GI Tumors Research Articles

Prediction of technically difficult endoscopic submucosal dissection for large superficial colorectal tumors: a novel clinical score model

Endoscopic submucosal dissection (ESD) is a promising technique for removing superficial GI tumors, but ESD is technically difficult. The aim of this study was to establish a clinical score model for grading technically difficult colorectal ESD. Data on patients, lesions, and outcomes of colorectal ESD at 2 centers were analyzed. The objective parameter of successful ESD within 60 minutes was set as an endpoint to evaluate the difficulty. Independent predictors of difficulty in the derivation cohort were identified by multiple logistic regression analysis and used to develop a clinical score. We validated the score model in the validation cohort. The clinical score comprised tumor size of 30 to 50mm (1 point) or≥50mm (2 points), at least two-thirds circumference of the lesion (2 points), location in the cecum (1 point), flexure (2 points) or dentate line (1point), and laterally spreading tumor nongranular lesions (1 point). Areas under the receiver operator characteristic curves for the score model were comparable (derivation [.70] vs internal validation [.69] vs external validation [.69]). The probability of successful ESD within 60 minutes in easy (score= 0), intermediate (score= 1), difficult (score= 2-3), and very difficult (score≥4) categories were 75.0%, 51.3%, 35.6%, and 3.4% in the derivation cohort; 73.3%, 47.9%, 31.8%, and 16.7% in the internal validation cohort; and 79.5%, 66.7%, 43.3%, and 20.0% in the external validation cohort, respectively. This clinical score model accurately predicts the probability of successful ESD within 60 minutes and can be applied to grade the technical difficulty before the procedure.

Induction of cytotoxic effector cells towards cholangiocellular, pancreatic, and colorectal tumor cells by activation of the immune checkpoint CD40/CD40L on dendritic cells

IntroductionGastrointestinal (GI) malignancies, such as cholangiocarcinoma, pancreatic carcinoma, and metastatic colorectal carcinoma, have a poor prognosis and effective therapeutic approaches are still challenging. Checkpoint inhibition with PD-1 or PDL-1 antibodies revealed promising results in different tumor entities; however, only few patients with GI tumors can potentially benefit from PD1/PDL1 inhibiting immunotherapy. Further immunotherapeutic strategies for GI malignancies are urgently needed. The aim of this study was to demonstrate that in vitro activation of the immune checkpoint CD40/CD40L can improve DC action towards bile duct, pancreas, and colorectal carcinoma.MethodsHuman DC were isolated from buffy coats from healthy donors, pulsed with tumor lysates and then transduced with adenoviruses encoding human CD40L (Ad-hCD40L). Using transwell assays, the effects of (m)CD40L on DC immunoactivation compared to (s)CD40L were analyzed. Surface marker and cytokine/chemokine expression were measured by flow cytometry, ELISA and cytokine arrays. Capacity of Ad-hCD40L-transduced DC to induce tumor-specific effector cells was tested using MTT proliferation assay and cytotoxicity assays. Apoptosis induction on tumor cells after culturing with supernatants of Ad-hCD40L-transduced DC was analyzed by flow cytometry.ResultsAd-hCD40L transduction induced a high expression of (s)CD40L and (m)CD40L on DC and seemed to induce a strong cellular CD40/CD40L interaction among DC, leading to the formation of cell aggregates. Due to the CD40/CD40L interaction, a significant upregulation of DC maturation markers and a Th1-shift on cytokines/chemokines in the supernatant of DC were achieved. Interestingly, a pure Th1-shift was only achieved, when a cellular CD40/CD40L interaction among DC took place. (s)CD40L induced almost no upregulation of maturation markers and rather resulted in a Th2-cytokine expression, such as IL-10. Correspondingly, (m)CD40L-expressing DC led to significant proliferation and stimulation of tumor-specific effector cells with increased cytotoxicity towards pancreatic, bile duct and colorectal tumor cells. Supernatants of Ad-hCD40L-transduced DC could also induce apoptosis in the different tumor cells in vitro.ConclusionStimulation of the immune checkpoint CD40L/CD40 by endogenous expression of (m)CD40L provokes a cellular interaction, which increases the immunomodulatory capacity of DC. A Th1 cytokine/chemokine expression is induced, leading to a significant proliferation and enabling cytotoxicity of effector cells towards human bile duct, pancreatic and colorectal tumor cells. The present data point to the promising approach for DC-based immunotherapy of gastrointestinal malignances by activating the CD40/CD40L immune checkpoint.

Validation and clinical application of a targeted next-generation sequencing gene panel for solid and hematologic malignancies.

BackgroundNext-generation sequencing (NGS) is a high-throughput technology that has become widely integrated in molecular diagnostics laboratories. Among the large diversity of NGS-based panels, the Trusight Tumor 26 (TsT26) enables the detection of low-frequency variants across 26 genes using the MiSeq platform.MethodsWe describe the inter-laboratory validation and subsequent clinical application of the panel in 399 patients presenting a range of tumor types, including gastrointestinal (GI, 29%), hematologic (18%), lung (13%), gynecological and breast (8% each), among others.ResultsThe panel is highly accurate with a test sensitivity of 92%, and demonstrated high specificity and positive predictive values (95% and 96%, respectively). Sequencing testing was successful in two-thirds of patients, while the remaining third failed due to unsuccessful quality-control filtering. Most detected variants were observed in the TP53 (28%), KRAS (16%), APC (10%) and PIK3CA (8%) genes. Overall, 372 variants were identified, primarily distributed as missense (81%), stop gain (9%) and frameshift (7%) altered sequences and mostly reported as pathogenic (78%) and variants of uncertain significance (19%). Only 14% of patients received targeted treatment based on the variant determined by the panel. The variants most frequently observed in GI and lung tumors were: KRAS c.35G > A (p.G12D), c.35G > T (p.G12V) and c.34G > T (p.G12C).ConclusionsPrior panel validation allowed its use in the laboratory daily practice by providing several relevant and potentially targetable variants across multiple tumors. However, this study is limited by high sample inadequacy rate, raising doubts as to continuity in the clinical setting.

S1194 Bariatric Surgery Associated With Reduced Incidence of Rectal Cancer

INTRODUCTION: The impact of morbid obesity and weight loss surgery (WLS) on GI malignancy remains uncertain. We aimed to investigate if obesity and WLS could alter the risk of GI tumors (GITs). METHODS: The study aims to investigate the cross-sectional relationship between prior WLS and GITs. Data were obtained from 2016 National Inpatient Sample (NIS) database. Multivariate analyses were performed to study primary outcome, the incidence of GITs. RESULTS: Patients with GITs were less morbidly obese (MO) (6.1% vs. 10.7%), more cachectic (3.9% vs. 0.8%) and malnourished (18.1% vs. 4.7%) compared to patients without GITs. Given that multiple factors that can affect weight loss in cancer patients, we selected MO patients with BMI≥35Kg/m2. Out of 622,834 MO patients, 19,932 (3.1%) had undergone WLS. Patients who underwent WLS were older (55.3 vs. 53.8 years, P < 0.01), more females (74.4% vs. 64.5%, P < 0.01), and more White (72.0% vs. 66.9%, P < 0.01). The incidence of tumors among MO patients was 0.4% for colon, 0.1% for rectum, 0.1% for gastric, and < 0.1% for esophageal and small bowel tumors. Based on multivariate analysis; esophageal, gastric, small bowel, and colon tumors had no statistically significant association with a prior history of WLS. Only rectal cancer was associated with reduced incidence following WLS (adjusted OR = 0.31[0.15,0.61], P < 0.01]). CONCLUSION: In MO patients, WLS may be associated with a reduced incidence of rectal cancer. This study does not show any association with other types of GITs. Future prospective studies should clarify the multifactorial relationship between WLS and the development of GITs.

S2862 Bowel Within the Bowel; A Case of Metastatic Melanoma Presenting as Small Bowel Intussusception

INTRODUCTION: Melanoma is notorious for metastasizing to almost any part of the body. Metastasis to the gastrointestinal tract is most commonly diagnosed on autopsy. A clinical diagnosis is rare and occurs in approximately 2% of cases. We present a rare case of metastatic melanoma to the small bowel that presented as melena and ultimately caused small bowel intussusception. CASE DESCRIPTION/METHODS: 84-year-old male was admitted to the hospital with one-week history of melena and worsening abdominal pain. Past medical history was significant for stage IIB metastatic melanoma. Melanoma was first diagnosed on bottom of right foot 10 years prior to admission and was treated with surgical excision and adjuvant pegylated interferon. Patient had recurrence of melanoma on his back 1 year prior to presentation and underwent surgical excision and was treated with nivolumab. Physical examination revealed two new dermal nodules on the left chest. Laboratory investigations showed a decrease in hemoglobin from 11.5 g/dl three months prior to 9.5 g/dl. Esophagogastroduodenoscopy (EGD) was remarkable for a large, purplish, smooth mass in the third portion of the duodenum which was biopsied. Colonoscopy was unremarkable. Histologic examination revealed neoplastic cells positive for MART-1 and negative for CD3 and CD20. Immunohistochemical staining demonstrated that the malignant cells were positive for S100 which confirmed the diagnosis of metastatic melanoma. The patient was discharged however again presented to the Emergency Department with severe abdominal pain. Computed tomography with contrast showed small bowel intussusception within the left mid abdomen with dilated loops of small bowel proximally and collapsed loops of small bowel distally. Patient was taken for an emergent laparoscopic small bowel resection due to concern of ischemia. He was found to have multiple intra-abdominal lesions studding the small bowel and mesentery. Further metastatic workup revealed lesions in the lungs and the brain suggestive of advanced disease. Decision was made to proceed with palliative ipilimumab chemotherapy and radiation. DISCUSSION: Small bowel tumors are rare, accounting for only 3–6% of all GI tumors. Small bowel melanomas can be primary or metastatic lesions. Clinical presentation of GI metastases includes abdominal pain, overt bleeding, anemia, intestinal obstruction or rarely intussusception. Surgery may not be curative, however is the treatment of choice as it is effective in palliating symptoms and may prolong survival.Figure 1Figure 2

S3328 An Unfortunate Case of Synchronicity

INTRODUCTION: Gastrointestinal stromal tumors (GISTs) account for less than 1% of GI tumors. They originate from the interstitial cells of Cajal and are the most common group of mesenchymal neoplasms. GISTs may occur in any portion of the alimentary tract. Recent literature suggests that GISTs may occur synchronously with other cancers more frequently than expected. CASE DESCRIPTION/METHODS: We present a case of a 78-year-old female with past medical history of hyperlipidemia who underwent an outpatient computed tomography (CT) for evaluation of abdominal pain. CT scan revealed three lesions: (1) 7.2 cm well-circumscribed hypodense hepatic lesion in segment 7 consistent with hydatid cyst (Figure 1a), (2) 3.6 cm ill-margined heterogeneous lesion of uncinate process (Figure 1a), and (3) 5.1 cm partially cystic intramural gastric body mass with exophytic extension (Figure 1b). The patient underwent esophagogastroduodenoscopy (EGD) and endoscopic ultrasonography (EUS). No intraluminal component of gastric mass was visualized on EGD. A 26.5 × 21.6 mm hypoechoic, heterogeneous and well-circumscribed lesion with several anechoic components was identified adjacent to gastric cardia on EUS. Fine needle biopsy (FNB) was performed with pathology revealing spindle cell tumor (Figure 2) and immunohistochemical staining consistent with GIST (CD 117 positive, S100 negative and SMA focally positive). Additionally, a 21.7 × 21.6 mm heterogeneous hypoechoic lesion with ill-defined borders was identified in an uncinate process. FNB was performed (Figure 3a) with pathology revealing adenocarcinoma (Figure 3b). Finally, a large hepatic lesion with multiple anechoic components surrounded by hyperechoic rims with acoustic shadowing was identified in the left lobe. DISCUSSION: Our case presents a rare finding of synchronous gastric GIST and pancreatic adenocarcinoma. The percentage of GIST occurring with other neoplasms is reported to range between 3% and 33%. There is no recognized pattern to ascertain whether the coexistence of these tumors is incidental or related to a genetic or pathologic process. The etiology of synchronous occurrence of GISTs with histologically unrelated tumors remains unclear, however, some authors have suggested that they may share common genetic mutations with proliferation of different cell lines. As there is a limited number of cases, future studies are needed to evaluate this link, but it is important for both pathologists and surgeons to be aware that this phenomenon does exist.Figure 1.: (a) CT scan with pancreatic head mass and left hepatic lobe lesion; (b) CT scan with proximal gastric mass.Figure 2.: Pathology slide displaying spindle cells obtained from FNB of gastric mass.Figure 3.: (a) EUS image showing FNB of pancreatic mass; (b) Pathology slide displaying malignant adenocarcinoma.

Clinical application of 18F-FDG PET/CT in&#x0D; oncology: Rare gastrointestinal malignant tumors&#x0D; (literature review)

Relevance: PET/CT is now becoming an integral part of cancer management protocols. 18F-fluorodeoxyglucose (18F-FDG)&#x0D; is the most common radiopharmaceutical for PET. However, the 18F-FDG PET/CT sensitivity and specificity vary widely in tumors of different histological structures and cell atypia degrees.&#x0D; The role of PET/CT in complex diagnostics of lymphomas is known. However, the specific use of this method in gastrointestinal neoplasms, especially at the initial stage of examination and in differential diagnostics, is not clearly defined since&#x0D; lymphomas account for only 1-5% of GI tumors.&#x0D; Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that arise from the diffuse neuroendocrine system&#x0D; enterochromaffin cells. NETs account for 0.5% of all neoplasms but become more common recently due to the advances in diagnostics. However, the significant achievements in the study of biological and molecular mechanisms of NETs’ behavior have&#x0D; not yet resulted in a common algorithm for their diagnostics and treatment.&#x0D; The purpose of this study was to review the experience of using 18F-FDG PET/CT in diagnostics of lymphomas and gastrointestinal neuroendocrine tumors as rare tumors to improve the criteria for the rational use of the 18F-FDG PET/CT method in&#x0D; their diagnostics and monitoring.&#x0D; Results: The use of 18F-FDG PET/CT is advisable at any stage of non-Hodgkin lymphomas, which are most common in the&#x0D; gastrointestinal tract, and for differential diagnostics, primary staging, and treatment efficiency monitoring in gastrointestinal&#x0D; lymphomas. 18F-FDG PET CT is also most valuable in aggressive non-Hodgkin lymphomas.&#x0D; Despite the importance of functional imaging in NETs, 18F-FDG PET/CT plays a supporting role in monitoring gastrointestinal NETs. 18F-FDG PET/CT is known to be efficient in prognosing the outcome of radionuclide therapy with peptide receptors&#x0D; in low-grade and progressive metastatic NETs.&#x0D; Conclusion: In lymphomas, 18F-FDG PET/CT is useful for primary staging, assessing early response to treatment, and&#x0D; re-staging. 18F-FDG PET/CT has a diagnostic value in undifferentiated gastrointestinal NETs, while its usefulness in well-differentiated gastrointestinal NETs is limited.

Abstract C001: Palliative radiation to bony metastases from GI tumors: Disparities, outcomes, and practice patterns

Abstract PURPOSE: To evaluate the use of palliative radiotherapy (pRT) for osseous metastases among patients with gastrointestinal malignancies by sociodemographic factors, tumor type, and survival. METHODS: The NCDB was used to identify 9297 patients with GI cancers who received pRT to bony metastases from 2004 to 2013. Cancers assessed included esophageal, stomach, pancreatic, hepatocellular (HCC), bile duct &amp; other, gallbladder, colon/sigmoid, and rectal. After excluding incomplete data, 5774 remained for analysis. Strata included age, race, sex, household income, Charlson-Deyo score (CDS), site of bony metastasis, Insurance status, treatment facility type, and distance from treatment site (crow-fly). Outcomes of interest included survival after diagnosis, survival after pRT, completion of pRT, and percent of remaining life spent receiving radiotherapy (PRLSRT). Chi-squared, Kaplan Meier curve with log rank analyses, and Cox Regression evaluated outcomes as a factor of sociodemographics. RESULTS: Patients were 69% male, 81% Caucasian (CA) and 13% African American (AA). Pancreas, HCC, and Colon/Sigmoid cancers made up 63% of primary tumors. The most commonly used pRT regimen was 30Gy in 10 fractions, and single-fraction 8Gy was increasingly utilized towards 2013. As survival decreased, use of single-fraction pRT increased indicating appropriate pairing of treatment duration to prognosis. This trend was consistent among both AA and CA patients. AA patients were younger and more likely to live &amp;lt;20mi from their treatment facility compared to CA’s. AA’s were more likely to have no insurance or Medicaid (9.7% vs 5.3%, or 18.1% vs 8% p&amp;lt;0.05), and have an annual household income below $30k (37.3 vs 11.4%) compared to CA’s. AA’s were less likely to have pancreatic cancer. Slightly more AA’s completed pRT than CA’s (69.2% vs 65.2%, p&amp;lt;0.05), and had longer survival after diagnosis compared to CA (10.2 vs 9.7 months) but shorter survival after pRT suggesting a delay in palliation. Additionally, those who lived 40-60 miles from treatment facility had higher mean survival. Patients with private insurance and those treated at integrated network programs survival advantages. PRLSRT did not differ by race, but decreased from 2004 to 2013. PRLSRT&amp;gt;50% (p50) did not differ by crow-fly or facility type, but men and those with Medicare were more likely to have p50. A PRLSRT of 10% or less (p10) was more frequent in those who were treated at an academic facility, lived &amp;gt;60mi away, had private insurance, a lower CDS, or earned $48-63k/yr in 2012. Sites with more p50 were the spine, skull, and spinal cord. Sites with higher p10 were extremity, shoulder, and ribs. CONCLUSION: This study evaluated trends of pRT use among patients and stratified analyses by sociodemographic factors. Further research may uncover mechanisms of these trends and highlight potential strategies to optimize the use of pRT. Citation Format: Jason Hirshberg, Charles Hsu, Jared Robbins. Palliative radiation to bony metastases from GI tumors: Disparities, outcomes, and practice patterns [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C001.

Outcomes of transarterial chemoembolization (TACE) of the liver in patients with metastatic triple-negative breast cancer (TNBC).

e13107 Background: TACE is widely used in oncology in patients with metastasis in liver from GI tumors, meanwhile its opportunities in management pts with TNBC are unknown. The purpose of the study was to analyze the results of TACE of the liver metastases from TNBC. Methods: The study included 60 TNBC pts with unresectable liver metastases. 34 pts of the main group underwent chemotherapy including taxanes in standard regimens. After 6-12 chemotherapy cycles, the main group received 1-2 TACE procedures (doxorubicin 30 mg/m², 5-fluorouracil 600 mg/m², 10 ml of lipiodol and 1-2 ml of 300-500 µm HepaSphere microspheres). The control group (n = 32) received only 6-12 cycles of taxane-containing chemotherapy. Pts were aged 32-66 years, mean age in the main group 49.4, in controls 55 years. Primarily advanced breast cancer with unresectable liver metastases was diagnosed in 6 (17.6%) pts of the main group and in 5 (15.6%) controls. Progression after previous treatment was observed in 91.2% (31) main group and 90.6% (29) controls. Sizes of metastatic foci were 2.7-7.3 cm, average number 7.5. Bilobar metastases were most common. Liver metastases were own accompanied by metastases to the bones, intrathoracic lymph nodes, lungs and pleura. Obtained data were processed with software package “Statistica 7.0”. Results: Main group received a total of 46 TACE procedures performed for a maximal number of metastatic lesions, especially for those progressing after systemic therapy and the largest ones, when possible. Post-embolization syndrome after performing TACE, was observed in 60.86% (28) of cases, managed with conservative therapy for 2-7 days. Icterus was not observed. The tumor response rate was 94.1% in the main group vs. 80.6% in controls, with significant differences in PR (44.1% and 15.3% respectively, p &lt; 0.05). Median of duration treatment response was 13.4 months in the main group and 9.3 months in control group (p &lt; 0.05). CR was not achieved. Median follow-up was 17 months. 3-year disease-free survival was 63.2% in the main group and 43.8% in controls (p = 0.039). Conclusions: TACE resulted in better response to the therapy as well as improved disease-free survival in pts with TNBC. TACE is possible to be used to consolidate the achieved effect of the chemotherapy.

Comprehensive gene expression analysis of IDH1/2 mutant biliary cancers (BC).

4598 Background: Isocitrate dehydrogenases (IDH) mutations (mut) identify a distinct subtype of BC that has yet to be fully characterized. We recently showed that IDH1/2 mutant (mIDH) BC harbor specific gene alterations involving chromatin remodeling and DNA repair, and a differential immune markers profile compared to other mIDH GI tumors. Here we aim to further dissect the molecular profile of mIDH BC through a comprehensive gene expression profiling analysis. Methods: 524 BC samples (303 intrahepatic cholangiocarcinoma, IHCC, 67 extrahepatic cholangiocarcinoma, EHCC, 141 gallbladder, 13 unspecified) collected between February to December of 2019 were included. Samples were analyzed using NextGen DNA sequencing (NextSeq, 592 gene panel), whole transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). EBseq was used to identify differentially expressed genes in mIDH vs wild type (WT) tumors with control for FDR ( Q &lt; 0.2). Pathway and functional enrichment analysis was performed using g:Profiler and Enrichr. Results: mIDH frequency in our cohort was 11.4% (60/524), with higher prevalence of IDH1 mut (8.8%). IHCC showed the highest mut prevalence: IDH1 13.5%, IDH2 4.6%. mIDH was more common in females ( P = 0.0036). A total of 774 genes were significantly differentially expressed between mIDH and WT: 582 underexpressed (Fold change, FC: 0.025~0.699); 192 overexpressed (FC: 1.43~3.3). Pathway enrichment showed a significant decrease of gene expression in cytokine-cytokine receptor interaction ( Q = 0.002) and inflammatory response genes ( Q = 0.005) in mIDH. Interferon-γ- and PD1 signaling-related genes expression was significantly lower in mIDH vs WT ( Q = 0.02) including IFNG (FC 0.32), NKG7 (FC 0.36), CD8B (FC 0.37), BATF (FC 0.40), PD1 (FC 0.53), SLAMF6 (FC 0.55) and PD-L2 (FC 0.60). Wnt and cadherin signaling were also enriched for altered expression in several genes in mIDH BC ( Q = 3.86e-7 and &lt; 0.00001, respectively). Conclusions: To our knowledge, this is the largest and most extensive gene expression profiling study focused on mIDH BC. Our data show for the first time a distinct gene expression profile characterizing mIDH tumors which display significant downregulation of inflammatory response pathways and immune-related genes. These findings contribute to further the understanding of mIDH BC and may inform the future development of rational combination therapies.

Next-Generation Sequencing of Advanced GI Tumors Reveals Individual Treatment Options.

PURPOSEPrecision oncology connects highly complex diagnostic procedures with patient histories to identify individualized treatment options in interdisciplinary molecular tumor boards (MTBs). Detailed data on MTB-guided treatments and outcome with a focus on advanced GI cancers have not been reported yet.PATIENTS AND METHODSNext-generation sequencing of tumor and normal tissue pairs was performed between April 2016 and February 2018. After identification of relevant molecular alterations, available clinical studies or in-label, off-label, or matched experimental treatment options were recommended. Follow-up data and a response assessment that was based on radiologic imaging were recorded.RESULTSNinety-six patients were presented to the MTB of Tuebingen University Hospital. Sixteen (17%) showed “pathogenic” or “likely pathogenic” germline variants. Recommendations on the basis of molecular alterations or tumor mutational burden were given for 41 patients (43%). Twenty-five received the suggested drug, and 20 were evaluable for best response assessment. Three patients (15%) reached a partial response (PR), and 6 (30%), stable disease (SD), whereas 11 (55%) had tumor progression (progressive disease). Median progression-free survival (PFS) for all treated and evaluable patients was 2.8 months (range, 1.0-9.0 months), and median overall survival (OS) of all treated patients was 5.2 months (range, 0.1 months to not reached). Patients with SD for ≥ 3 months or PR compared with progressive disease showed both a statistically significant longer median PFS (7.8 months [95% CI, 4.2 to 11.4 months] v 2.2 months [95% CI, 1.5 to 2.8 months], P < .0001) and median OS (18.0 months [95% CI, 10.4 to 25.6 months] v 3.8 months [95% CI, 2.3 to 5.4 months], P < .0001).CONCLUSIONNext-generation sequencing diagnostics of advanced GI cancers identified a substantial number of pathogenic or likely pathogenic germline variants and unique individual treatment options. Patients with PR or SD in the course of MTB-recommended treatments seemed to benefit with respect to PFS and OS.

The multi-kinase inhibitor lenvatinib interacts with the HDAC inhibitor entinostat to kill liver cancer cells

Prior studies from our group have combined the multi-kinase inhibitor sorafenib with HDAC inhibitors in GI tumor cells that resulted in the trials NCT02349867 and NCT01075113. The multi-kinase inhibitor lenvatinib, for the treatment of liver cancer, has fewer negative sequelae than sorafenib. We determined the mechanisms by which lenvatinib interacted with the HDAC inhibitor entinostat to kill hepatoma cells. Lenvatinib and entinostat interacted in an additive to greater-than-additive fashion to kill liver cancer cells. The drugs inactivated mTORC1 and mTORC2 and interacted to further increase the phosphorylation of ATM, ATG13 and eIF2α. Elevated eIF2α phosphorylation was responsible for reduced MCL-1 and BCL-XL expression and for increased Beclin1 and ATG5 expression. Over-expression of BCL-XL or knock down of Beclin1 or ATG5, significantly reduced killing. The drugs synergized to elevate ROS production; activation of ATM was ROS-dependent. ATM activation was required for enhanced phosphorylation of γH2AX, eIF2α and ATG13 S318. The drug combination reduced histone deacetylase protein expression which required autophagy. Knock down of HDACs1/2/3 prevented the lenvatinib and entinostat combination from regulating PD-L1 and MHCA expression. Collectively, our data demonstrate that lenvatinib and entinostat interact to kill liver cancer cells via ROS-dependent activation of ATM and inactivation of eIF2α, resulting in greater levels of toxic autophagosome formation and reduced expression of protective mitochondrial proteins.

Current status of immunotherapy in gastrointestinal malignancies.

Gastrointestinal (GI) malignant neoplasms have a high global incidence and a huge impact on cancer-associated mortality. In the past years, excitement was growing among oncologists and patients alike for the use of immunotherapy, specifically immune checkpoint inhibitors. The approval of several PD-1/PD-L1 and CTLA-4 inhibitors radically changed the treatment landscape in many cancer types and established immune-oncology as a new treatment strategy against cancer. Despite major breakthrough reports, shortcomings of immune checkpoint inhibitors (ICI) have been observed, including primary and acquired treatment resistance, especially in patients receiving ICIs as a single treatment. Several immunotherapies for the treatment of GI tumors have recently emerged; however, checkpoint inhibition has not yet shown similar success in GI malignancies compared to other solid tumors. Various phase I-III trials focusing on immunotherapies for GI tumors have found only moderate to unsatisfactory objective response rates (ORR), ranging between 10 % and 25 %. In particular, negative studies have been reported in gastric and pancreatic cancer. Nevertheless, small subsets of cancers, such as DNA mismatch repair deficient (dMMR)/microsatellite instable (MSI) cancers, among others, seem to benefit from treatment with immune checkpoint inhibition. Routine testing for the rare molecular features that can predict response should be implemented in clinical routine for all GI tumors, and large scale clinical trials to identify predictive biomarkers are needed. This article will address the current use and evidence for immunotherapy in GI malignancies and future trends in this area for clinical practice.

Safety and efficacy of anti-PD-1 antibody dostarlimab in patients (pts) with mismatch repair deficient (dMMR) GI cancers.

218 Background: Dostarlimab (TSR-042) is an investigational humanized anti-PD-1 monoclonal antibody that binds the PD-1 receptor, blocking the interaction with ligands PD-L1 and PD-L2. The ongoing GARNET trial (NCT02715284) is evaluating dostarlimab in pts with advanced solid tumors. Here we present safety and efficacy data from cohort F. Methods: Cohort F in the GARNET trial enrolled pts with dMMR or microsatellite instability high (MSI-H) non-endometrial solid tumors, the majority of which were GI in origin. Pts must have progressed following prior systemic therapy for advanced disease, assessed by independent central review (ICR). Pts received 500 mg dostarlimab Q3W for 4 cycles and 1000 mg Q6W thereafter. Objective response rate (ORR) and duration of response (DOR) were assessed by ICR per RECIST v1.1. Pts were included in the efficacy analysis if they received ≥1 dose of dostarlimab, had measurable disease at baseline, and ≥24 weeks of follow up. All pts who received ≥1 dose were included in the safety analysis. Results: 109 pts were included in the safety analysis, with 48 dMMR pts in the efficacy analysis. Of the 48 pts, 42 (88%) had GI tumors. Confirmed ORR in dMMR pts was 43.8% (95% CI: 29.5, 58.8), with a complete response rate of 8.3%. ORR was consistent across tumor type (Table). Median DOR was not reached. The probability of maintaining response at 12 months was 85.9%. Treatment-related adverse events (TRAEs) were reported in 55% of pts; 7.3% of pts experienced grade ≥3 TRAEs, including 1 each of adrenal insufficiency, rash, diarrhea, and fatigue. Treatment-related serious AEs (SAEs) were reported in 6 (5.5%) pts, and 2 pts (1.8%) discontinued dostarlimab due to a TRAE. No treatment-related deaths were reported. Conclusions: Dostarlimab demonstrated robust, durable antitumor activity in a cohort of dMMR solid tumor pts, the majority of whom had GI cancers, with an acceptable safety profile. Clinical trial information: NCT02715284. [Table: see text]

Stereotactic radiotherapy in oligometastatic (OM) gastrointestinal (GI) tumors: A single institution retrospective analysis.

825 Background: Metastatic GI cancers are mainly treated with systemic treatment (ST), in selected patients (pts), surgery is considered depending on pts characteristics and institutional preferences. Stereotactic Radiotherapy (SRT) is a growing treatment option in such landscape aiming to improve local disease control and maximize ST results for oligometastatic pts. Methods: This is a single center retrospective study. Data were collected from sequential pts with GI tumors who underwent SRT for OM-GI cancers from May 2014 to July 2019. Information was collected on pts characteristics, primary site, clinical staging at diagnosis, sites undergoing SRT, whether there was progression after the first SRT, time between the first SRT and progression and the last follow-up date. Results: 381 pts underwent SRT in our center, of these, 75 pts had OM-GI tumors and underwent 120 courses of SRT. 50,7% were women, the median age at diagnosis was 60 years and the median follow-up was 36 months. 76% had colorectal cancer (CRC) being 26% from the right, 26% from the left colon and 30% were from the rectum, in 18% of the patients we could not determine sidedness. 35% already had metastatic disease at diagnosis. The lung was the site with largest number of lesions treated with SRT (50), followed by central nervous system (CNS) (42), bones (32), liver (29) and lymph nodes (16). After a median follow up of 15.3 months, 11% of patients were progression-free and only 24% had progressed on treated lesions. The median progression free survival following SRT was 4.5 months (0.6-45.8 range) for distant metastasis and was not achieved for treated sites. Conclusions: This retrospective study adds to the previous body of evidence supporting the use of SRT to improve GI cancer management. Detailed information on pts characteristics, pathology, toxicity and previous treatments will be presented.

Comprehensive molecular profiling of IDH1/2 mutant biliary cancers (BC).

479 Background: Isocitrate dehydrogenases (IDH) play a key role in energetic metabolism and IDH mutations (mut) promote oncogenesis via epigenetic and genetic changes. Data addressing the molecular contexture of IDH1/2 mut in BC are lacking. We aimed to characterize the molecular profile of IDH1/2 mutant (mIDH) GI cancers with a focus on BC. Methods: 27954 GI cancer samples collected between August 2000 and July 2019 were included: 2057 BC (1159 ICC, 277 extrahepatic CC, 573 gallbladder, 48 unspecified CC), 13807 colorectal, 4183 gastric/esophageal, 3060 other. Samples were analyzed using NextGen DNA sequencing, in situ hybridization, RNA sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous missense mut. MMR/MSI status was evaluated by a combination of IHC, Fragment Analysis and NGS. Results: mIDH frequency in BC was 10.3% (211/2057), with higher prevalence of IDH1 mut (8.2%). ICC showed the highest mut prevalence: IDH1 13.5%, IDH2 4%. Mut rates in other GI cancers types were &lt; 1%, except for HCC (1.9%, 11/582) and small bowel (1.1%, 8/736). When compared to IDH wild type (WT), mIDH BC showed lower mut rates in TP53 (13 vs 43%), KRAS (8 vs 19%), CDKN2A (1 vs 9%), and SMAD4 (0 vs 9%), whereas PBRM1 mut were higher (14 vs 5%) ( P &lt; .001 for all comparisons). There was a trend towards higher frequency of ARID1A and BAP1 in mIDH BC. HER2 expression and amplification rates were lower in mIDH vs WT BC (0.5 vs 3%, P = .048 and 0 vs 6%, P = .002). FGFR2 fusion was detected in 7% of WT vs 2% of mIDH BC. mIDH BC showed a lower TMB (0.7 vs 3.7%, P = .048) and a trend for lower MSI rates (0.6 vs 3%, P = .06) vs WT BC. Conversely, IDH mut were associated with higher TMB and MSI ( P &lt; .001) and higher PD-L1 expression in other GI cancers. Conclusions: This is the largest and most extensive profiling study to investigate the molecular makeup of mIDH BC and GI tumors. Our data show distinct gene alteration patterns characterizing mIDH BC, involving genes related to chromatin remodeling and DNA repair, and a differential expression of immune related markers compared to other mIDH GI tumors. These findings can contribute to the development of rational combination therapies and to improved patient selection in the future.

Magnetic marking clip for easier laparoscopic localization of small gastrointestinal tumors.

386 Background: Laparoscopic surgery for gastrointestinal tumors requires fast and precise tumor localization. As tumor palpation is not possible during laparoscopic surgery, tumor identification is often difficult for some cases. Despite various methods, such as tattooing or endo-clipping, have been introduced for the localization of tumors, these methods own clear limitations. To overcome the drawbacks of these conventional marking methods, we designed a magnetic marking device linked to an endo-clip(MMC, Magnetic Marking Clip) for endoscopy. We performed preoperative endoscopic clipping with MMC and analyzed the intraoperative localization efficacy and safety during laparoscopic surgery. Methods: Study enrolled 30 patients with gastric and colorectal neoplasms scheduled to undergo endoscopic clipping before laparoscopic surgery at the Korea University Medical Center, Korea, between August 2017 and June 2019. A silicone-coated high-power neodymium marking device (ring or rod type) was fixed together with an endo-clip and applied on the center of the lesion during preoperative endoscopy. During laparoscopic surgery, a detecting magnetic body was inserted through a laparoscopic trocar and was used to localize the tumor that is marked with MMC. The time needed for endoscopists to place MMC at the lesion, laparoscopic clip detection time and success rate were studied. Results: Endoscopists placed MMC within 30 seconds. It was possible to find MMC in all cases of laparoscopic surgery. Time needed to find the MMC laparoscopically was relatively shorter than the time conventionally taken just with an endo-clip itself. There was no reported dislodgement of the clip before the surgery or any other adverse events associated with the MMC procedure. Conclusions: The MMC method enabled simple and fast tumor localization and showed excellent outcomes in efficacy of tumor localization. The MMC method may help surgeons localize GI tumor lesions easily and safely during laparoscopic surgery.

A phase II, open-label pilot study evaluating the safety and activity of Nal-IRI in combination with 5-FU and oxaliplatin in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI Study) (NCT03483038).

TPS790 Background: Neoadjuvant treatment for borderline resectable pancreatic cancer (PCa) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Irinotecan liposomal injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PCa. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with borderline resectable PCa without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board, adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive FOLFNal-IRINOX regimen as per Table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30 day postoperative complication rate. Clinical trial information: NCT03483038 . [Table: see text]

GZ17-6.02 initiates DNA damage causing autophagosome-dependent HDAC degradation resulting in enhanced anti-PD1 checkpoint inhibitory antibody efficacy.

Our studies examined the molecular mechanisms by which the novel cancer therapeutic GZ17-6.02 (NCT03775525) killed GI tumor cells. TZ17-6.02 activated ATM which was responsible for increased phosphorylation of nuclear γH2AX and AMPKα T172. ATM-AMPK signaling was responsible for the subsequent inactivation of mTORC1 and mTORC2, dephosphorylation of ULK1 S757, and increased phosphorylation of ULK1 S317 and of ATG13 S318, which collectively caused enhanced autophagosome formation. GZ17-6.02 interacted with 5-fluorouracil in an additive to greater than additive fashion to kill all of the tested GI tumor cell types. This was associated with greater ATM activation and a greater mammalian target of rapamycin inactivation and autophagosome induction. As a result, autophagy-dependent degradation of multiple histone deacetylase (HDAC) proteins and chaperone proteins occurred. Loss of HDAC expression was causal in reduced expression of programed death ligand 1 (PD-L1), ornithine decarboxylase, and indole amine 2,3-dioxygenase (IDO1) and in the elevated expression of major histocompatibility complex Class IA (MHCA). Treatment with GZ17-6.02 also resulted in enhanced efficacy of a subsequently administered anti-PD1 checkpoint inhibitory antibody. Thus, the primary mode of GZ17-6.02 action is to induce a DNA damage response concomitant with ATM activation, that triggers a series of interconnected molecular events that result in tumor cell death and enhanced immunogenicity.

SETD2, an epigenetic tumor suppressor: a focused review on GI tumor.

Significant progress has been made in our understanding of the role of epigenetic modifiers in many types of human cancer. Here, we review currently available studies on the unique histone methyltransferase, SETD2, which is responsible for H3 lysine 36 tri-methylation (H3K36me3). SETD2 plays pivotal roles in RNA alternative splicing regulation, DNA damage repair, and cytoskeleton protein methylation; inactivation of SETD2 and resultant dysregulation of these functions may lead to tumorigenesis. Despite being a newly discovered tumor suppressor, SETD2 has been found to be mutated in multiple types of cancer, including gastrointestinal tumor. Some tumors can acquire a selective growth advantage after SETD2 inactivation, which could happen in different stages in tumor progression. Decreased level of H3K36me3 caused by SETD2 inactivation has been shown to associate with higher tumor grade, tumor stage, metastasis risk, and shorter survival. Some studies also suggest that SETD2 mutation is associated with therapy resistance, therefore these SETD2-deficient tumors may need different therapeutic strategies.