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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 (n = 78) and 8-week on-treatment (n = 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.

Comparison of tumor PD-L1 expression and tumor immune infiltrate between baseline tumor biopsies from responders and nonresponders (STS only)

Comparison of tumor PD-L1 expression and tumor immune infiltrate between baseline biopsies and at 8 weeks on treatment (STS only)

Response to anti-PD1 therapy is associated with higher levels of PD-L1 expression by (A) tumor cells and (B) tumor infiltrating macrophages and higher density of sarcoma-associated immune infiltrates at baseline. Tumor biopsies obtained from patients who responded to pembrolizumab therapy had higher baseline density (cell count/mm2) of tumor infiltrating (C) T lymphocytes, (D) cytotoxic T lymphocytes, (E) antigen experience T lymphocytes, (F) antigen experienced cytotoxic T lymphocytes, (G) activated cytotoxic T lymphocytes, (H) effector memory cytotoxic T lymphocytes, and (I) regulatory T lymphocytes. Baseline tumor samples available for immune profiling by IHC were obtained prior to anti-PD1 treatment (8 responder and 58 non-responder patients). Error bars represent SEM. * = p{less than or equal to}0.05, ** = p{less than or equal to}0.01, *** = p{less than or equal to}0.001, n.s. = not significant.

Comparison of tumor PD-L1 expression and tumor immune infiltrate between baseline biopsies and at 8 weeks on treatment (bone only)

SARC028 tumor biopsies obtained at baseline and after 8 weeks treatment and associated patient response to pembrolizumab

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Demographic and clinical characteristics of 84 eligible, treated patients

Comparison of tumor PD-L1 expression and tumor immune infiltrate between baseline biopsies and at 8 weeks on treatment (UPS/DDLPS only)

Comparison of tumor PD-L1 expression and tumor immune infiltrate between baseline tumor biopsies from responders and nonresponders (UPS/DDLPS only)

BACKGROUND Bone sarcoma survivors are at high risk for multiple chronic diseases at a young age, which can be characterized as premature aging. Bone sarcoma survivors have the highest cumulative incidence of multiple serious chronic conditions according to analysis of the Childhood Cancer Survivor Study 1. Cardiovascular biomarkers can be used to detect CAD, and enable early intervention in asymptomatic patients. METHODS Patients are seen annually at the Sarcoma Survivorship Clinic at the University of Michigan and includes high risk patients over the age of 18 who are at least two years free of disease after treatment completion. Clinical data includes: Blood Pressure, BMI, lipid profile, high sensitivity C-Reactive Protein, and imaging. RESULTS 30% of patients aged 18-39 exhibit elevations in the cardiovascular biomarker hsCRP, in addition to the traditional biologic markers of elevated lipids, hypertension, and BMI at their most recent clinic visit (Table 1). A subset of patients independently evaluated by 2 nuclear cardiologists also show evidence of coronary artery calcifications (CAC), which is considered pathognomonic of CAD. 40% have been diagnosed with 2 or more of the following chronic diseases: dyslipidemia, obesity, renal insufficiency, anxiety and/or depression, pulmonary disease, cardiovascular disease, thyroid dysfunction, hypertension, liver disease, and anemia. CONCLUSION The overall cardiac risk profile among high risk bone sarcoma survivors is characteristic of premature aging. Examining the underlying mechanism of premature aging is essential in this population. Proposed investigation includes alteration of immune pathway as effected by diet, the microbiome, metabolomics, and cellular senescence. REFERENCES: 1. Gibson TM et al: Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970-99: a report from the Childhood Cancer Survivor Study cohort. The Lancet Oncology 2045:1-12, 2018 Characteristics of bone sarcoma survivors, aged 18-39 (n=20)Chronic Disease Diagnosis%1502253+15Cardiovascular biomarkershsCRP ≥ 2.030BMI ≥ 3015Cholesterol ≥ 200 mg/dL12Hypertension ≥130/8015Glucose ≥ 100 mg/dL20CAC>015 Citation Format: Laurence H. Baker, Denise Reinke, Philip Boonstra, Erin Peregrine Antalis. Detection of premature aging among adolescent and young adult osteosarcoma and Ewings sarcoma survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3145.

Contains fulltext : 167540.pdf (Publisher’s version ) (Open Access) This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24-25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas.

Gastrointestinal stromal tumors (GISTs) have an incidence of 7-15 occurrences per million people. Tyrosine kinase inhibitors (TKIs) have significantly improved clinical outcomes as part of multidisciplinary disease management. The authors will review developments in the management of GISTs, including diagnosis, risk stratification, prognosis, and treatment with imatinib. Imatinib is recommended for postsurgical adjuvant therapy and, where appropriate, neoadjuvant therapy. Clinical practice guidelines recommend first-line imatinib for metastatic and unresectable GISTs based on trials showing efficacy at the standard dose (400 mg per day) and at higher doses of 600-800 mg per day. Oncology nurses play a key role in patient management through (a) patient education about GISTs and their treatment including the use of imatinib, (b) timely scheduling of radiologic follow-up to assess treatment response, (c) monitoring treatment adherence, (d) helping to sustain imatinib dose intensity by monitoring toxicities and drug interactions and by counseling patients to prevent treatment interruptions, and (e) collaborating with the multidisciplinary medical team to pursue imatinib dose escalation or other treatment options if patients have primary or acquired mutation-based resistance to imatinib.

Standing orders serve an important role in various healthcare settings by empowering nurses to implement certain procedures and activities on behalf of physicians, enabling more immediate interventions, and ultimately improving patient care. Standing orders are based on established clinical practice guidelines and are well suited for supportive interventions. Several evidence-based clinical practice guidelines are available for the treatment of anemia in patients with cancer. The guidelines can serve as a basis for the development of standing orders for the management of treatment-related anemia in patients with cancer, which will enable the delivery of consistently high-quality care to patients. A major advantage to the implementation of standing orders is that patients with suboptimal hemoglobin levels can be treated by oncology nurses in a timely manner and receive high-quality care that is consistent with available clinical evidence.

Purpose Gemcitabine as a single agent and the combination of gemcitabine and docetaxel have activity in patients with metastatic soft tissue sarcoma. To determine if the addition of docetaxel to gemcitabine improved clinical outcome of patients with metastatic soft tissue sarcomas, we compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. Patients and Methods In this open-label phase II clinical trial, the primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions. Results One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999. Conclusion Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy.

Oral chemotherapy is emerging as a new option for well-selected patients who can manage potentially complex oral regimens and self-monitor for potential complications. If a choice between oral and parenteral therapy is available, patients may opt for oral chemotherapy because it is more convenient to administer, allows them to avoid multiple office visits, and gives them a sense of control over their own cancer care. Whether these potential advantages are maintained in regimens that combine oral and parenteral drugs is less clear. The use of oral chemotherapeutic agents profoundly affects all aspects of oncology, including creating significant safety and adherence issues, shifting some traditional roles and responsibilities of oncologists, nurses, and pharmacists to patients and caregivers. The financing of chemotherapy is also affected. To address these issues, the NCCN convened a multidisciplinary task force consisting of oncologists, nurses, pharmacists, and payor representatives to discuss the impact of the increasing use of oral chemotherapy.