high-performing organizations. Methods: Using Noel Burch’s framework, this presentation shares effective methods of propelling leaders from uninspired to results-focused performers. With a focus on real-life examples, this interactive session gives instruction on how to maximize human talent as a means to driving enterprise-wide success. The topics to be covered include: (1) Conscious Competence Ladder: What Is It?; (2) Noel Burch’s work; (3) Key tenets of the Ladder; (4) Common misperceptions of the Ladder; (5) Conscious Competence Ladder and Healthcare: Why Does it Matter?; (6) Application of the Ladder to the healthcare industry; (7) Realities of Human Capital in healthcare; (8) “Exercising” Leadership: Is That Even Possible?; (9)Development of leadership as a skill; (10) Four-Step Process to Leadership Development in Healthcare: But How Do We Do That?; (11) Application of Leadership: But Won’t This Be Hard?; (11) Common pitfalls in leadership development; (12) Success Stories: Has Anyone Ever Even Done This in Healthcare?; (13) Conclusions, Q&A: What Happens Next? Results: This session will enable participants to: (1)Describe the Conscious Competence Ladder model and its relevance to healthcare organizations; (2) Authenticate leadership as a skill that can be developed, and understand how to mature that skill within healthcare leaders using an efficient four-step process; and (3) Provide practical, effective methods to help people understand, process and use leadership skills to maximize the success of their peers, patients and community. Conclusions: In Q4 2017, for the first time ever, healthcare passed both manufacturing and retail as the United States’ largest employer. Simply put, there are now more health care laborers than any other industry. In sheer numbers alone, this is impressive. But, more impressive is the need to utilize and motivate this work force. Using effective and appropriate tools (such as those to be provided in this presentation), this massive healthcare work force can be empowered to drive significant benefits for an organization, its patients and its broader community.
Oncology fellows’ knowledge and current practice regarding outpatient oncology and palliative care.
Authors: Johnson Amy , Newton Erin V. , Fettig Lyle , Comer Amber
Published: March 2020

10527

Background: Patients with advanced cancers often suffer from a number of symptoms and need guidance when discussing treatment goals as their diseases’ progress. Palliative care competencies include the assessment and management of both physical and psychological symptoms, as well as, the conduct of goals of care conversations and advanced care planning. Palliative medicine is subspecialty that specially addresses these needs in patients with advanced cancers, but is not universally available. Oncology fellowship training must include these competencies and there is little evidence regarding the palliative care educational experiences of oncology fellows. This study examines fellows’ experiences with palliative care education and fellows’ attitudes about concurrent palliative care in the outpatient setting. Methods: An electronic nationwide survey of medical oncology fellows was conducted in the second half of the academic year in 2018. Results: 43 of 191, 22.5%, of oncology fellows contacted at 17 institutions responded. 96% of fellows indicated they would strongly agree or agree with having a Palliative Care team in their future outpatient clinics. 93% of fellows agree or strongly agree with being comfortable managing cancer related pain, but only half agree or strongly agree with being comfortable managing depression and anxiety. 91% agree or strongly agree they are comfortable with discussions about transitions to best supportive care, while only 31% of fellows always or often assist patients in completing advance care documents. 70% of fellows are always, often, or sometimes receiving feedback on their communication and symptom management skills. Conclusions: Oncology fellows fell comfortable with some aspects of palliative care more than others. Fellows in this survey report feeling comfortable with goals of care conversations and pain management, but are not as comfortable managing other symptoms like depression and anxiety. Respondents are not universally assisting patients in advanced care documentation and only two-thirds of responding fellows are receiving frequent feedback on their communication and symptom skills. There is a consensus among responding fellows about a desire to have palliative care embedded in their future clinics.
Medical oncology trainees’ perceptions of their education and preparedness for independent practice.
Authors: Linford Geordie , Hammad Nazik , Dalgarno Nancy , Cofie Nicholas , Ramjeesingh Ravi , Tomiak Anna T.
Published: March 2020

10536

Background: This original research assesses Canadian Medical Oncology (MO) residents’ perceptions and satisfaction with their education and preparedness for practice prior to initiation of Competency Based Medical Education (CBME). Methods: Digital surveys were sent to MO residents in Canadian training institutions yearly from 2014–2017. Because of lower than expected response rates, invitations were subsequently extended to recent graduates completing training between 2009–2014. Ethics and funding were granted by Queen’s University. Results: A total of 71 surveys were received with representation from 11 training programs. Preparedness for Practice: Current trainees and recent graduates ranked preparedness for practice similarly in all assessment domains except Medical Expert (trainee mean 3.50, graduate mean 4.45, p=0.004; 1=not prepared, 5=well prepared). Means for the combined cohort shown in table. Usefulness of teaching modalities: Participants ranked learning in a clinical setting as most useful (6.53/8, 1=least useful, 8=most useful) and educational sessions by residents (4.24/8) and Journal Club (3.74/8) as least useful. Most participants felt their training was a shared learner-teacher responsibility (56.1%) or was learner-centered (22.5%). Quality of teaching: Participants reported similar levels of satisfaction with teaching across domains except for Manager which scored lowest (3.46/5, 1=poor, 5=excellent). Self-assessment of skills: Participants were most satisfied by their ability to assess their own performance and competence at the end of training (7.16/10, 1=not satisfied, 10= very satisfied). The degree to which their programs set expectations about required knowledge, skills, or attitudes at various points in training (6.63/10) and participants abilities to self-assess these skills during their training (6.64/10) scored lower. Conclusions: Participants reported low satisfaction with their ability to self-assess during their training and their training programs’ ability to communicate expectations. Transition to CBME training may address these issues, and follow-up is required.[Table: see text]
Using blended learning to improve education on clinical pathways for breast cancer management in Nigeria: Preliminary results.
Authors: Eguzo Kelechi Ngozi , Ismaila Nofisat , Akpanudo Usenime , Chukwuemeka Oluoha , Jacob Aniekan , Udoekong Mfonobong , Adisa Charles Adeyinka
Published: March 2020

10539

Background: Most Nigerian clinicians lack adequate skills and resources in screening, diagnosis, and managing women with breast cancer. The absence of locally-sensitive clinical pathways in hospitals in Abia State impact patient outcomes and clinicians job satisfaction. Blended learning (BL), a combination of online and face-to-face teaching methods, has been used in other settings to improve the competencies of clinicians. Research seeks to develop and evaluate a BL course that will train clinicians in Abia State on using NCCN breast cancer management guidelines, and to develop and implement locally-sensitive clinical pathways. Methods: The course is divided into four online modules delivered via Google Classroom and a workshop module to be delivered in 3 cities. Course evaluation involves an objective-focused method, following a mixed-methods design. Data collection includes pre-and-post-tests, course evaluation and focus group discussions. Data analysis involved descriptive statistics and t-test. Comments deductively analyzed to identify common themes. A sample size of 107 individuals is required to identify a moderate effect size for the BL course. Results: Forty-three participants (physicians=15, Nurses=28) have been recruited for cohort 1, with average age of 44 (±9.9) years. Most participants have never taken an online class (65%) but use mobile phones (60%) to access the course. With a maximum of 20 points in each test, there is a pattern of improvement in the post-tests performance compared with the pre-tests. Table shows mean scores. Most participants have expressed satisfaction with the course. Conclusions: Results show improvement in learning. More participants are being recruited. The workshops will hold at after the online modules.[Table: see text]
Implementing a quality improvement curriculum for medical oncology residents: A pilot study at the Ottawa Hospital Cancer Centre.
Authors: Brule Stephanie Yasmin
Published: March 2020

10540

Background: With increasing cancer care costs and demands in Canada, quality improvement (QI) efforts are urgently needed. Yet no formal QI education exists in the Canadian Medical Oncology setting. We created an Oncology-specific QI curriculum and sought to assess its feasibility and efficacy among Medical Oncology residents. Methods: In this prospective, pre-experimental pilot study using a pre-post curriculum design, Medical Oncology residents at The Ottawa Hospital Cancer Centre participated in a new QI curriculum. It consisted of four 2-hour sessions encompassing a combination of didactic and interactive learning. The primary measures were self-assessment of confidence in QI skills with the Self-Assessment Program (SAP) and objective assessment of QI knowledge with the revised QIKAT (QIKAT-R). The SAP and QIKAT-R were completed at baseline and post-curriculum. The primary outcome was feasibility of the educational approach. Results: Five Medical Oncology participated, while four (80%) completed the assessments at both timepoints. Self-assessment in the skills needed to execute a process improvement project improved with participation in the curriculum. Mean SAP scores improved from 19.6 pre-curriculum to 33.5 post-curriculum. SAP scores improved for each of the 10 quality improvement skills evaluated. Objective assessment using the QIKAT-R also improved post-curriculum, with a mean score of 17 pre-curriculum and 24 post-curriculum. Mean scores of each domain of “Aim, Measure, and Change” evaluated by the QIKAT-R improved. Conclusions: Self-assessed confidence and objective knowledge in QI concepts in Medical Oncology residents improved after participation in this Oncology-specific QI curriculum. Feasibility of this approach was demonstrated, and therefore a larger scale study will be implemented in the future.
Neoadjuvant chemotherapy in high-risk soft tissue sarcomas: Final results of a randomized clinical trial from the Italian Sarcoma Group, the Spanish Sarcoma Group (GEIS), the French Sarcoma Group (FSG), and the Polish Sarcoma Group (PSG).
Authors: Gronchi Alessandro , Palmerini Emanuela , Quagliuolo Vittorio , Martin Broto Javier , Lopez Pousa Antonio , Grignani Giovanni , Brunello Antonella , Blay Jean-Yves , Diaz Beveridge Robert , Ferraresi Virginia , Lugowska Iwona , Merlo Franco Domenico , Fontana Valeria , Palassini Elena , Morosi Carlo , Stacchiotti Silvia , Dei Tos Angelo Paolo , Picci Piero , Bruzzi Paolo , Casali Paolo Giovanni
Published: March 2020

11000

Background: A ISG randomized trial on 5 cycles of adjuvant epirubicin+ifosfamide (EI) versus no chemotherapy suggested an OS benefit in localized high-risk STS (JCO 2001;19:1238). A subsequent trial showed no difference between 3 vs 5 cycles of the same neoadjuvant regimen (JCO 2012;30:850). The aim of this trial was to compare 3 cycles of EI versus a histology-tailored (HT) neoadjuvant regimen in selected localized high-risk STS. Methods: This is a multicenter European randomized trial comparing EI versus a HT regimen: gemcitabine+docetaxel in undifferentiated pleomorphic sarcoma (UPS); trabectedin in high-grade myxoid liposarcoma; high-dose prolonged-infusion ifosfamide in synovial sarcoma (SS); etoposide+ifosfamide in malignant peripheral nerve sheath tumors (MPNST); gemcitabine+dacarbazine in leiomyosarcoma (LMS). Patients had localized high-risk (grade = 3; size ≥5 cm) STS of extremities or trunk wall. Primary end-point was Disease Free Survival (DFS). The final analysis was planned after the observation of 130 events. This allows an 80% power to detect a significant difference at the 5% 2-sided level, if the true HR is 0.6 in favor of EI, as shown by the interim analysis (Lancet Oncol 2017;18:812-822). Results: From May 2011 to May 2016, 287 patients were randomized (97 = UPS; 65 = myxoid liposarcoma; 70 = SS; 27 = MPNST; 28 = LMS). The median follow-up was 51.75 months for the alive patients (IQ 28.03) The DFS and OS probability at 60 months were 0.48 and 0.55 (HR:1.232; 95%CI: 0.875-1.733; log rank p=0.323) and 0.66 and 0.76 (HR:1.766; 95%CI:1.101-2.831; log rank p=0.018), in the HT and EI arm, respectively. Conclusions: The final analysis shows a non-statistically significant DFS difference in favor of EI over HT chemotherapy with a larger and statistically significant OS difference. The outcome of patients on EI overlapped previous ISG trials. EI should remain the regimen of choice when neoadjuvant chemotherapy is used in high-risk localized STS. However this trial cannot be used as a formal proof of efficacy of (neo)adjuvant chemotherapy per se. EUDRACT 2010 – 023484 – 17. Funding source: Eurosarc FP7 278472. Clinical trial information: NCT01710176.
Anlotinib and irinotecan for advanced Ewing sarcoma after failure of standard therapy: A multicenter, two-cohort, single-arm, open label, phase Ib/II trial (NCT03416517).
Authors: Xu Jie , Xie Lu , Guo Wei , Tang Xiaodong , Yang Rongli , Yan Taiqiang , Liu Kuisheng , Gu Jin
Published: March 2020

11012

Background: Both protracted irinotecan and anti-angiogenesis therapy have shown promising results in Ewing sarcoma. We did this phase Ib/II trial to first define the proper dose of irinotecan in combination with anlotinib in Ewing sarcoma and then evaluate efficacy. Methods: Patients diagnosed with recurrent or refractory Ewing sarcoma were enrolled and sub-classified into cohort A (≥16y) or cohort B ( < 16y). In the dose-defining phase Ib portion, anlotinib was given at a fixed dose of 12mg D1-14every 21 days, while the de-escalated 3+3 design was used to detect the recommended dose of irinotecan in each cohort from an initial level of 20mg/m2/d dx5x2. Recommended phase 2 dose (RP2D) was defined as the highest dose at which no more than 30% patients experience a DLT in the first two courses. In the next dose-expanding phase II portion, the primary endpoint was objective response rate at 12 weeks (ORR12w). A conventional two-stage study design model was used. Results: 41 patients were enrolled with 29 in cohort A and 12 in cohort B. For cohort A, first 5 patients were treated at initial level in phase Ib portion, two of whom subsequently experienced delayed diarrhea as dose-limiting toxicity (DLT). Additional six patients were then treated at a lower dose of 15mg/m2. Since no more DLT was recorded, it was used as RP2D. 23/24 patients in cohort A phase II were available for response evaluation at 12 weeks, with one complete response (CR), 14 partial response (PR) (including one CMR who has a negative PET/CT scan but still abnormal lesions in MR scan), 2 stable disease (SD) and 6 progressive disease (PD). ORR12wwas 62.5%. For cohort B, no DLT was noticed in the first six patients treated at the initial level which was used as RP2D later. Finally, 12 patients were included in cohort B. ORR12wwas 83.3% with two CR, 8 PR (including one CMR) and two PD. Although effective, cohort B were closed because of slow enrollment. Most common grade 3/4 adverse events were diarrhea, abdominal pain and neutropenia. The genotype of UGT1A1*1 and UGT1A1*28 were not associated with the risk of diarrhea. Conclusions: The combination of irinotecan and anlotinib demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in advanced Ewing sarcoma. Clinical trial information: NCT03416517.
A double-blind placebo-controlled randomized phase II trial assessing the activity and safety of regorafenib (REG) in patients (pts) with nonadipocytic soft tissue sarcoma (STS) previously treated with pazopanib (PAZ).
Authors: Penel Nicolas , Blay Jean-Yves , Wallet Jennifer , Ray-Coquard Isabelle Laure , Le Cesne Axel , Ryckewaert Thomas , Italiano Antoine , Salas Sebastien , Delcambre Corinne , Bompas Emmanuelle , Bertucci Francois , Saada-Bouzid Esma , Chaigneau Loic , Chevreau Christine , Thery Julien , Decoupigny Emilie , Vanseymortier Marie , Le Deley Marie-Cecile , Mir Olivier
Published: March 2020

11021

Background: After we demonstrated the activity of REG in pts with advanced non-adipocytic STS (MirTLO 2016), we conducted a dedicated study in pts previously treated with PAZ+chemo. Methods: We report here the 5th cohort of a double-blind randomized phase 2 trial (NCT01900743). Pts were treated with regorafenib (160mg/d, 21/28d) or placebo (PB). Pts receiving placebo were offered optional cross-over in case of centrally confirmed disease progression. The primary endpoint was centrally-reviewed RECIST-based progression-free survival (PFS), evaluated on the intent-to-treat dataset. A total of 24 events was required to ensure a 90%-power for HR = 0.33 (median PFS, 3·6 vs 1·2 months), with a 1-sided α = 0·1. Overall survival (OS) was a secondary endpoint. Results: From 12/2015 to 10/2017, 37 pts were randomized (18 REG vs 19 PB) and included in the final analysis. The median age was 60 (36-76). There were 28 women (76%). All pts had a performance status 0 or 1. Histological subtypes included 24 leiomyosarcoma (11 vs 13, in REG and PB, respectively), 1 synovial sarcoma (REG), 12 other sarcoma (7 vs 5). All pts had previously been treated with PAZ +chemo (including doxorubicin: 19 vs 17; ifosfamide: 11 vs 3; trabectedin: 11 vs 9; and dacarbazine: 7 vs 6), with 2-6 prior lines. The median relative dose intensity of REG was 0·86, range 0·41-1. Out of 19 pts assigned to placebo, 13 switched to REG after progression. There was no reported objective response. We observed a significant benefit of REG compared to PB in terms of PFS (HR = 0·38; 95%CI, 0·19-0·76; p = 0·007; median PFS = 2·1 vs 1·1 months, respectively), and OS despite the cross-over (HR = 0·41; 95%CI, 0·17-0·98; p = 0·04; median OS = 18·6 vs 8·2 months). Before cross-over, the most common clinically significant grade 3 or higher adverse events were diarrhea (4 vs 0), dyspnea (3 vs 1), arterial hypertension (2 vs 0), hand-foot skin reaction (2 vs 0). Conclusions: The present study demonstrates that regorafenib has a clinically meaningful anti-tumor activity in pts with non-adipocytic soft tissue sarcoma pretreated by both chemotherapy and pazopanib, improving PFS and OS. Clinical trial information: NCT01900743.
ALT-GIST: Randomized phase II trial of imatinib alternating with regorafenib versus imatinib alone for the first-line treatment of metastatic gastrointestinal stromal tumor (GIST).
Authors: Yip Desmond , Zalcberg John Raymond , Blay Jean-Yves , Eriksson Mikael , Espinoza David , Price Timothy Jay , Marreaud Sandrine , Italiano Antoine , Steeghs Neeltje , Boye Kjetil , Underhill Craig , Naher Sayeda , Oostendorp Martinus , Gebski Val , Simes John , Gelderblom Hans , Joensuu Heikki
Published: March 2020

11023

Background: Imatinib (IM) is the standard first-line treatment for advanced GIST and regorafenib (REG) is approved for third line therapy. We studied if an alternating regimen of two tyrosine kinase inhibitors, IM and REG, delays resistance to IM and improves outcomes. Methods: ALT-GIST (NCT02365441) is a randomised non-comparative phase II trial to investigate the efficacy of an alternating regimen (ALT) of 21-25 days of IM 400mg orally daily followed by a 3-7-day gap for washout followed by 21 days of REG 160 mg orally daily and a 7-day gap for washout. The control arm was continuous IM 400mg daily. Delayed recruitment led to revised endpoints of activity and safety. To assess clinical activity, the best objective tumor response (OTR) at 9 months was deemed to be an appropriate endpoint in the revised protocol. Results: Seventy-six eligible patients (ALT 40, IM 36) enrolled from June 2015 to September 2018 were evaluable for the OTR. The patients (pts) were predominately male (n = 51, 67%). Median age was 58 (range, 24-81) in the ALT arm and 65 (range, 35-82) in the IM arm. KIT was mutated in 63, PDGFR in 2, and wildtype in 5 tumors. Relative dose intensity in the ALT arm 102% for IM and 82% for REG and was 93% in the IM arm. Median follow-up time was 19.3 months (range 6.0-40.0).The best responses to the ALT and IM treatments were similar at 9 months, 1 vs 0 pts had complete response, 23 vs 23 partial response, 15 vs 13 stable disease, and the OTR was 60% (95% CI, 45-74%) and 64% (95% CI, 48-78%), respectively. Seven (18%) pts in ALT arm and 10 (28%) in IM arm discontinued treatment due to progressive disease. Seven pts (18%) in the ALT arm stopped protocol therapy due to unacceptable toxicity, and none in the IM arm. Fifteen (38%) pts in the ALT arm and 14 (38%) in the IM arm had serious adverse events, mostly grade 3. Progression free survival (PFS) at 1 year was ALT 0.86 (95%CI:0.69,0.94) and IMI 0.83 (95% CI 0.65-0.92), p logrank = 0.57. Conclusions: There was no meaningful difference in the primary endpoint of OTR and in PFS between the groups in this first analysis of ALT-GIST, and no unexpected safety signals. The study is ongoing and other endpoints will be reported in due course. Clinical trial information: ACTRN12614000950662.
Secondary genomic alterations in Ewing sarcoma.
Authors: Uche An , Chow Warren Allen , Millis Sherri Z.
Published: March 2020

11024

Background: Ewing sarcoma (ES) is the second most common bone cancer in children and young adults. The prognosis of recurrent or metastatic ES is poor, with a 5-year overall survival <30%. ES is characterized by translocations involving ETS transcription factors ( EWS– FLI and EWS– ERG translocations are the most common). Secondary somatic alterations in ES are infrequently described. Aberrations in fibroblast growth factor receptor 4 ( FGFR4), a receptor tyrosine kinase protein that plays an important role in cellular processes,have been shown to contribute to carcinogenesis in different types of cancer.More recently, the FGFR4-Gly388Arg (G388R) single nucleotide polymorphism (SNP), with the substitution of arginine instead of glycine in the transmembrane domain of the receptor, is found to significantly increase the risk of breast and prostate cancer. Mouse embryonic fibroblasts derived from knock-in strain of homologous FGFR4-G388R mice display a transformed phenotype, and TGFα-induced mammary carcinogenesis in this strain is significantly enhanced. The association between FGFR4 G338R SNP and ES has not been evaluated. We evaluated the frequency of FGFR4 G338R and whether comprehensive genomic profiling (CGP) might uncover additional, potentially targetable, genomic alterations (GA) in ES. Methods: Tissue from 253 patients with ES was assayed by hybrid-capture based CGP (FoundationOne Heme, next generation sequencing (NGS), analysis which includes both DNA sequencing of 406 genes and RNA sequencing of 265 genes), performed in the course of clinical care to evaluate GAs, including base substitutions, indels, amplifications, copy number alterations and gene fusions/rearrangements. Tumor mutational burden (TMB) was calculated from a minimum of 1.4 Mb sequenced DNA and reported as mutations/Mb. Microsatellite instability (MSI) status was determined by a novel algorithm analyzing 114 specific loci. Results: CGP identified several GAs in ES: TP53 (n= 50, 20%), MLL3 (n=15, 6%), MSH3 (n=14, 5%), ARID1A (n=11, 4%) and FGFR4 (n=3, 1%). FGFR4 G338R SNP was found in almost half of the patients (n=123, 49%). Conclusions: Secondary GAs in TP53, MLL3, MSH3, ARID1A and FGFR4 were found in more than one third of patients with ES (n=93, 37%). FGFR4 G388R SNP was detected in nearly half of patients, and may represent an alternative method of sarcomagenesis. Overall, the frequency of these GAs is significantly greater than previously reported. These GAs may inform the potential for targeted therapies.
Outcomes of extra-skeletal versus skeletal Ewing sarcoma patients treated with standard chemotherapy protocol.
Authors: Salah Samer , Abuhijla Fawzi Jamil , Ismaeel Taleb , Yaser Sameer , Sultan Iyad Yasin , Shehadeh Ahmad , Abelal Samer , Al-Mousa Abdelatif , Abuhijlih Ramiz
Published: March 2020

11027

Background: Extra-skeletal ewing sarcomas (ES) are rare, and data on outcomes following standard ES chemotherapy protocols are very limited. Methods: We retrospectively collected data on skeletal and extra-skeletal ES patients who presented with localized disease from January, 2006 to June, 2018. Disease and treatment characteristics were compared between the two groups by the chi-square test. Overall survival (OS) and local recurrence free survival (LRFS) were estimated by the Kaplan-Meier method and compared by the Log-rank test. Results: A total of 120 patients were included. Twenty-nine (24%) had extra-skeletal and 91 (76%) had skeletal ES. Location was in the extremity in 51 (43%) and non-extremity in 69 (57%). For extra-skeletal ES, tumors originated from soft tissue in 23 (79%), and viscera in 6 (21%). All patients received standard vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VDC-IE), with a plan for local control at week 12 of the protocol. Local control was by surgery in 76 (63%) and radiotherapy in 44 (37%). At a median follow up of 38 months, there was no difference in 5-year OS between extra-skeletal and skeletal ES patients (67% and 70% respectively, p = 0.96). Patients with visceral ES had inferior 5-year OS compared to all others (soft-tissue extra-skeletal and skeletal ES); 33% vs. 72%; p = 0.013. Resectability rate was not different between extra-skeletal and skeletal ES patients (54% and 69% respectively, p= 0.11). Furthermore, among patients who underwent surgery, there was no difference between extra-skeletal and skeletal ES patients in R0 resection rate (86% and 89% respectively, p= 0.52) and poor ( < 90%) tumor necrosis rate (62% and 46% respectively, p= 0.31). However, more local recurrences (28% vs. 10%, p= 0.034) and inferior 5-year LRFS (74% vs. 83%; p = 0.042) were observed in the extra-skeletal group, although more extra-skeletal patients received adjuvant radiotherapy; 11 (73%) vs. 21 (36%), p = 0.01. Conclusions: Patients with localized extra-skeletal ES have OS outcomes that are comparable to skeletal ES treated with standard VDC-IE chemotherapy. However, extra-skeletal ES patients are at significantly higher risk of local recurrence.
Clinical characteristics of nonosteogenic, non-Ewing’s sarcoma of the bone: Experience at the Toronto Sarcoma Program.
Authors: Veitch Zachary William Neil , Ferguson Peter Charles , Griffin Anthony , Alshammari Kanan , Al-Ezzi Esmail Mutahar , Malone Eoghan Ruadh , Demicco Elizabeth , Dickson Brendan , Catton Charles N. , Chung Peter W. M. , Gupta Abha A. , Abdul Razak Albiruni Ryan , Wunder Jay
Published: March 2020

11029

Background: Non-osteogenic sarcoma of the bone is a rare entity comprising a heterogenous group of malignant tumors. Clinical characteristics and outcome data are sparse in the literature. We evaluated the characteristics and long-term outcomes of patients (pts) with this disease. Methods: Pts with non-osteogenic sarcoma of the bone treated at the Toronto Sarcoma Program from 1987-2017 were identified from our institutional sarcoma database. Patient characteristics (ie: age, gender, tumor size, histology, grade, necrosis, tumor location), treatment modality (ie: surgical management, chemotherapy, radiotherapy), and survival information were collected. Survival was estimated by Kaplan-Meier (log-rank). Multi-variate analysis (MVA) was used to evaluate characteristics for sarcoma specific survival. Results: Of 130 pts identified, 106 had non-metastatic disease with a median age of 46 (range 18-89). Male-to-female predominance was 1.5:1. Common histologies were undifferentiated pleomorphic sarcoma (UPS; 42%), leiomyosarcoma (21%), and fibrosarcoma (11%). Tumors were generally high grade (59%) and > 5 cm in size (73%). The majority of pts received chemotherapy (68%), with Cisplatin/Doxorubicin based regimens (95%). R0 resection was achieved in 85% of cases. Survival for the entire cohort, showed a median (m)DFS of 8.13 years (95%CI:2.52-18.02), and a mOS of 11.72 (95%CI:7.00-not reached [NR]). Median sarcoma specific survival was NR, however 15- and 25-year survivals were 60.4% and 52.6% respectively. MVA demonstrated axial tumor location (HR = 13.03; p = 0.005), no chemotherapy (HR = 4.50; p = 0.017) and tumor grade (G2: HR = 36.21; p = 0.012; G3: HR = 20.30; p = 0.015) as risk factors for sarcoma specific death. Tumor size > 10cm (p = 0.085) and necrosis > 90% (p = 0.082) trended towards significance. Conclusions: Non-osteogenic sarcoma of the bone is a rare tumor entity, with a predominant UPS histology. Patient outcomes are reasonable, with measurable long-term survival. Axial tumor location, absence of chemotherapy, and high-grade disease predict for worse survival outcome. Further evaluation with larger data series is warranted to more fully understand this disease.
Multidisciplinary treatment of 99 adult osteosarcoma (OST) patients (pts) with synchronous and metachronous metastases (mets): A retrospective series of the French Sarcoma Group (FSG).
Authors: Lavit Elise , Aldea Mihaela , Isambert Nicolas , Kurtz Jean-Emannuel , Delcambre Corinne , Lebrun-Ly Valerie , Soibinet-Oudot Pauline , Chevreau Christine , Bompas Emmanuelle , Le Maignan Christine , Boudou-Rouquette Pascaline , Le Cesne Axel , Mancini Julien , Blay Jean-Yves , Duffaud Florence
Published: March 2020

11030

Background: Treatment (trt) options for metastatic OST are scarce. Following failure of standard 1st line therapy pts who relapse present a challenging trt dilemma, and have poor prognosis. Surgical removal of all mets is essential. Currently, there are no standardized 2nd line trt options in relapsed OST. Methods: Pts were identified from 2 sarcoma databases; Netsarc and ConticaBase. Clinical data prospectively registered in the databases were supplemented with retrospective review of the medical records. Results: From January 2009 to December 2016, we identified 99 pts, in 12 FSG centers; 30 with synchronous (SC) and 69 with metachronous (MC) mets, with 62 males. Median age was 25 years (18-53). Total number of mets was 1 for 31 pts, 2-5 for 26 and > 5 for 42. Mets sites were lung, bone and other in 77, 14 and 22 pts respectively. Median time to first MC mets was 22 months (mo) (4-97). All pts except 10 with MC mets received a 1st line systemic trt for relapse, 65 a 2d-line, 38 a 3d-line, and 20 a 4th line, with 27 pts included in a clinical trial. Sixty five pts had local trt of distant mets (surgery for 54, irradiation for 5 and radioablation for 6). Eighteen pts had repeated thoracotomies (2 for 13 pts, 3 for 5, 1 for 1 pt). Nine of 10 MC mets pts (with ≤ 5mets) who never received any systemic trt had complete mets resection, 1 had mets radioablation, all were alive at last follow-up (FU). Median FU was 16.5 mo (2-132). Median progression free survival (PFS) and overall survival (OS) were 5.5 (95%CI 4-7) and 16.5 mo (95%CI 10-25) respectively. In multivariate analysis; > 5 mets, time to 1st mets < 24 mo, were negative prognostic factors on OS and PFS (p= 0.03, 0.01 and p=0.013, 0.00 respectively). Bone mets and absence of mets surgery were negative prognostic factors on OS only (with p=0.012, 0.008). Conclusions: Adult OST pts with distant mets are heterogeneous with poor prognosis. Complete surgery of distant mets remains essential. In reference sarcoma center, OST pts at relapse with > 1 mets commonly receive >1st line of systemic trt, and are included in clinical trial. Multidisciplinary trt combining complete mets local trt and systemic therapy seems to be rational.
Multi-institutional european single-arm phase II trial of pazopanib in advanced typical solitary fibrous tumors (SFT): A collaborative Spanish (GEIS), Italian (ISG), and French (FSG) sarcoma groups study.
Authors: Jurado Josefina Cruz , Dumont Sarah Naomie , Penel Nicolas , Luna Fra Pablo , Alava Enrique , Hindi Nadia , Blay Jean-Yves , Stacchiotti Silvia , Collini Paola , Redondo Andres , Bernabeu Daniel , Lopez-Pousa Antonio , Grignani Giovanni , Moura David Silva , Martinez-Trufero Javier , Terrier Philippe , Karanian Marie , Le Cesne Axel , Casali Paolo Giovanni , Martin Broto Javier
Published: March 2020

11038

Background: SFT is a ubiquitous uncommon soft tissue sarcoma with a pronounced hemangiopericytoma-like vascular pattern, exhibiting rich VEGF (tumor and endothelial cells) and VEGFR1/2 (endothelial cells) expression. Pathologists distinguish typical SFT (T-SFT) and malignant SFT (M-SFT) based on mitosis (≤4 vs > 4), pleomorphism or necrosis. Yet, not clear boundaries are always seen between both subtypes. We have recently published a phase II trial exploring the activity of pazopanib (P) in M-SFT (Lancet Oncol Dec 2018). Here, we present the outcome of the T-SFT cohort of the same trial. Methods: Most relevant inclusion criteria were: unresectable or metastatic, T-SFT (tumor tissue from diagnostic time) confirmed by central pathology review before accrual, with evidence of STAT6 overexpression (IHC and FISH and/or NGS), ≥18 years, ECOG 0-2, progressive, measurable disease and no previous antiangiogenic agents. Main endpoint was response rate according to Choi criteria. Central radiological assessment was mandatory. P was administered at 800 mg/d continuously till progression or toxicity. Results: From June 2014 to December 2018, 34 patients were enrolled in this cohort. The median age was 64 y (31-81). At baseline, ECOG 0/1/2 was distributed as 16/15/3; whereas, locally advanced/metastatic distribution was 11 (32%) and 23 (68%) respectively. At the time of the present analysis, 24 patients were deemed eligible and evaluable for response. Response rates according to local and central assessment were PR 6 (25%), SD 15 (62%), PD 3 (12%) and PR 12 (50%), SD 11 (46%), PD 1 (4%). With a median follow-up of 21 months, the median PFS following local and central assessment were 18.4 (6.6-30.1) and 9.8 (7.5-12.2) months respectively, both were clearly superior to that previously published in M-SFT cohort (5.57 m). The median of OS was 49.8 months. High tumor burden at baseline > 116 mm, ECOG 1-2 vs 0, and PD by local or central response assessment showed significantly worse OS. Metastatic vs locally advanced patients had a similar outcome regarding OS. Conclusions: T-SFT cohort exhibited clearly longer PFS than previous reported M-SFT cohort to pazopanib treatment, and pazopanib showed to improve the historical outcome obtained with chemotherapy in advanced SFT. Clinical trial information: NCT02066285.
Survival and signals of response in advanced sarcoma patients enrolled on phase 1 trials in the era of precision oncology and novel immunotherapies.
Authors: Sen Shiraj , Hess Kenneth R. , Hong David S. , Falchook Gerald Steven , Pestana Roberto , Janku Filip , Naing Aung , Benjamin Robert S. , Patel Shreyaskumar , Meric-Bernstam Funda , Subbiah Vivek
Published: March 2020

11063

Background: Few effective US FDA approved therapies exist for refractory, metastatic sarcomas. Many of these patients therefore enroll onto phase 1 clinical trials. Because tumor-specific outcomes are not always reported in less common cancers such as sarcomas, outcomes of sarcoma patients treated with novel immunotherapy and targeted therapy approaches remains unknown. Methods: We analyzed clinical and next generation sequencing data from all sarcoma patients treated on phase 1 trials at MD Anderson Cancer Center (MDACC) and performed logistic and Cox proportional hazards regression analyses to evaluate response rate (RR), median time to progression (mTTP), clinical benefit rate (CBR; defined as CR, PR, or SD > 6 months), and median overall survival (OS). Results: Among the 406 patients with advanced sarcomas (321 soft tissue sarcoma, 85 bone sarcomas) treated on phase 1 trials at MDACC from May 2006 to May 2018, median age was 53 (range 11-84), 48% were female, with a median 3 prior lines of therapy (range 0-9). The most commonly treated soft tissue sarcoma subtypes included leiomyosarcoma (n = 66; 16%), liposarcoma (n = 52; 13%), GIST (n = 44; 11%), UPS (n = 14; 3%), and synovial sarcoma (n = 11; 3%) and most commonly treated bone sarcomas included osteosarcoma (n = 34; 8%), chondrosarcoma (n = 28; 7%), and Ewing’s sarcoma (n = 25; 6%). RR was 7% (95% CI 5, 10), mTTP was 2.9 months (95%CI 2.6, 3.1), CBR was 24% (95% CI 20, 29), mOS was 17.2 months (95% CI 13.8, 20.8). 2 patients had a CR as best response, 1 chondrosarcoma patient treated with an anti-APO2L/Trail agent and 1 Ewing’s sarcoma patient treated with the combination of an IGF1R inhibitor plus mTOR inhibitor. 26 patients (6%) had a PR as best response using novel immunotherapies targeting PD1, PDL1 plus CCR4, CTLA4 plus KIT, and TLR7/8 and novel targeted therapies against TRK, LRRC15, cMET, mTOR, VEGF, MDM2, KIT/PDGFRA, and FGFR. Responses were seen across sarcoma subtypes - ASPS, UPS, myxoid sarcoma, liposarcoma, GIST, carcinosarcoma, clear cell sarcoma, embryonal rhabdomyosarcoma, epitheliod sarcoma, fibrious histiosarcoma, and Ewing’s sarcoma. Conclusions: Our analysis identifies a reasonable survival in heavily pretreated, metastatic refractory sarcoma patients with responses seen with novel targeted therapies and immunotherapies that are not yet US-FDA approved. Biomarker analysis is ongoing to help identify the subset of responders in our cohort. Advanced sarcoma patients should be considered for molecular profiling and early phase clinical trials.
Translational study associated to a phase II study evaluating the activity of pazopanib in patients (pts) with advanced/metastatic liposarcoma (LPS): A joint Spanish Sarcoma Group (GEIS) and German Interdisciplinary Sarcoma Group (GISG) study.
Authors: Valverde Morales Claudia Maria , Fernandez Serra Antonio , Ramírez-Calvo Marta , Lopez-Martin Jose A. , Romagosa Cleofe , Carrasco Juan Antonio , Bauer Sebastian , Martinez Trufero Javier , Jurado Josefina Cruz , Reichardt Peter , Serrano Cesar , Grünwald Viktor , Luna Fra Pablo , Persiva Oscar , Varona Diego , Morales-Barrera Rafael , Kasper Bernd , Martin Broto Javier , Ruiz-Sauri Amparo , Lopez-Guerrero Jose Antonio
Published: March 2020

11067

Background: GEIS 30 was a phase II study showing moderate activity of pazopanib in well-differentiated/dedifferentiated LPS (cohort A:37 pts, Progression free Survival (PFS) at 12 weeks (w) 43.2%) and no activity in Myxoid/round cell LPS (cohort B: 15 pts, PFS at 12w 13.3%). The present study aims to identify tumor and plasma biomarkers that are differently expressed in long responders (LRs) PFS > 24 w. Methods: Serum samples and paraffin-blocks at diagnosis were collected for 28 pts in cohort A and 11 in B. A total of 13 pts were LRs. Serum samples were obtained at baseline, after 3 w of treatment and at progression. A panel of 15 cytokines and growth factors were evaluated using Luminex technology (Millipore). Paraffin-blocks were evaluated for microvessel density (MVD) by CD31 immunostaining and Image Pro-Plus 7.0 Image Analysis System (Media-Cybernetics). For RNA expression analysis, the Oncology Biomarker Panel with probes for 2559 transcripts was used (HTG Molecular Diagnostics). Results: Serum cytokines showed that expression of angiopoietin (AGO) and BMP9 decreases during treatment, whereas GCSF increases. In addition, AGO and BMP overexpression at baseline was associated with worse prognosis in arm A (p = 0.09) and B (p = 0.01) respectively. No differences between study arms and outcome were appreciated by MVD. Gene expression revealed differences in some immunomodulators: PDL-1 was correlated with serum cytokines VEGFD (p = 0.04) and LEPTIN (p = 0.02); and PD-1 with VEGFD (p = 0.04), LEPTIN (p = 0.02), VEGFA (p = 0.02) and ANGIO (p = 0.03). PD1, in addition,was overexpressed in LRs (p = 0.05). Interestingly, three groups were identified in cohort A according to gene expression: Cluster 1, characterized by short-responder patients with the shortest overall survival, whereas cluster 3 (40% LRs) and 2 (63.6% LRs) showed longer survival rates (14.3%, 45.5% and 30% respectively) (p = 0.001). Conclusions: Gene expression profiling unveils three WD/DD-LPS biotypes according to their response to pazopanib, which could be potentially used to select pts for treatment
Frequent mutations of genes predisposing to Rho GTPase signal activation and autophagy inhibition in metastatic soft tissue sarcoma unveiled by paired somatic and germline genomic analyses.
Authors: Takahashi Katsuhito , Motoki Ayako , Yashima Jun , Masaki Noriyuki , Sano Hiroko , Yamamoto Hiromasa , Sou Junichi , Takahashi Yuko , Toyooka Shinichi , Oyama Yu , Nomori Hiroaki , Narahara Hiroyuki , Yotsumoto Junko , Ono Yasuo , Tonsho Makoto , Teraoka Satoshi
Published: March 2020

11071

Background: Soft tissue sarcoma (STS) is well-known rare cancer with few therapeutic options. Although recent genomic analyses of sarcoma revealed few somatic mutations, massive copy number variations (CNV) and chromoplexy which correlate with worse clinical outcomes, their molecular and genomic mechanisms remain to be understood. Methods: We recruited 116 patients (102 female and 14 male, mean age 50, 80 LMS, 14 LPS, 3 AS and others) and performed whole exome sequencing with the methods as reported in ASCO2018. In addition to somatic mutations, we evaluated germline and CNV contributions in tumor to find LOH mutations by Strelka and Virmid analysis softwares. Results: Of the total of 135-4717 (mean 1129) mutations in tumors, 3-111 (mean 32) mutations were found in 595 COSMIC genes including both somatic and LOH mutations. Less than 33% LOH in the total of somatic and LOH mutations significantly correlated with improved 5-year survival rate as compared with patients with more LOH (81% vs 52%, P=0.01). Among the 224 genes reported in somatic mutations of sarcoma, damaging mutations in ARHGAPs, Rho GTPase signal inactivating genes, were most frequently detected in 59% of total (n=116) and 63% of leiomyosarcoma (n=80) patients as in somatic and/or LOH mutations. Patients with ARHGAP mutations were significantly reduced 5-year survival rates as compared with patients without mutation (51% vs 76%, P=0.007). Among the 163 genes involved in autophagy, a key silencing process for active RhoGTPase, one or more damaging mutations as in somatic and/or LOH mutations were found in 87% in total and 96% in leimyosarcoma patients. Conclusions: Our results, for the first time, suggest an important role of mutations in genes involved in Rho GTPase and autophagy signaling, both well known regulator of chromosomal stability, invasion and metastasis of tumor cells, and thus implicate a potential therapeutic target in STS.