Delta-Radiomics Predicts Response to First-Line Oxaliplatin-Based Chemotherapy in Colorectal Cancer Patients with Liver Metastases

The purpose of this paper is to develop and validate a delta-radiomics score to predict the response of individual colorectal cancer liver metastases (lmCRC) to first-line FOLFOX chemotherapy. Three hundred one lmCRC were manually segmented on both CT performed at baseline and after the first cycle of first-line FOLFOX, and 107 radiomics features were computed by subtracting textural features of CT at baseline from those at timepoint 1 (TP1). LmCRC were classified as nonresponders (R−) if they showed progression of disease (PD), according to RECIST1.1, before 8 months, and as responders (R+), otherwise. After feature selection, we developed a decision tree statistical model trained using all lmCRC coming from one hospital. The final output was a delta-radiomics signature subsequently validated on an external dataset. Sensitivity, specificity, positive (PPV), and negative (NPV) predictive values in correctly classifying individual lesions were assessed on both datasets. Per-lesion sensitivity, specificity, PPV, and NPV were 99%, 94%, 95%, 99%, 85%, 92%, 90%, and 87%, respectively, in the training and validation datasets. The delta-radiomics signature was able to reliably predict R− lmCRC, which were wrongly classified by lesion RECIST as R+ at TP1, (93%, averaging training and validation set, versus 67% of RECIST). The delta-radiomics signature developed in this study can reliably predict the response of individual lmCRC to oxaliplatin-based chemotherapy. Lesions forecasted as poor or nonresponders by the signature could be further investigated, potentially paving the way to lesion-specific therapies.

411 INNATE: immunotherapy during neoadjuvant therapy for rectal cancer to elucidate local and systemic therapeutic responses

BackgroundThe relative risk of developing rectal cancer has quadrupled in young adults over the last 40 years and approximately 50% of patients develop recurrence within 3 years. Thus, there is a critical need for new approaches to improve survival but cancer Immunotherapy has had little impact on colorectal cancer. The anti-CD40 agonist immunotherapy is emerging and APX005M has shown promise in phase I and ongoing phase II trials. Anti-CD40 can stimulate both innate and adaptive immune responses and a greater response can be achieved combining anti-CD40 with radiation therapy (RT) in animal models. We developed the INNATE trial, a phase II randomized trial of neoadjuvant short course RT followed by chemotherapy with or without the addition of APX005M for rectal cancer (NCT04130854).MethodsThe INNATE trial is a multi-center, 58 patient, 3:2 randomization clinical trial, that adds APX005M to short course RT (SCRT) and subsequent FOLFOX chemotherapy prior to definitive radiation. Eligibility includes stage III and high risk stage II rectal cancer and candidates for standard neoadjuvant therapy and no contraindications for immunotherapy or radiation. Patients receive 5Gy x 5 fractions over five days and if randomized to experimental arm will receive APX005M on day 3 of radiation. After a two week break patients receive an optional endoscopy and biopsy followed by standard FOLFOX chemotherapy with APX005M infusion after disconnection of 5-FU chemotherapy pump. Study arm receives APX005M with 5 of 6 cycles of FOLFOX. After treatment patients undergo restating, endoscopy, and trans abdominal resection. The primary endpoint is pathologic complete response with the null estimated to be 20% and alternative 50% for a power of 0.8 and type 1 error of 0.1. Secondary endpoints include overall survival, toxicity analysis, and disease free survival. For correlative analysis, tissue is collected pre-treatment, two weeks after RT, and at surgery, then blood collected during treatment and at follow up.ResultsTo date 16 patients have been randomized and initiated treatment. The treatment is well tolerated. Fiveteen patients received pre- and post-SCRT biopsies. The study team plans correlative analysis including single cell RNA sequencing, multiplex imunohistochemistry, and bulk sequencing. Preliminary data shows changes in the immune tumor microenvironment from patients treated as their own control and between SCRT versus SCRT + APX00M.ConclusionsThe INNATE trial shows feasibility of incorporating novel immunotherapies with an emerging standard of care incorporating short course RT. It serves as an important platform for scientific and clinical investigation.Trial RegistrationClinicaltrialsgov: NCT04130854Ethics ApprovalThe clinical trial has institutional review board approval at the University of Texas Southwestern, Oregon Health and Sciences University, Wake Forest, and Moffitt. All patients have provided informed consent.

Transcriptomic Analysis Identifies Complement Component 3 as a Potential Predictive Biomarker for Chemotherapy Resistance in Colorectal Cancer

Objective: 5-fluorouracil- and oxaliplatin-based FOLFOX regimens are mainstay chemotherapeutics for colorectal cancer (CRC) but drug resistance represents a major therapeutic challenge. To improve patient survival, there is a need to identify resistance genes to better understand the mechanisms underlying chemotherapy resistance.Methods: Transcriptomic datasets were retrieved from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and combined with our own microarray data. Weighted gene co-expression network analysis (WGCNA) was used to dissect the functional networks and hub genes associated with FOLFOX resistance and cancer recurrence. We then conducted analysis of prognosis, profiling of tumor infiltrating immune cells, and pathway overrepresentation analysis to comprehensively elucidate the biological impact of the identified hub gene in CRC.Results: WGCNA analysis identified the complement component 3 (C3) gene as the only hub gene associated with both FOLFOX chemotherapy resistance and CRC recurrence after FOLFOX chemotherapy. Subsequent survival analysis confirmed that high C3 expression confers poor progression-free survival, disease-free survival, and recurrence-free survival. Further correlational analysis revealed significant negative association of C3 expression with sensitivity to oxaliplatin, but not 5-fluorouracil. Moreover, in silico analysis of tumor immune cell infiltration suggested the change of C3 expression could affect tumor microenvironment. Finally, gene set enrichment analysis (GSEA) revealed a hyperactivation of pathways contributing to invasion, metastasis, lymph node spread, and oxaliplatin resistance in CRC samples with C3 overexpression.Conclusion: Our results suggest that high C3 expression is a debilitating factor for FOLFOX chemotherapy, especially for oxaliplatin sensitivity, and C3 may represent a novel biomarker for treatment decision of CRC.

Adenocarcinoma of the Jejunum: A Case Report and Literature Review

Small intestine cancers account for 1-3% of all gastrointestinal tumors, with only 11-25% of these tumors located in the jejunum. We report the case of a woman who has been experiencing abdominal pain for the last six months, accompanied by nausea, vomiting and appearance of dark-colored stools, who has lost 20 kg in weight during the last few months. Laboratory findings indicated anemia and no significant changes were identified in the abdominal ultrasound. By endoscopic examination of the stomach and duodenum and by colonoscopy, no infiltrations were found. Serum markers were elevated and CT scan of the abdomen showed thickening of a part of the jejunum wall with swollen lymph nodes in the mesentery, along the inferior vena cava and abdominal aorta, in the retroperitoneal space. By opening the abdominal cavity, we observed an infiltration in the initial part of the jejunum with an infiltration of the entire wall. Resection of the jejunum with related mesenthery, vessels and lymph nodes therein was performed. Histopathology revealed an invasive adenocarcinoma of the small intestine, with an invasion of all layers of the wall and mesentery. Adjuvant FOLFOX chemotherapy was introduced, 6 cycles in total, and following each cycle, tumor markers have been constantly decreasing. No relapse has been identified after nine months. Due to often deep position in the small intestine, atypical symptomatology and lack of screening, an early diagnosis is difficult. Surgical resection of the affected small intestine followed by an additional chemotherapy is the optimal treatment strategy.