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Purpose: Success of clinical trials increasingly relies on effective selection of the target patient populations. We hypothesize that computational analysis of pre-accrual imaging data can be used for patient enrichment to better identify patients who can potentially benefit from investigational agents. Methods: This was tested retrospectively in soft-tissue sarcoma (STS) patients accrued into a randomized clinical trial (SARC021) that evaluated the efficacy of evofosfamide (Evo), a hypoxia activated prodrug, in combination with doxorubicin (Dox). Notably, SARC021 failed to meet its overall survival (OS) objective. We tested whether a radiomic biomarker-driven inclusion/exclusion criterion could have been used to improve the difference between the two arms (Evo + Dox vs. Dox) of the study. 164 radiomics features were extracted from 296 SARC021 patients with lung metastases, divided into training and test sets. Results: A single radiomics feature, Short Run Emphasis (SRE), was representative of a group of correlated features that were the most informative. The SRE feature value was combined into a model along with histological classification and smoking history. This model as able to identify an enriched subset (52%) of patients who had a significantly longer OS in Evo + Dox vs. Dox groups [p = 0.036, Hazard Ratio (HR) = 0.64 (0.42–0.97)]. Applying the same model and threshold value in an independent test set confirmed the significant survival difference [p = 0.016, HR = 0.42 (0.20–0.85)]. Notably, this model was best at identifying exclusion criteria for patients most likely to benefit from doxorubicin alone. Conclusions: The study presents a first of its kind clinical-radiomic approach for patient enrichment in clinical trials. We show that, had an appropriate model been used for selective patient inclusion, SARC021 trial could have met its primary survival objective for patients with metastatic STS.

Supplementary Methods, radiologist's reading of CT images, supplementary figure legends, supplementary references

microCT scans

SFigure 1: Histological examination of mouse lungs; SFigure 2: Tissue sections from human lung adenocarcinoma; SFigure 3: Cabozantinib (CBT) and vandetanib (VDT) resistant cells; SFigure 4: Comparison of in vitro inhibition of RET, RETV804L and RETV804M by ponatinib, cabozantinib, vandetanib, and lenvatinib; SFigure 5: Ponatinib treatment schedule and body weight measurements; SFigure 6: Lung section histology from Dox-induced C/KR mice and treated with vehicle or ponatinib for 1 months; SFigure 7: μCT examination of dox-induced C/KR mice with lung tumors before and after one month treatment with vehicle or ponatinib.

We report a case of a 25-year-old pregnant woman diagnosed with a large, unresectable retroperitoneal synovial sarcoma. Successful neoadjuvant treatment with doxorubicin plus ifosfamide prepartum and continuing postpartum resulted in significant disease response allowing for later tumor resection. Following the first prepartum chemotherapy cycle, a decreased amniotic fluid index was noted, representing a potential complication of chemotherapy. Induction of labor was performed at 33 weeks gestation with excellent outcome in the newborn. This case highlights the complex medical decision-making process in the setting of cancer diagnosed during pregnancy, balancing oncologic and obstetric concerns, and to our knowledge is only the second reported case of synovial sarcoma treated with neoadjuvant cytotoxic chemotherapy in the antepartum period.

Lessons from extinction can be used in trials designed to pursue a cure for cancer. When cancer cannot be cured, similar strategies may be unwise, and strategies that leverage the adaptations of cancer to therapy should be considered.

TPS7594 Background: Phosphoinositide 3-kinase (PI3K) inhibitors have shown promising activity in lymphoid malignancies such as mature T cell lymphoma, diffuse large B cell lymphoma, and mantle cell lymphoma. Duvelisib’s PI3K-δ and PI3K-γ activity in T cell lymphoma is promising as a single agent (Horwitz, Koch et al. 2018). While the safety profile can generally be managed, certain autoimmune adverse events may limit its adaptation in clinical practice. Azacitidine, a pyrimidine nucleoside analog of cytidine, is active in T cell lymphoma (Saillard, Guermouche et al. 2017) as well as in DLBCL (Martin, Bartlett et al. 2018). Hypomethylators could enhance the activity of PI3K inhibitors through increasing PTEN expression (Spangle, Roberts et al. 2017), and upregulation of tumor suppressor genes (Zuo, Liu et al. 2011). Duvelisib’s immune mediated adverse events may be related to shifts in T cell differentiation towards Th17 phenotype and decreases in T reg differentiation that found to be more pronounced in patients with higher immune related toxicity (Gadi, Kasar et al. 2019). Studies have shown that T regs can be induced from Cd4+CD25- T cells using DNA methyltransferase inhibition with azacitidine (Fagone, Mazzon et al. 2018). Thus, the intermittent administration of azacytidine can potentially restore the balance by increasing T regs to decrease the autoimmune toxicity while maintaining Th17 phenotype that enhances tumor killing as shown in myelodysplastic syndrome (Jia, Yang et al. 2020). Methods: This is a 3+3 phase I dose escalation study designed to determine the maximum tolerated dose (MTD) of CC-486 in combination with duvelisib in patients with lymphoid malignancies. The MTD is defined as the highest dose with an observed incidence of dose limiting toxicity (DLT) in no more than one out of six patients treated at a particular dose level. Secondary endpoints include best overall response, disease control rate and duration of response. Exploratory end points will be biomarker driven with focus on the composition of different T cell compartments during the administration of the combination. Efficacy biomarkers will include measuring the phosphorylation of AKT in peripheral CD3+ T cells. Oral duvelisib will be given continuously with the dose escalation maintained during the first 2 cycles while CC-486 schedule will be 14 days on/14 days off. The first cohort of patients are enrolled, and are in the DLT testing period. Clinical trial information: NCT05065866.

PurposeSuccess of new cancer therapies relies strongly on effective selection of the target patient populations. We hypothesize that computational analysis of imaging data can be used for patient enrichment in clinical trials and hence aimed to establish the appropriate framework for this analysis.MethodsThis was tested among soft-tissue sarcoma (STS) patients accrued into a randomized clinical trial (SARC021) that evaluated the efficacy of evofosfamide (Evo), a hypoxia activated prodrug, in combination with doxorubicin (Dox). Notably, SARC021 failed to meet its overall survival (OS) objective. We tested whether a radiomic biomarker-driven inclusion/exclusion criterion could have been used to result in a significant treatment benefit of the Evo+Dox combination compared to Dox monotherapy. 164 radiomics features were extracted from 303 SARC021 patients with lung metastases, divided into training and test sets.ResultsA single radiomics feature, Short Run Emphasis, was identified as the most informative. Combined into a model along with histological classification and smoking history, an enriched subset (42%) of patients had longer OS in Evo+Dox vs. Dox groups [p=0.01, Hazard Ratio (HR) =0.57 (0.36-0.90)]. Applying the same model and threshold value in an independent test set confirmed the significant survival difference [p=0.002, HR=0.29 (0.13-0.63)], identifying patients most likely to benefit from doxorubicin alone.ConclusionThe study presents a first of its kind clinical-radiomic approach for patient enrichment in clinical trials. We show that, had an appropriate model been used for selective patient inclusion, SARC021 trial could have met its primary survival objective for patients with metastatic STS.

BACKGROUND: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent sarcoma. Nab-paclitaxel is a taxane modified to improve drug exposure and increase intratumoral accumulation and, in combination with gemcitabine, is standard therapy for pancreatic cancer. Applying the dosages and schedule used for pancreatic cancer, we performed a phase II trial to assess the response rate of gemcitabine and nab-paclitaxel in patients with relapsed Ewing sarcoma. PROCEDURE: Using a Simon’s two-stage design to identify a response rate of ≥ 35%, patients received nab-paclitaxel 125 mg/m(2) followed by gemcitabine 1000 mg/m(2) i.v. on days 1, 8, and 15 of four-week cycles. Immunohistochemical analysis of archival tissue was performed to identify possible biomarkers of response. RESULTS: Eleven patients from four institutions enrolled, with a median age of 22 years (range, 14–27). Patients were heavily pretreated (median 3 prior regimens, range, 1–7). Thirty-five cycles were administered (median 2, range, 1–8). Accrual was stopped after 11 patients, due to only one confirmed partial response. Two other patients had partial responses after two cycles, but withdrew because of adverse effects or progression before confirmation of continued response. The predominant toxicity was myelosuppression, and four (36%) patients were removed due to hematologic toxicity despite pegfilgrastim and dose reductions. Expression of secreted protein, acidic and rich in cysteine (SPARC) and CAV-1 in archival tumors was not predictive of clinical benefit in this small cohort of patients. CONCLUSIONS: In patients with heavily pretreated Ewing sarcoma, the confirmed response rate of 9% was similar to multi-institutional studies of gemcitabine and docetaxel.

Fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) hybrid examinations (PET/computed tomography, PET/magnetic resonance imaging) have become the most common PET imaging tools in the evaluation of the oncologic patient. Therefore it is of paramount importance that physicians who take care of oncology patients in any capacity are familiar with the basics of when these examinations are indicated, know how to best prepare the patients, and understand the benefits and limitations of the procedure. Additionally, it is important to understand which medical conditions and medications need to be controlled to maintain the diagnostic accuracy of these tests. In this article we aim to explain what 18F-FDG is, how to best prepare our patients, what PET is, and how these examinations are interpreted. Finally, we discuss some of the limitations of these examinations.

Parachordoma is a rare entity with less than 50 cases described in the literature. This soft-tissue tumor resembles chordomas as well as extraskeletal myxoid chondrosarcomas and has only recently been fully characterized. Here we describe the case of a patient with a lower back parachordoma and its subsequent postresection recurrence 9 years after the initial procedure, emphasizing the importance of long-term follow-up in individuals with this diagnosis. Keywords: Recurrent parachordoma, Chordoma periphericum, Chordoid sarcoma

105 Background: In the era of precision medicine, development of new cancer therapies relies strongly on effective selection of target patient population. We hypothesize that computational analysis of imaging data can be used for development of a quantitative population enrichment strategy in clinical trials and thus we aim to establish an appropriate framework for this analysis. Methods: This hypothesis was tested among soft-tissue sarcoma (STS) patients accrued into a randomized Phase III clinical trial (SARC021) that evaluated the efficacy of evofosfamide (Evo), a hypoxia activated prodrug, in combination with doxorubicin (Dox). Notably, SARC021 failed to meet its survival objective (PMC7771354). We tested whether an inclusion/exclusion model based on radiomic analysis and relevant clinical covariates could have been employed to result in a significant treatment benefit of the Evo+Dox combination compared to the standard Dox monotherapy. A total of 163 radiomics features were extracted from lung metastases of 303 patients from the SARC021 trial, divided into demographically matched training and test sets. Stability analysis identified the most reproducible features. Univariable and multivariable models were utilized to discriminate OS in the two treatment groups. Results: A bespoke enrichment framework was established for individualized patient selection, based on model-derived risk score threshold. A radiomic feature, Short Run Emphasis, was identified as the most informative. When combined with tumor histology and smoking history information, an enriched subset (42%) of patients had longer OS in Evo+Dox vs. Dox groups [p = 0.01, Hazard Ratio (HR) = 0.57 (0.36-0.90)], overperforming a clinical-only approach. Application of the same model and threshold value in an independent test set confirmed the significant survival difference (p = 0.002, HR = 0.29 (0.13-0.63), 38% patients included). The breakdown of Dox+Evo treatment benefit depending on proportion of patients included based on the model is shown in the Table. Notably, this process also identified patients most likely to benefit from doxorubicin alone. Conclusions: The study presents a first of its kind radiomic approach for patient enrichment in clinical trials based on a quantitative score. In particular, we have shown that had the novel model been used for selective patient inclusion into the SARC021 trial, it would have met its primary survival objective for patients with metastatic STS.[Table: see text]

Fluorine-18 fluorodeoxyglucose (

Kaposi sarcoma (KS) is an uncommon angioproliferative malignancy that is associated with human herpesvirus 8. Although there has been recent enthusiasm for evaluating immune checkpoint inhibition as a therapeutic option for viral-associated tumors, the clinical utility in this disease is currently unknown. We report a case of advanced classic KS refractory to multiple lines of chemotherapy that experienced a partial response to anti-PD-1 therapy. Comprehensive molecular profiling was performed on a diagnostic tumor biopsy sample. Molecular profiling data from 8 additional male patients with KS were reviewed and compared with those of the index case. The genomic profile of the index case was notable for higher-than-typical somatic mutational burden, including pathogenic mutation in multiple well-described cancer genes, such as TP53, CDKN2A, NOTCH1, and KRAS Our case suggests that further clinical study of checkpoint inhibitor therapy in classic KS is warranted, and provides a hypothesis for future immunogenomic biomarker analysis in this disease.