FOLFOX Chemotherapy Research Articles

Immune microenvironment in patients with mismatch-repair-proficient oligometastatic colorectal cancer exposed to chemotherapy: the randomized MIROX GERCOR cohort study.

In the era of immune checkpoint inhibitors, understanding the metastatic microenvironment of proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) is of paramount importance to both prognostication and the development of more effective novel therapies. In this study, primary and paired metastasis tissue samples were collected from patients with resectable metastatic CRC treated with adjuvant FOLFOX or peri‐operative chemotherapy in the MIROX phase III prospective study. In total, 74 cancer tissues were stained for CD3, CD8, Forkhead box protein 3 (FOXP3), programmed cell death protein‐1 (PD‐1, invasive front, stromal, intra‐epithelial compartments), and programmed death‐ligand 1 (PD‐L1, tumor, immune cells). The immune profiling of primary CRC had a limited value to predict the immune context of paired metastases for all markers but CD3+. The expression of CD8 and PD‐L1 was higher in metastases after neoadjuvant FOLFOX. In metastases, both CD3 T cells at the invasive front and PD‐L1 expressions on immune cells were predictive of better disease‐free survival. These results show that the effect of FOLFOX on modifying the immune microenvironment in resected CRC metastases and measurement of PD‐L1 expression and tumor‐infiltrating CD8 T cells in pMMR/MSS metastatic tissue samples could improve treatment strategies of metastatic CRC patients.

Durvalumab (MEDI 4736) with extended neoadjuvant regimens in rectal cancer: A randomized phase II trial (PRIME-RT).

TPS231 Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but many patients still die from distant disease. There is increasing recognition that with neoadjuvant treatment some patients achieve a complete response and may avoid surgical resection. The PRIME-RT trial tests the inclusion of neoadjuvant immunotherapy with the aim of enhancing complete response rates, improving stoma-free survival and reducing distant relapse. Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients are randomised to Arm A: short course radiotherapy (25 Gray in 5 fractions) with concomitant durvalumab, followed by durvalumab and FOLFOX chemotherapy, or Arm B: long course chemoradiotherapy (50 Gray to primary tumour, 45 Gray to elective nodes, in 25 fractions with capecitabine) with concomitant durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Bio-specimens including serial tumour biopsies and peripheral blood samples are collected prior to, during, and following treatment to explore the molecular and immunological factors underpinning treatment response. The main trial will recruit up to 42 patients and commence after a safety run-in (n≥6) which is recruiting patients with metastatic disease. After opening in January 2021, three patients have been treated within the safety run-in; 2 in Arm A and 1 in Arm B. Early recruitment to PRIME-RT has shown that adding immunotherapy in the neoadjuvant setting for LARC is feasible. The expectation is that the trial will provide efficacy and safety information which allows the optimal treatment approach to be tested within a larger phase clinical trial. Funding information Core funding (Glasgow CRUK CTU) and trial specific funding (Astrazeneca). Trial registration Clinicaltrials.gov NCT04621370 (Registered 9 Nov 2020) ISRCTN18138369 (Registered 27 October 2020) Clinical trial information: NCT04621370.

KEYNOTE-B79 phase 1b trial to evaluate the allogeneic CAR T-cells CYAD-101 and pembrolizumab in refractory metastatic colorectal cancer patients.

TPS227 Background: The allogeneic chimeric antigen receptor (CAR) T-cell treatment CYAD-101 utilizes the NKG2D receptor that targets eight ligands expressed on tumor cells and also on stromal and immunosuppressive immune cells of the tumor microenvironment. CYAD-101 co-expresses a T-cell receptor (TCR) inhibitory peptide with the aim to eliminate the potential of graft versus host disease (GvHD), the main safety risk associated with engineered cells of allogeneic origin. In the previous alloSHRINK trial (NCT03692429), CYAD-101 was administered post FOLFOX preconditioning chemotherapy to 15 patients with progressive metastatic colorectal cancer (mCRC) who were previously treated with FOLFOX. Overall, the treatment was well tolerated with no evidence of GvHD. The disease control rate was 73.3% with two patients presenting a confirmed partial response per RECIST’s criteria (4 months and 8 months of duration from first CYAD-101 infusion) and nine had stable disease with a median duration of 4.6 months. Evidence of increase in the TCR repertoire and modulation of the cytokine profile post-treatment with CYAD-101 were observed implying that CYAD-101 may also be modulating the immune suppressive environment in patients mirroring what was demonstrated in pre-clinical models. We considered that a sequential therapy with the anti-PD1 monoclonal antibody pembrolizumab to further release the anti-tumor potential of this expanded T-cell population may drive deeper, more durable and new clinical responses beyond that currently demonstrated with the CAR T-cells alone. Methods: The phase 1b KEYNOTE-B79 trial (NCT04991948) will evaluate, according to a Simon’s two stage study design, the safety and clinical activity of three consecutive infusions of CYAD-101 (1x109 cells per infusion) post FOLFOX preconditioning chemotherapy with two-week interval between cycles, followed by pembrolizumab treatment (200 mg administered every three weeks for up to two years) in microsatellite stable/mismatch-repair proficient mCRC patients with recurrent/progressing disease after at least one metastatic line of therapy, which must include FOLFOX chemotherapy. The pembrolizumab treatment will be initiated 3 weeks after the last CYAD-101 infusion to fall outside the classical time window of potential CAR T-cell toxicities (e.g., cytokine release syndrome). The co-primary endpoints of the trial are the occurrence of dose-limiting toxicities (DLTs) at any time from the first FOLFOX preconditioning treatment up to 3 weeks after the first pembrolizumab treatment and the objective response rate (ORR) at the tumor assessment planned 6 weeks after the first pembrolizumab treatment administration. The KEYNOTE-B79 study will be initiated in Q4-2021 in five sites in USA and Europe. Clinical trial information: NCT04991948.

A Novel Scoring System in Predicting Prognosis After Adjuvant FOLFOX Chemotherapy in Gastric Cancer.

Purpose: To evaluate the impact of neutrophil-to-lymphocyte ratio (NLR) and preoperative prognostic nutritional index (PNI) on prognosis of gastric cancer (GC) after adjuvant FOLFOX chemotherapy. Materials and Methods: Data on 749 GC patients who received operation after by adjuvant FOLFOX chemotherapy between January 2013 and December 2015 were enrolled in this study, retrospectively. Receiver-operating characteristic curve analysis was employed to assess optimal cutoff thresholds for PNI and NLR. The GC subjects having a low PNI (<52.8) and high NLR (>1.79) received a score of 2. Any variable that met these standards was scored as 1. If none of the two variables met these standards of the patient was assigned a score of 0. Correlation between PNI-NLR score and GC stage was also evaluated. Results: The mean overall survival (OS) and 5-year OS rate for subjects with PNI-NLR = 2 was lower than those of subjects with PNI-NLR = 1, or 0 (40.9% vs. 52.1%, 76.4% [46.0 vs. 61.0], 68.0 months, p ≤ 0.001). In multivariate analyses, the PNI-NLR score (p ≤ 0.001) and WHO grade (p ≤ 0.001) showed potential to independently influence OS. Conclusions: High PNI-NLR scores can independently affect worse prognosis of GC. Thus, it can be utilized to differentiate low risk from high risk subjects.

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

Simple SummaryOxaliplatin-based chemotherapy remains the mainstay of first-line therapy in patients with metastatic colorectal cancer (mCRC). Unfortunately, only approximately 60% of treated patients achieve response, and half of responders will experience an early onset of disease progression. Furthermore, some individuals will develop a mixed response due to the emergence of resistant tumor subclones. The ability to predicting which patients will acquire resistance could help them avoid the unnecessary toxicity of oxaliplatin therapies. Furthermore, sorting out lesions that do not respond, in the context of an overall good response, could trigger further investigation into their mutational landscape, providing mechanistic insight towards the planning of a more comprehensive treatment. In this study, we validated a delta-radiomics signature capable of predicting response to oxaliplatin-based first-line treatment of individual liver colorectal cancer metastases. Findings could pave the way to a more personalized treatment of patients with mCRC.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.

The Association of Epidermal Growth Factor Receptor and Human Epidermal Growth Factor Receptor 2 with Prognosis of Colorectal Cancer under FOLFOX Chemotherapy

To clarify association of epidermal growth factor receptor, human epidermal growth factor receptor 2 with prognosis of colorectal cancer under FOLFOX chemotherapy. A total of 108 colorectal cancer patients under FOLFOX chemotherapy in the hospital from October 2017 to October 2019 were chosen as research subjects. The baseline data of patients were recorded before treatment and levels of serum tumor markers carcino embryonic antigen and carbohydrate antigen 125 and serum epidermal growth factor receptor and human epidermal growth factor receptor 2 were measured and recorded. After 6 courses of FOLFOX chemotherapy, prognosis of patients was observed. The effective patients were included in good prognosis group and the remaining ones were included in poor prognosis group. The baseline data and laboratory indicators before treatment were assessed between two groups and association of epidermal growth factor receptor and human epidermal growth factor receptor 2 with prognosis of colorectal cancer under FOLFOX chemotherapy was evaluated. Among 108 colorectal cancer patients completing FOLFOX chemotherapy, 18 (16.67 %) had complete response, 29 (26.85 %) had partial response, 37 (34.26 %) had stable disease and 24 (22.22 %) had progressive disease and 56.48 % (61/108) had poor prognosis. Carcino embryonic antigen, carbohydrate antigen 125, epidermal growth factor receptor and human epidermal growth factor receptor 2 in poor prognosis group presented elevation relative to those in good prognosis group, with statistical significance (p<0.05). Logistic regression analysis demonstrated that carcino embryonic antigen, carbohydrate antigen 125, epidermal growth factor receptor and human epidermal growth factor receptor 2 had association with prognosis of colorectal cancer under FOLFOX chemotherapy (odds ratio >1, p<0.05). The receiver operating curve demonstrated that area under curve of serum epidermal growth factor receptor and human epidermal growth factor receptor 2 levels before treatment alone and in combination to predict prognosis of colorectal cancer under FOLFOX chemotherapy were 0.709, 0.766 and 0.828, respectively, all of which had certain predictive value. The up regulation of serum epidermal growth factor receptor and human epidermal growth factor receptor 2 may be a risk factor for unfavourable prognosis of colorectal cancer under FOLFOX chemotherapy, which can be used for predicting prognosis of colorectal cancer under FOLFOX chemotherapy.

Another treatment option for locally advanced hepatocellular carcinoma: Interventional arterial infusion of FOLFOX chemotherapy from the FOHAIC-1 study

Advanced stage primary hepatocellular carcinoma (HCC) accounts for more than half of all cases worldwide. Poor prognosis is mainly attributed to intrahepatic tumor burden caused by high-risk factors, including Vp4-portal vein tumor thrombosis or tumor occupancy of &gt;50% of the liver. In 2020, the combination of a VEGF/PD-L1 blocker was superior to a single tyrosine kinase inhibitor and associated with a median overall survival of 19.2 months. However, overall survival dramatically declined from 19.2 months to 7.6 months for patients with high-risk factors. In this present study, the FOHAIC-1 trial, interventional hepatic arterial infusion chemotherapy of FOLFOX (HAIC-FO) showed favorable survival outcomes in patients with high-risk advanced HCC. Compared with a tyrosine kinase inhibitor, in the high-risk subgroup, HAIC-FO achieved an overall survival of 10.8 months (vs. 5.7 months, hazard ratio 0.343, 95% confidence interval, 0.219–0.538). This study also observed disease downstaging in 16 (16/130) patients who received HAIC-FO; 15 (93.8%) patients received curative or regional treatments afterward. Therefore, for advanced HCC with localized high-risk factors, the clinical efficacy of HAIC-FO is significant and may be a better option than systemic therapies.

Abstract P015: Characterization and prognostic impact of DC-HIL in advanced colorectal cancer

Abstract Introduction: DC-HIL is the T cell-inhibitory receptor that is expressed by exponentially expanding CD14+HLA-DRno/low myeloid-derived suppressor cells (MDSC) and critically mediates the immunosuppressive function. We previously reported that this DC-HIL expression is associated with colorectal cancer (CRC) progression. The purpose of this investigation was to determine the correlation of DC-HIL-expressing MDSC subpopulation in blood with clinical outcomes in advanced CRC. Methods: Patients with metastatic CRC (n = 63) were analyzed by flow cytometry for DC-HIL or PDL1 expression on blood CD14+HLA-DRno/low MDSC. A retrospective chart review was performed to obtain data on demographics, tumor, and clinical characteristics including tumor laterality, histology, mutational and microsatellite stability status, stage, metastatic sites, CEA level, and white blood cell count, and differential and treatment outcomes including response to therapy and survival. Baseline characteristics were compared using the two-tailed Student's t-test, ANOVA test, or Pearson correlation test as appropriate. Survival analysis was estimated using the Kaplan-Meier method and Cox regression model, and groups were compared using the log-rank test. Results: Median age at diagnosis was 56 years (range 30-78) and patients were predominantly male (59%) and white (76%). Forty pts had left-sided tumors (63%), the majority had moderately differentiated adenocarcinoma (66%) and stage IV colorectal cancer at diagnosis (68%). At the time of DC-HIL collection, 95% of pts had stage IV disease. Most (95%) pts had microsatellite stable disease, 24% of pts had a KRAS mutation and 22% had a BRAF mutation, 69% of patients underwent surgical resection of the primary malignancy or metastatic site or both. Median CEA level was 40 ng/ml, median white blood cell (WBC) count was 5.9 × 109, median absolute monocyte count (AMC) was 0.64 × 109, median absolute neutrophil count (ANC) was 3.6 × 109, median monocyte to lymphocyte ratio (M/L) was 0.53 and median neutrophil to lymphocyte ratio (N/L) was 2.7. Most pts (90%) received FOLFOX chemotherapy as first-line and 84% of pts received an anti-VEGF agent throughout the course of their treatment. Median CD14+/PBMC for pts was 14.4, median %MDSC/PBMC was 7.0, median %DC-HIL+/MDSC was 66, median %DC-HIL+/MDSC/PBMC was 4.1 and median sDC-HIL was 20.0 ng/ml. Our results showed that there was a statically significant correlation between % MDSC/PBMC, %DCHIL+MDSC/PBMC, and the monocyte/lymphocyte (M/L) ratio with p=0.047 and p=0.03 respectively. There was no statistically significant correlation between DCHIL+/MDSC levels and response to therapy, time-to-next therapy (p=0.11), or overall survival (p=0.67). Conclusion: DC-HIL+ MDSC is positively correlated with M/L ratio, a possible prognostic marker in CRC patients. DC-HIL correlates poorly with other clinical outcomes; chemotherapy response, time-to-next therapy, or overall survival. Citation Format: Jude Khatib, Jin-Sung Chung, Sarah Reddy, Nivan Chowattukunnel, Allante Milsap, Yasin Goksu, Kiyoshi Ariizumi, Syed Kazmi. Characterization and prognostic impact of DC-HIL in advanced colorectal cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P015.

Pathologic complete response in metastatic right-sided colon cancer treated with panitumumab and FOLFOX4 chemotherapy regimen

Introduction. Recommended biological agents for the first-line treatment of left-sided metastatic colorectal cancer (mCRC) without mutations in RAS/BRAF genes are cetuximab or panitumumab, while for rightsided mCRC bevacizumab is advised instead. For transversal colon mCRC the data about biological treatment efficacy is lacking. We present a patient with right-sided mCRC originated from transversal colon where panitumumab and chemotherapy treatment resulted in an excellent outcome. Case outline. A 56-year-old woman was diagnosed with transversal colon adenocarcinoma, without RAS genes mutations, with multiple liver metastases disseminated in both lobes. After the operation of the primary tumor, the patient was treated with panitumumab and FOLFOX4 chemotherapy regimen. After two months of treatment, the dramatic response was evident ? The diameter sum of the target lesions decreased by 70.5%. After two more months of therapy, further decrease by 22.5% was evident. Liver metastases were operated on. Histopathology revealed fibrotic and necrotic tissue in all suspicious lesions, except in one focus, where adenocarcinoma was found, but with 90% of surrounding necrosis. Twelve months after liver surgery the patient is without signs of the progressive disease. Conclusion. Detailed comprehensive studies of genetic features of mCRC hold a key to personalized treatment options and better outcomes for patients with mCRC.

A rare case of jejunal adenocarcinoma with brain metastasis

Small bowel malignancies are rare entity, with adenocarcinoma being one of common type along with neuroendocrine tumours. Associated with Crohns, celiac disease, FAP and HNPCC. Jejunal adenocarcinoma produce vague symptoms, accounting for late presentation leading to difficult and delayed diagnosis in favour of poor prognosis. Diagnosis is established by CECT abdomen and CEA levels. Ro resection with regional lymphadenectomy and jejunojejunal anastomosis is preferred followed by adjuvant FOLFOX chemotherapy. Here we presenting a 68 years old male, anaemic with vague abdominal pain for 3 months, CECT showed malignant wall thickening involving 10 cm of proximal jejunal loop with no enlarged lymph nodes and CEA was elevated. Proceeded with laparotomy, an irregular hard mass of 10×10 cm involving 20 cm of jejunum with transverse colon infiltration with multiple mesenteric nodes found, composite resection with jejunojejunostomy and colocolic anastomosis done. Histopathology showed poorly differentiated jejunal adenocarcinoma with colonic infiltration with reactive nodes and post operatively on day 7, patient developed seizures and weakness of left upper and lower limbs, MRI brain showed solitary metastasis 2×2 cm in right frontal region and PET CT showed brain metastasis and multiple intraabdominal lymph node, lung and prostate metastasis, planned SBRT for brain metastasis and palliative chemotherapy. Lymph node, liver and peritoneum are common site of metastasis for small bowel adenocarcinoma, very rarely brain metastasis can occur in short time and to be considered if neurological symptoms occur pre and postoperatively.

Feasibility of Organ Preservation With Short Course Radiation Therapy as Part of Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer During the COVID-19 Pandemic

Purpose/Objective(s)While long course chemoradiation therapy has been studied as part of a watch-and-wait (WW) strategy for patients with locally advanced rectal cancer, it is unclear whether short-course radiation therapy (SCRT) will be associated with similar rates of organ preservation. We hypothesized that a WW strategy to facilitate organ preservation with SCRT, as part of a total neoadjuvant therapy (TNT) approach during the COVID-19 pandemic, would be both safe and feasible.Materials/MethodsFrom March to June of 2020, due to the COVID-19 pandemic, per institutional policy, all patients undergoing radiation therapy for locally advanced rectal cancer were treated with SCRT. After completion of SCRT-TNT, patients were clinically restaged by exam, endoscopy and MRI and the decision was made to manage the patient surgically or with a WW approach. The decision for WW or surgery was made by the surgeon in conjunction with patient consent. After IRB waiver was obtained, we reviewed consecutive patients treated during our SCRT mandate. The main outcome of interest was total mesorectal excision (TME)-free survival among patients eligible for WW after SCRT-TNT.ResultsOur cohort included 42 patients with a median age of 57 years (Interquartile Range [IQR] 48-67), 24 (57%) of whom were male. Median follow-up from end of SCRT-TNT was 7 months (IQR 6-8). The median tumor cranio-caudal size was 4.1 cm (IQR 3.3-5.2) with a median distance from the anal verge of 7 cm (IQR 5-9). The majority had cT3 (71%) or cN+ (74%) disease. Patients underwent a median of 14 weeks (IQR 13-15) of FOLFOX or CAPEOX chemotherapy, with 32 (76%) patients receiving chemotherapy prior to SCRT and 10 (24%) patients receiving chemotherapy after SCRT. The median time from completion of TNT to endoscopic restaging was 9 weeks (IQR 7-10). Nineteen (45%) patients were recommended to undergo surgical resection, of whom 17 went on to TME and 2 refused TME. Of the 15 patients with pathology available, 2 had a pCR (13%). Notably, one of these patients had a cCR at post-TNT endoscopy, but due to the presence of a stricture, WW was deemed unfeasible. Of the 23 patients managed by a WW strategy after SCRT-TNT completion, 19 had a clinical complete response (cCR), 3 had a near-CR, and 1 had an incomplete response. The 6-month TME-free survival was 85% for patients on WW. Four (17%) patients had a local regrowth at a median of 20 weeks (IQR 17-24), 3 of whom were salvaged with TME and 1 who declined surgery and opted for further surveillance. One of these patients had regrowth confirmed by biopsy, but had a pCR confirmed in the TME specimen. The 6-month TME- free survival of the entire cohort was 52%, and the combined pCR/6-month cCR was 52%.ConclusionOur data suggest WW after SCRT-TNT is feasible. Longer term follow-up is required to confirm the durability and oncologic safety of these results.

Colonoscopy surveillance of colorectal cancer post-surgery in Sanglah General Hospital, Bali, Indonesia: a descriptive study

Background: The postoperative surveillance of patients treated for colorectal cancer is intended to prolong survival by diagnosing recurrent and metachronous cancers at a curable stage as well as preventing metachronous cancer by detection and removal of precancerous polyps. This study evaluates the surveillance colonoscopy and its association with sociodemographic and clinical findings in a descriptive study.Methods: This is a cross sectional study of colorectal cancer patients who underwent surveillance colonoscopy as follow up after tumor resection from January 2020 to September 2021 in Sanglah General Hospital. Clinical data were gathered from medical records and databases by a qualified reviewer. Data were analyzed descriptively using SPSS version 20 for Windows.Results: The majority of patients who underwent surveillance colonoscopy were male (82.40%), tumor location at rectum (58.8%), stage IV (29.40%), underwent low anterior resection surgery (35.30%) and received Folfox (35.30%) or Capeox (35.30%) adjuvant chemotherapy. There was 2 (11.80%) residual mass found in this study. There was no significant difference between subjects who underwent surveillance colonoscopy with residual mass and without residual mass in all variables assessed (p&gt;0.05).Conclusion: Colonoscopy surveillance plays an important role in early detection for any recurrence or pre-cancer lesion and metachronous cancer in a patient with colorectal malignancies in Sanglah General Hospital, Bali, Indonesia.

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.

Outcomes of FOLFOX4 Chemotherapy as a Second-Line Treatment for Advanced Biliary Tract Cancer

Objective: After progression on platinum-gemcitabine, patients with advanced biliary tract cancer (aBTC) have limited treatment options. The objective of the present study was to evaluate the outcomes and adverse events of FOLFOX4 as a second-line chemotherapy. Materials and Methods: This was a retrospective study included aBTC patients who previously treated with platinum/gemcitabine and received the FOLFOX4 regimen as a second-line treatment in Srinagarind Hospital between June 2014 and June 2018. Survival analysis was done using the Kaplan-Meier method and the log-rank test. Results: A total of 19 patients of biliary tract cancer were included, the median age was 59 years (42 to 75), and 14 patients (73.6%) were male. Most patients had ECOG 1 and were intrahepatic subtype in primary. Two patients achieved partial response and 8 patients had stable disease. The median progression-free survival and overall survival (OS) were 2.6 and 6.2 months respectively. The 6- and 12-month survival rate was 52.6% and 11.8%. The median OS in patients who achieved disease control was significantly longer than who progressed on FOLFOX (9.1 vs. 4.7 months), hazard ratio 0.11 (95% CI 0.12 to 0.73, p=0.02). Grade 3 or higher adverse events were observed in seven patients (36.8%), with no patient discontinue the treatment from toxicity. Conclusion: In patients with aBTC who progressed after platinum-gemcitabine, FOLFOX4 is effective with manageable toxicity. Keywords: Advanced biliary tract cancer; Second-line chemotherapy; FOLFOX; Cholangiocarcinoma

S3715 A Leather Bottle Stomach: Rare Case of Gastric Adenocarcinoma With Signet Cell Features

Introduction: Gastric cancer is one of the most common cancers worldwide - and was previously the leader of cancer related mortality until the 1980’s. With advancements in discovery of etiologies, namely the detection of H. Pylori - incidence of gastric cancer has declined over the past decades. A common finding on imaging is the diffuse gastric wall thickening - the “leather water bottle” or Linitis Plastica. A representation of diffuse infiltration of the cancer into the wall of a hollow organ, in this case - the stomach, giving it’s rugged and preserved structural shape. We present a case of poorly differentiated gastric adenocarcinoma with signet ring cell features in setting of portal hypertensive gastropathy. Case Description/Methods: 70-year-old female with PMH of HCV (treated with SVR) and 20 pack year tobacco history presented with complaints of weight loss, decreased appetite and early satiety with no other complaints for one month. Physical exam significant for bi-temporal wasting otherwise unremarkable. Initial chemistries within normal limits. CT abdomen and pelvis revealing a prominent thickening of the wall of the stomach as well as inhomogeneous soft tissue attenuation in the omentum concerning for neoplastic disease. EGD showed evidence of portal hypertensive gastropathy with distal gastric body thickening in addition to the examined duodenum revealing duodenitis. Biopsies of the stomach revealed poorly differentiated adenocarcinoma with signet ring cell features while the duodenal mucosa was negative for significant histopathologic abnormality. H. pylori immunostain was negative. Insufficient tissue for HER2 and PDL-1 assessment. Oncology evaluation included PET CT with significant circumferential thickening and hypermetabolic activity of the stomach with additional focus of modular hypermetabolic activity at pyloric and duodenal 2nd portion suggestive of multi centric disease. Diffuse omental modularity and ascites at low level metabolic activity consistent with omental metastasis and malignant ascites. Discussion: While our patient presented late in the disease course, there are still available palliative chemotherapy opportunities. Advances have been made in molecular identification and subtypes within the gastric cancer umbrella for more targeted therapy. Recent FDA approval (April 2021) of the addition of Opdivo (immunotherapy) to FOLFOX (chemotherapy) for treatment of metastatic gastric cancer has allowed our patient to receive the most up to date treatment option.Figure 1.: Figures 1-A through C are endoscopic images of the gastric body (evidence of portal hypertensive gastropathy), the duodenal bulb (suggesting duodenitis) and the 2nd portion of the duodenum. Figure 1-D is a CT Abdomen-Pelvis with Contrast depicting the classic radiographic finding of gastric cancer - 'linitis plastica' with surrounding peri-gastric lymphadenopathy. Figures 1-E and F are NM PET scan's with evidence of diffuse hypermetabolic activity in the stomach wall with uptake of SUV max 10.1 in addition to the 2nd portion of the duodenum with uptake of SUV max 5.7 - suggestive of multi-centric disease.

FLUOROURACIL-INDUCED PULMONARY TOXICITY PRESENTING AS DIFFUSE ALVEOLAR HEMORRHAGE

TOPIC: Diffuse Lung Disease TYPE: Fellow Case Reports INTRODUCTION: Fluorouracil (5-FU) is a chemotherapy medication often used alone or in combination with other agents (e.g., FOLFOX regimen) to treat gastrointestinal malignancies. Adverse effects of 5-FU include pancytopenia, alopecia, cardiotoxicity, and gastrointestinal symptoms. We describe a rare case of pulmonary toxicity associated with 5-FU. CASE PRESENTATION: The patient is a 78-year-old female with a history of unresectable metastatic cholangiocarcinoma on maintenance FOLFOX chemotherapy without Oxaliplatin (discontinued due to peripheral neuropathy and thrombocytopenia) presented with acute onset of dyspnea and pleuritic chest pain five days after a 5-FU and Leucovorin infusion. On initial evaluation, a chest radiograph showed pulmonary infiltrates for which she was treated with oral Levofloxacin as an outpatient. Despite this, she had progressive worsening of dyspnea, prompting further evaluation. Blood work revealed normal WBC and platelet counts, mild anemia with hemoglobin 9.4 g/dL, and normal BNP and troponin levels. ECHO showed normal systolic function. She was noted to be hypoxemic, requiring supplemental oxygen necessitating hospitalization. Repeat Chest radiograph showed worsening left upper lobe and lingular infiltrates. Her oxygen requirements rapidly increased from 3-4 L/min via nasal cannula to 12L/min via Oxymask. Despite treatment with broad-spectrum IV antibiotics, her dyspnea and hypoxia persisted. CTA chest was then performed, revealing extensive bilateral infiltrates and reactive enlarged mediastinal/hilar lymph nodes with no evidence of pulmonary embolism. She had a negative infectious workup, including a COVID-19 PCR. She underwent diagnostic bronchoscopy, which showed no endobronchial lesions or secretions. Bronchoalveolar lavage of the right middle lobe with three serial aliquots obtained progressively bloody returns diagnosing diffuse alveolar hemorrhage (DAH). The procedure was complicated by worsening hypoxia, and the patient required emergent intubation and transferred to the critical care unit, where she was treated with pulse dose steroids for three days. She was extubated to supplemental O2 via NC within 24 hours of treatment. Further lab evaluation showed negative ANA, ANCA, Anti GBM antibodies, Anti-dsDNA, and normal C3, C4 levels. Cytology of BAL was negative for malignancy. Given negative infectious and autoimmune workup, the diagnosis of DAH due to 5-FU was made. Steroid dose was reduced to Prednisone 1mg/kg with slow taper with improvement in clinical status and oxygen requirements. DISCUSSION: The diagnosis of 5-FU related pulmonary toxicity is based on clinical suspicion upon exclusion of infection, autoimmune disease, heart failure, and cancer progression. CONCLUSIONS: 5-FU induced pulmonary toxicity presenting as DAH is a rare entity. Prompt diagnosis can lead to early drug cessation and the use of high-dose steroids can improve patient outcomes. REFERENCE #1: Fernandez, L., Dominguez, A., Martinez, W., Sanabria, F., Leib, C. S., & Biomedical Research Group in Thorax. (2018). Pulmonary Toxicity Due to 5-Fluorouracil (5-FU) Manifested as Diffuse Alveolar Hemorrhage: Case Report. In D34. LUNG TRANSPLANT AND DRUG INDUCED LUNG DISEASE: CASE REPORTS (pp. A6577-A6577). American Thoracic Society. DISCLOSURES: No relevant relationships by Rajesh Kunadharaju, source=Web Response No relevant relationships by Puja Mehta, source=Web Response No relevant relationships by Ahmed Munir, source=Web Response No relevant relationships by Vandana Pai, source=Web Response No relevant relationships by Musa Saeed, source=Web Response

Improvement in immune dysfunction after FOLFOX chemotherapy for Stage III colon cancer is associated with improved minimal residual disease prognostic subtype and outcome

Minimal residual disease (MRD) is the net result of the biological properties of disseminated tumour cells and the effect of the immune system and treatment to eliminate them. The aim of this work is to report the changes in MRD status and immune function (lymphocyte count) after FOLFOX chemotherapy, and the outcome in Stage III colon cancer patients. This study is a prospective, single-centre observational study. Lymphocyte counts were determined prior to and 1, 2 and 3months after the completion of chemotherapy. Circulating tumour cells (CTCs) and bone marrow micrometastases were determined using immunocytochemistry with anticarcinoembryonic antigen prior to and 1month after chemotherapy. MRD was classified as negative (Group I), micrometastasis positive only (Group II) and CTC positive (Group III). Changes in lymphocyte counts and MRD subtype following chemotherapy and relapse-free progression were analysed. Of the total of 185 patients, 83 (44.9%) relapsed. The risk of relapse significantly increased from Groups I to III (p<0.001) and with decreasing lymphocyte count (p<0.01). The lymphocyte count significantly decreased from Groups I to III (p<0.001). Multivariance Cox regression analysis showed hazard ratios of 3.58 (Group II), 17.43 (Group III) and 0.39 (lymphocyte count) in predicting relapse. Following chemotherapy, improved lymphocyte count was associated with improved MRD subtype (p<0.0001). Neither baseline lymphocyte count nor MRD subtype predicted response to chemotherapy. Five-year relapse-free survival for combined lymphocyte-MRD subtypes was 95%, 57% and 5% for Groups I to III, respectively (p<0.001). Following chemotherapy, improvements in immune function were associated with improved MRD subtype and a better relapse-free survival.

INVESTIGATING THE EFFECT OF PROBIOTICS ON THE GUT MICROBIOME AND ON THE OUTCOME OF FOLFOX CHEMOTHERAPY IN COLORECTAL CANCER PATIENTS

Colorectal cancer (CRC) is the 5th most diagnosed cancer in Sub-Saharan Africa (SSA). In Kenya, CRC incidence rates have tripled from 1997-2017,with a rising incidence of early-onset CRC. Suggested pathobiology for this increase in CRC rates is gut microbiome dysbiosis. Moreover, FOLFOX chemotherapy for metastatic CRC is associatedwith gastrointestinal toxicity, and it also alters the patient's gut microbiome. Saccharomyces boulardii (S. boulardii),a probiotic with anti-inflammatory and anti-neoplastic effects, is a potential treatment for 5-FU induced-intestinal mucositis, chemotherapy-induced diarrhea. Given an increasing CRC incidence rate, the unknown local generalizability of CRC/microbiome research, and the high burden of chemotherapy-related morbidity, there is an unmet need to better underst and how these factors influence CRC epidemiology in Kenya.AIM OF THE WORKTo provide an overview of the microbiota composition differentiating CRC patients' gut profiles from healthy individuals' gut profiles.To demonstrate the effect of probiotic supplementation on the outcome of FOLFOX chemotherapy in CRC patients.To demonstrate the effect of probiotic supplementation on dysbiosis in CRC patients.

SPTAN1 Expression Predicts Treatment and Survival Outcomes in Colorectal Cancer.

Simple SummaryColorectal cancer (CRC) is a common and deadly form of cancer. Non-erythroid spectrin αII (SPTAN1), a protein of the cytoskeleton, is thought to be involved in CRC development and progression. In this study, we explore whether measuring SPTAN1 levels in resected CRC specimens might help to predict patient survival outcomes and response to chemotherapy. Indeed, we find that higher SPTAN1 protein and mRNA levels in CRC specimens associate with longer patient survival times. Using cell culture experiments, we then show that cells with lower SPTAN1 levels are less susceptible to FOLFOX chemotherapy, a standard treatment regimen for patients with CRC. Overall, our study underscores the importance of cytoskeletal proteins in shaping tumour biology and treatment responses and nominates SPTAN1 as a biomarker to improve patient stratification and refine therapeutic decisions in CRC.Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality. In a cohort of 189 patients with CRC, we recently showed that expression of the cytoskeletal scaffolding protein non-erythroid spectrin αII (SPTAN1) was lower in advanced metastatic tumours. The aim of the present study was to clarify the association of intratumoural SPTAN1 expression levels with treatment and survival outcomes in patients with CRC. The analysis was based on histologic assessment of SPTAN1 protein levels in our own CRC cohort, and transcriptome data of 573 CRC cases from The Cancer Genome Atlas (TCGA). We first establish that high intratumoural levels of SPTAN1 protein and mRNA associate with favourable survival outcomes in patients with CRC. Next, a response prediction signature applied to the TCGA data reveals a possible link between high SPTAN1 transcript levels and improved patient responses to FOLFOX chemotherapy. Complementary in vitro experiments confirm that SPTAN1 knockdown strains of the colon cancer cell lines HT-29, HCT116 mlh1-2 and Caco-2 are less responsive to FOLFOX chemotherapy compared with SPTAN1-proficient control strains. Taken together, we identify SPTAN1 as a novel prognostic biomarker in CRC and show that SPTAN1 expression levels may predict patient responses to chemotherapy. These investigations illustrate how an affordable, histology-based diagnostic test could directly impact therapeutic decision-making at the bedside.

Comparing neoadjuvant long-course chemoradiotherapy with short-course radiotherapy in rectal cancer

BackgroundThe purpose of this study was to compare short-course radiotherapy (SC) or neoadjuvant long-course chemoradiotherapy (LC) treatment for locally advanced rectal cancer patients.MethodsPatients with a diagnosis of locally advanced rectal cancer (LARC) who had undergone neoadjuvant radiotherapy before surgery between 2013 and 2018 at the medical center in China were included in this study. All patients’ MRI confirmed T2N+M0 or T3-4N0-3M0 clinical stages. Patients in the SC group received pelvic radiotherapy with a dose of 5 × 5 Gy (with or without chemotherapy at any time), followed by immediate or delayed surgery. Patients in the LC group received a dose of 50–50.4 Gy in 25–28 fractions, concomitantly with FOLFOX or capecitabine-based chemotherapy, followed by surgery 4–6 weeks later. All clinical data were retrospectively collected, and long-term follow-up was completed and recorded at the same time.ResultsA total of 170 were eligible to participate in this study, 32 patients in the SC group, and 138 in the LC group. The median follow-up time of living patients was 39 months. The disease-free survival (DFS) and overall survival (OS) rates in the SC group and LC group at 3 years, were, 84.9% versus 72.4% (P = 0.273) and 96.2% versus 87.2% (P = 0.510), respectively. The complete pathological response (pCR) rates in the SC group and LC group were, 25% versus 18.1% (the difference was not statistically significant, P = 0.375), respectively. However, the SC group had better node(N) downstaging compared to the LC group (P = 0.011).ConclusionsThere were no differences observed in DFS and OS between short-course radiotherapy and long-course chemoradiation, and both can be used as treatment options for patients with locally advanced rectal cancer.