Gastrointestinal Malignancies Research Articles

Intra-tumoral immunomodulatory therapy for advanced abdominal cancers using lipopolysaccharide: The Regional Immuno-Oncology Trial-1 (RIOT-1) protocol (NCT05751837)

BackgroundIntra-tumoral immunotherapy has shown potential in treating advanced cancers. Delivery challenges have limited exploration of these modalities in intra-abdominal tumors. In this study, we explore the safety of injecting intra-abdominal tumors with lipopolysaccharide (LPS) from Escherichia coli 0113. This agonist of toll-like receptor 4 (TLR4) holds promise as an agent to enhance the anti-tumor immune response within the tumor microenvironment. MethodsThis Phase I study will recruit adult patients with peritoneal metastases from gastrointestinal primary malignancies who have at least two suitable intra-abdominal soft tissue tumors for injection. LPS will be administered as a single 1 μg dose during diagnostic laparoscopy in patients in whom a subsequent interval laparotomy is planned. A control injection of saline will be injected into a second lesion. Primary outcome is safety, with secondary outcomes being biomarkers of the tumor immune microenvironment in pre- and post-treatment biopsies. ResultsThe primary endpoint is to determine the safety (frequency and nature of adverse events) following intra-tumoral LPS injection. Adverse events will be classified using Common Terminology Criteria for Adverse Events. Secondary endpoints include cellular and molecular biomarkers of immune response. The study will proceed until twelve patients have completed the protocol. DiscussionPatients undergoing standard-of-care laparoscopy in preparation for interval cytoreductive surgery may be ideal candidates for intra-tumoral immunotherapy. This study seeks to establish the safety of using E. coli LPS for injection into intra-abdominal tumors and to establish precedent for interval tumor immune microenvironment assessment as a window-of-opportunity concept in the context of abdominal metastatic disease. Trial RegistrationThe trial is registered at Clinical Trials.gov; NCT05751837 (registered February 28th, 2023).

Evaluation of Gastro Intestinal Stromal Tumor in a Tertiary Care Center

INTRODUCTION: Gastrointestinal stromal tumour (GIST) is an uncommon entity in clinical practice. It accounts for only <1% of all Gastrointestinal (GI) malignancies. Stomach is the commonest site for this tumour. Other sites of GI tract are also affected with GIST. AIMS AND OBJECTIVES: This study aimed evaluate the prognostic factors, and recurrence patterns among the patients of eastern India. MATERIAL AND METHODS: This was a retrospective observational study which was conducted at the Department of Pathology in a tertiary care centre of eastern India. The specimens sent for HPE during the period June, 2018 to June, 2023 were included in the study. A total number of 2897 GI specimens sent to the Department for histopathological examinations were selected for the study. Out of which 77 specimens were diagnosed as GIST. The information of the vital parameters of the patient, type of tumour and type of treatments offered were collected for evaluation. The histological examinations relied on morphological features on Hematoxylin & Eosin stain and confirmation with immunohistochemistry markers CD34 and CD117 and S100. Patients with operable GIST underwent Surgery followed by adjuvant therapy. Patients with inoperable/ borderline operable disease underwent neoadjuvant Tab. Imatinib 400 mg/day followed by reassessment for surgery. RESULTS: The mean (±S.D.) age of the patients was 54.58±11.24 years with range of 28 -74 years and the median age was 54 years. 66.2% of the patients were with age< 60 years (p<0.001). Proportion of females (54.5%) was higher than males (45.5%) but it was not significant. Stomach (54.5%) was the most common site of tumour which was significantly higher than small intestine (27.3%) and large intestine (18.2%) (p<0.0001). At presentation non-metastatic cases (62.3%) were significantly higher than metastatic (35.1%) and locally recurrent cases (2.6%) (p<0.0001). In most of the cases the mitotic rate was between 5 – 10 /50 HPF (53.2%) which was significantly higher than mitotic rate <5/50 HPF (32.5%) and >10/50 (14.3%) (p=0.0042). Spindle cell type tumour (71.4%) was significantly higher than mixed (Spindle and Epithelioid) (20.8%) and Epithelioid type tumour (7.8%) (p<0.0001). CONCLUSION: GIST is a rare tumor of the GI tract. It usually occurs in the stomach. The treatment of choice is surgery followed by adjuvant therapy.

Disparities in clinical trial enrollment among patients with gastrointestinal cancer relative to minority-serving and safety-netting hospitals

BackgroundFor results to be generalizable to all cancer patients, clinical trials need to include a diverse patient demographic that is representative of the general population. We sought to characterize the impact of receiving care at a minority-serving hospital (MSH) and/or safety-net hospital on clinical trial enrollment among patients with gastrointestinal (GI) malignancies. MethodsAdult patients with GI cancer who underwent oncologic surgery and were enrolled in institutional/National Cancer Institute-funded clinical trials between 2012-2019 were identified in the National Cancer Database. Multivariable regression was used to assess the relationship between MSH and/or safety net status relative to clinical trial enrollment. ResultsAmong 1,112,594 patients, 994,598(89.4%) patients were treated at a non-MSH, while 117,996(10.6%) were treated at an MSH. Only 1,857(0.2%) patients were enrolled in a clinical trial; the vast majority received care at a non-MSH (n=1,794, 96.6%). On multivariable analysis, the odds of enrollment in a clinical trial were markedly lower among patients treated at an MSH versus non-MSH. (OR 0.32, 95%CI 0.22-0.46). In addition, even after controlling for receipt of care at MSH, Black patients remained at lower odds of enrollment in a clinical trial versus White patients (OR 0.72, 95%CI 0.53–1.00) (both p<0.05). ConclusionsOverall clinical trial participation among patients with GI cancer was extremely low. Patients treated at MSH and high safety-net burden hospitals, as well as Black individuals, were much less likely to be enrolled in a clinical trial. Efforts should be made to improve trial enrollment, as well as address disparities in trial representation.

Gastrointestinal Sistem Malignitesi Olan Hastalarda Peroperatif Dönemde Olan Kilo Kaybının ve Beden Kitle İndeksi Değişimlerinin İncelenmesi

Amaç: Malnütrisyon, kanser hastalarını hastalıklarının seyri boyunca büyük ölçüde etkileyen bir sorundur. Tanı anında kilo kaybı yaşayan hastaların oranı, kanser türüne bağlı olarak %15-40 arasında değişmektedir. Hastalık ilerledikçe malnütrisyon insidansı artar ve sonunda hastaların %80'ini etkiler. Malnütrisyon, kanserli hastaların enfeksiyon insidansını, hastanede kalış süresini ve ölüm riskini artırır. Bu çalışmayı bir eğitim ve araştırma hastanesinin genel cerrahi kliniğinde Gastrointestinal Sistem (GİS) malignitesi tanısı ile ameliyat olan hastalardaki malnütrisyon durumunu değerlendirmek amacıyla yaptık. Gereç ve yöntemler: Çalışmaya hastanemiz genel cerrahi kliniğinde GİS malignitesi sebebiyle 01.06.2021-01.08.2021 tarihleri arasında ameliyat olan hastalar alındı. Görüşme yöntemi ile hastaların 4 ayrı dönemdeki kiloları ve beden kitle indeksi (BKİ) değerleri (sağlıklı dönem- hastaneye yatış esnasında - taburcu oldukları sırada - taburcu olduktan 1 ay sonra) not edildi. Hastaların yaş-cinsiyet bilgileri kaydedildi. Çalışmaya katılmanın gönüllülük esasına bağlı olduğu bildirilerek ilgili kurumdan ve çalışmaya katılan hastalardan izin alındı. Bulgular: Bu çalışma yaşları 20-83 arasında, 19’u (%31,7) kadın ve 41’i (%68,3) erkek olmak üzere toplam 60 hasta ile yapılmıştır. Hastaların yaşları ortalaması 50±15, boyları 150-190 (168±9) cm’dir. Hastaların hastalık öncesi BKİ 18,9-37,3 (27,5±4,1) bulundu. Yatışa kadar kilo kaybı 0-30 (8±8) kg saptandı. Hastaların yatış BKİ 16-33,6 (24,8±3,7) bulundu. Hastane yatış sürecinde kaybedilen kilo 0-11(3±3) kg saptandı. Taburculuk BKİ 14-31,9 (23,9±3,7) olduğu bulundu. Taburcu olduktan 1 ay sonraki BKİ 14-31,9 (23,9±3,7) olduğu bulundu. Taburcu olduktan sonraki dönemde kaybedilen kilo 0-15 (2±4) kg arasında saptandı. Hastaların; hastalık öncesi dönemden yatış anına kadar, yatış sürecindeki ve taburculuk anından 1 ay sonraki döneme kadar BKİ kayıpları değerlendirildiğinde, her üç dönemde de istatistiksel anlamlı kilo-BKİ kaybı olduğu görüldü. Sonuç: GİS malignitesi olan hastaların malnütre olduklarının takip eden klinisyen tarafından tespiti, hastalığın klinik seyri açısından önemlidir. Yapılan bu çalışmada görüldüğü üzere hastalar her dönemde kilo kaybetmiştir. Sonuç olarak, malnütrisyonun kanserlerde özellikle de GİS malignitelerinde oldukça sık görüldüğünün dikkate alınması kilo kaybının ve bu sebeple ortaya çıkan sorunların önüne geçilmesini sağlayacaktır.

Publication Bias in Upper Gastrointestinal Oncology Clinical Trials.

Evidence-based medicine requires evaluation of the medical literature to guide clinical reasoning and treatment recommendations. The presence of publication bias towards exclusion of non-statistically significant clinical trials may be leading to an incomplete evaluation of the literature and cause potentially incomplete guidance for patients. We aimed to compare publication rates and impact of publications of positive and negative outcome clinical trials. We queried the US National Library of Medicine Clinical Trials database identifying clinical trials with reported results on the topics of pancreatic, liver, and gastric cancer. A "positive" trial was defined as having a statistically significant difference between the treatment arms, while a "negative" did not. Data collected included termination cause, intervention, funding type, publication rates, and journal characteristics. In total, 535 clinical trials were examined, across all pathologies clinical trials with significant findings for the primary outcome were published at a higher rate (99%) compared to those with non-significant findings (77%) (p < 0.01). Significantly, more studies with significant findings reached at least 80% of their estimated enrollment goal versus non-significant studies, 72% and 53% respectively (p < 0.01). Three of four metrics for impact of publication showed no difference between significant and non-significant studies once they reached publication. These findings suggest that clinical trials of three of the most common upper gastrointestinal malignancies have a publication bias towards studies with significant primary outcome findings. This study has implications to the way evidence-based medicine is practiced as the medical literature appears to be failing to capture important data for consideration of clinical decision making.

Feasibility and safety of minimally invasive multivisceral resection for T4b rectal cancer: A 9-year review.

Colorectal cancer is the third most common cancer and the second highest cause of cancer-related mortality worldwide. About 5%-10% of patients are diagnosed with locally advanced rectal cancer (LARC) on presentation. For LARC invading into other structures (i.e. T4b), multivisceral resection (MVR) and/or pelvic exenteration (PE) remains the only potential curative surgical treatment. MVR and/or PE is a major and complex surgery with high post-operative morbidity. Minimally invasive surgery (MIS) has been shown to improve short-term post-operative outcomes in other gastrointestinal malignancies, but there is little evidence on its use in MVR, especially so for robotic MVR. To assess the feasibility and safety of minimally invasive MVR (miMVR), and compare post-operative outcomes between robotic and laparoscopic MVR. This is a single-center retrospective cohort study from 1st January 2015 to 31st March 2023. Inclusion criteria were patients diagnosed with cT4b rectal cancer and underwent MVR, or stage 4 disease with resectable systemic metastases. Patients who underwent curative MVR for locally recurrent rectal cancer, or metachronous rectal cancer were also included. Exclusion criteria were patients with systemic metastases with non-resectable disease. All patients planned for elective surgery were enrolled into the standard enhanced recovery after surgery pathway with standard peri-operative management for colorectal surgery. Complex surgery was defined based on technical difficulty of surgery (i.e. total PE, bladder-sparing prostatectomy, pelvic lymph node dissection or need for flap creation). Our primary outcomes were the margin status, and complication rates. Categorical values were described as percentages and analysed by the chi-square test. Continuous variables were expressed as median (range) and analysed by Mann-Whitney U test. Cumulative overall survival (OS) and recurrence-free survival (RFS) were analysed using Kaplan-Meier estimates with life table analysis. Log-rank test was performed to determine statistical significance between cumulative estimates. Statistical significance was defined as P < 0.05. A total of 46 patients were included in this study [open MVR (oMVR): 12 (26.1%), miMVR: 36 (73.9%)]. Patients' American Society of Anesthesiologists score, body mass index and co-morbidities were comparable between oMVR and miMVR. There is an increasing trend towards robotic MVR from 2015 to 2023. MiMVR was associated with lower estimated blood loss (EBL) (median 450 vs 1200 mL, P = 0.008), major morbidity (14.7% vs 50.0%, P = 0.014), post-operative intra-abdominal collections (11.8% vs 50.0%, P = 0.006), post-operative ileus (32.4% vs 66.7%, P = 0.04) and surgical site infection (11.8% vs 50.0%, P = 0.006) compared with oMVR. Length of stay was also shorter for miMVR compared with oMVR (median 10 vs 30 d, P = 0.001). Oncological outcomes-R0 resection, recurrence, OS and RFS were comparable between miMVR and oMVR. There was no 30-d mortality. More patients underwent robotic compared with laparoscopic MVR for complex cases (robotic 57.1% vs laparoscopic 7.7%, P = 0.004). The operating time was longer for robotic compared with laparoscopic MVR [robotic: 602 (400-900) min, laparoscopic: Median 455 (275-675) min, P < 0.001]. Incidence of R0 resection was similar (laparoscopic: 84.6% vs robotic: 76.2%, P = 0.555). Overall complication rates, major morbidity rates and 30-d readmission rates were similar between laparoscopic and robotic MVR. Interestingly, 3-year OS (robotic 83.1% vs 58.6%, P = 0.008) and RFS (robotic 72.9% vs 34.3%, P = 0.002) was superior for robotic compared with laparoscopic MVR. MiMVR had lower post-operative complications compared to oMVR. Robotic MVR was also safe, with acceptable post-operative complication rates. Prospective studies should be conducted to compare short-term and long-term outcomes between robotic vs laparoscopic MVR.

Clinical characteristics of acute non-varicose upper gastrointestinal bleeding and the effect of endoscopic hemostasis.

Acute non-variceal upper gastrointestinal bleeding (ANVUGIB) constitutes a prevalent emergency within Gastroenterology, encompassing 80%-90% of all gastrointestinal hemorrhage incidents. This condition is distinguished by its abrupt onset, swift progression, and notably elevated mortality rate. To gather clinical data from patients with ANVUGIB at our hospital in order to elucidate the clinical characteristics specific to our institution and analyze the therapeutic effectiveness of endoscopic hemostasis. We retrospectively retrieved the records of 532 patients diagnosed with ANVUGIB by endoscopy at our hospital between March 2021 and March 2023, utilizing our medical record system. Data pertaining to general patient information, etiological factors, disease outcomes, and other relevant variables were meticulously collected and analyzed. Among the 532 patients diagnosed with ANVUGIB, the male-to-female ratio was 2.91:1, with a higher prevalence among males. Notably, 43.6% of patients presented with black stool as their primary complaint, while 27.4% had hematemesis as their initial symptom. Upon admission, 17% of patients exhibited both hematemesis and black stool, while most ANVUGIB patients primarily complained of overt gastrointestinal bleeding. Urgent routine blood examinations at admission revealed that 75.8% of patients had anemia, with 63.4% experiencing moderate to severe anemia, and 1.5% having extremely severe anemia (hemoglobin < 30 g/L). With regard to etiology, 53.2% of patients experienced bleeding without a definitive trigger, 24.2% had a history of using gastric mucosa-irritating medications, 24.2% developed bleeding after alcohol consumption, 2.8% attributed it to improper diet, 1.7% to emotional excitement, and 2.3% to fatigue preceding the bleeding episode. Drug-induced ANVUGIB was more prevalent in the elderly than middle-aged and young individuals, while bleeding due to alcohol consumption showed the opposite trend. Additionally, diet-related bleeding was more common among the young age group compared to the middle-aged group. Gastrointestinal endoscopy identified peptic ulcers as the most frequent cause of ANVUGIB (73.3%), followed by gastrointestinal malignancies (10.9%), acute gastric mucous lesions (9.8%), and androgenic upper gastrointestinal bleeding (1.5%) among inpatients with ANVUGIB. Of the 532 patients with gastrointestinal bleeding, 68 underwent endoscopic hemostasis, resulting in an endoscopic treatment rate of 12.8%, with a high immediate hemostasis success rate of 94.1%. ANVUGIB patients exhibit diverse characteristics across different age groups, and endoscopic hemostatic treatments have demonstrated remarkable efficacy.

Advances in the treatment of anti-HER-2 antibody drug conjugates in pan-tumor with low HER-2 expression

Antibody-drug conjugates (ADCs) are drugs that combine monoclonal antibody drugs targeting specific antigens and small molecule cytotoxic drugs through linker molecules. ADCs combine the advantages of high specificity targeting and potent killing effects, achieving precise and efficient targeting of cancer cells. Nowadays, ADCs are one of the hotspots in cancer drug development. Human epidermal growth factor receptor 2 (HER-2) is a known oncogene that can drive the occurrence and development of various types of tumors. HER-2 is also an important tumor target for ADCs approved for solid tumors. Anti-HER-2 ADCs can not only be used to treat HER-2-positive tumors but also effectively target HER-2-low tumors. The emergence of ADCs has broken the traditional classification of HER-2 in tumors, bringing significant treatment breakthroughs for HER-2-low tumors. Anti-HER-2 ADCs are widely used in the treatment of solid tumors and have substantial evidence for HER-2-low tumors. This article presents the progress of various anti-HER-2 ADCs in HER-2-low tumors including breast cancer, gastrointestinal malignancies, urothelial carcinoma, lung cancer. And this article summarizes the current status of preclinical studies, clinical studies, and safety of anti-HER-2 ADCs in order to provide reference for the clinical use of HER-2-low tumors.

Abstract 2547: KRAS Q61 mutations in patients with gastrointestinal malignancies and association with real-world clinical outcomes

Abstract Introduction: Gene-wide KRAS mutation has been associated with worse outcomes in multiple malignancies with newer data suggesting differential impact based on specific allele. Mutation at codon Q61 is relatively infrequent with clinical significance not well understood. Here we aim to investigate the clinical significance of KRASQ61 mutation in gastrointestinal (GI) malignancies. Methods: The Foundry software platform was used to retrospectively query electronic health records to identify patients diagnosed with colorectal (CRC), pancreatic (PDAC), appendiceal (AA), cholangiocarcinoma (CC) and gastroesophageal carcinoma who underwent clinical testing for KRAS mutations in our institution between 2002-2023; clinical, molecular, and overall survival (OS) data were collected. Results: KRAS mutation was tested in 9,088 patients with CRC, PDAC, CC, AA, and gastroesophageal carcinoma. Incidence of KRAS mutation was 47% (n= 3,181) for patient with CRC, 82% for PDAC (n= 579), 16% for CC (n= 76), 51% for AA (n= 236), and 7% for gastroesophageal carcinoma (n= 43). KRASQ61 mutation was in 5% (n=218) of patients with KRAS mutation (n= 4,115). Overall frequency of KRASQ61 was 2% (n= 156) for CRC, 5% (n= 36) for PDAC, 3% (n= 12) for CC, 2% (n= 10) for AA and 1% (n= 4) for gastroesophageal carcinoma. KRASQ61 fraction of KRAS mutations was 5% for CRC, 6% for PDAC, 16% for CC, 4% for AA, 9% for gastroesophageal carcinoma. KRASQ61H was the most frequent KRASQ61 mutation among all tumor types, 57%, 61%, 60%, 50% out of KRASQ61 for CRC, PDAC, AA, and gastroesophageal carcinoma respectively; followed by KRASQ61L (20%) for CRC, but KRASQ61R for PDAC (25%), AA (20%), and gastroesophageal (25%); Patients with CC showed exclusively KRASQ61H mutations. Compared to patients with KRAS wildtype, patients with KRASQ61 mutations had worse OS in PDAC (median OS=20 vs 37 months, HR=1.9, 95%CI=1.2-3, p=0.006), while (55 vs 63 months, HR=1.2, 95%CI=0.98-1.5, p=0.076) for CRC, (29 vs 25 months, HR=1.3, 95%CI=0.64-2.6, p=0.47) for CC, and (33 vs 52 months, HR=1.1, 95%CI=0.5-2.6, p=0.75) for AA. Compared to other KRAS mutations, KRASQ61 median OS was (55 vs 53 months, HR=1, 95%CI=0.81-1.3, p=0.96) for patients with CRC, (20 vs 26 months, HR=1.4, 95%CI=0.91-2.1, p=0.1) for PDAC, (25 vs 28 months, HR=1.1, 95%CI=0.54-2.5, p=0.72) for CC, (33 vs 78 months, HR=1.6, 95%CI=0.72-3.7, p=0.24) for AA. Conclusion: KRASQ61 mutations frequency varied from 1% to 5% across different GI malignancies, with highest frequency in PDAC and CC. KRASQ61 mutations had worse OS in patients with PDAC which may suggest different co-mutations rather than specific KRASQ61 activity difference. Further allele specific analysis of KRASQ61 and co-mutations landscape is underway. Citation Format: Mahmoud Yousef, Abdelrahman Yousef, Saikat Chowdhury, Mohammad Mahdi Fanaeian, Mark Knafl, Paul M. Roy, Ashwathy Pillai, Mohammad Zeineddine, Fadl Zeineddine, Jennifer Peterson, Brandon G. Smaglo, Robert A. Wolff, Shubham Pant, Michael Sangmin Lee, Jason A. Willis, Michael James Overman, Ethan Bernard Ludmir, Mark W. Hurd, John Paul Shen, Dan Zhao. KRAS Q61 mutations in patients with gastrointestinal malignancies and association with real-world clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2547.

Abstract 7493: Real-time monitoring of CTC number, biomarker expression, and kinetics as prognostic and predictive markers in patients with GI malignancies

Abstract Background: Most of the utility in the clinic regarding liquid biopsies has been around circulating tumor DNA (ctDNA). ctDNA analysis provides valuable insight into mutational burden and therapeutic targets, but the speed and cost of analysis are prohibitive especially when it comes to serial testing. Using a cohort of patients with advanced or metastatic gastrointestinal (GI) cancers, we herein show the feasibility of using circulating tumor cell (CTC) enumeration, biomarker analysis, and kinetics as complementary to or as an alternative to ctDNA testing. Methods: Using the RareCyte platform, nucleated cells from blood were collected, spread on slides, stained, and imaged with CyteFinder® for CTC identification (CK/EpCAM+, CD45-) and quantification of biomarkers (PD-L1/HER2 or Ki67/EGFR). CTC enumeration (CLIA-accredited CTC test) and biomarker status for each patient were tracked over time and compared with ctDNA mutational analysis and tumor burden. Results: CTCs were detected in 60/70 samples (86%) and in 36/38 unique patients (95%). On average, more CTCs were detected in baseline samples from colorectal cancer patients compared to other subtypes (Table 1). Moreover, multiple patients showed pronounced changes in CTC number that correlated with treatment response, as well as strong correlation between CTC and tissue biomarker expression e.g. HER2. Rapid decline and/or CTC clearance was seen as early as a few days into starting effective systemic therapy. The average turnaround time for CTC testing was 5-7 days. Table 1. CTC values in initial baseline blood draw sample Gastrointestinal cancer subtype # of patients Average # of CTCs per 7.5mL blood Median # of CTCs per 7.5mL blood Minimum # of CTCs per 7.5mL blood Maximum # of CTCs per 7.5mL blood Colorectal carcinoma 27 84 3 0 1378 Cholangiocarcinoma 3 8 3 1 23 Pancreatic cancer 3 2 2 0 3 Hepatocellular carcinoma 2 4 5 0 10 Gallbladder cancer 1 6 6 3 8 Appendix cancer 1 2 2 1 3 Anal cancer 1 0 0 0 0 Conclusions: Our study emphasizes that real-time monitoring of CTCs is complementary to traditional tumor burden monitoring via imaging and ctDNA analysis. CTCs offer multiple unique advantages vs ctDNA including early response assessment within days of initiating therapy, a substantial decrease in cost of serial testing, and the ability to assess clinically relevant cell surface protein biomarkers e.g. HER2 and PD-L1. Citation Format: Erin G. Bayer, Brock M. Bartels, Rachel N. Ponting, Areeb Lutfi, Maaz K. Afghan, Arturo B. Ramirez, Pashtoon M. Kasi. Real-time monitoring of CTC number, biomarker expression, and kinetics as prognostic and predictive markers in patients with GI malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7493.

Abstract 6707: IgG based B7-H3xCD3 bispecific antibody for treatment of gynecological tumors

Abstract Ovarian cancer is characterized by late stage disease and a poor prognosis. Endometrial cancer is a heterogeneous disease with different prognoses depending on the molecular subtype. Novel treatment strategies are needed to improve patient survival in both entities. T cell-based immunotherapy has significantly improved the treatment options for many malignancies. B7-H3 (CD276) is an interesting target for immunotherapeutic approaches because it is overexpressed on a wide range of tumor entities and has characteristics of immune checkpoint molecules. Its expression not only on tumor cells but also on the tumor vasculature allows improved infiltration of immune effector cells into the tumor to overcome the major limitation of T cell-based therapy of solid tumors, which is the access of immune cells to the tumor site. A novel bispecific antibody in an IgG-based format called CC-3 with B7-H3xCD3 specificity has already been shown to efficiently induce T cell responses against gastrointestinal malignancies. Here we show that B7-H3 is highly expressed on endometrial and ovarian cancer cell lines. Treatment with CC-3 induced T cell activation and degranulation as well as secretion of IL-2, IFNy and perforin. These results demonstrate CC-3 induced T cell reactivity against ovarian and endometrial cancer cells. In addition, CC-3 induced efficient T cell proliferation and formation of T cell memory subsets. This resulted in potent target cell lysis. Taken together, our results underscore the potential of CC-3, which is currently in GMP manufacturing, to enable clinical evaluation for the treatment of gynecologic malignancies. Citation Format: Sarah Maria Greiner, Jonas Mauermann, Martina Lutz, Ilona Hagelstein, Engler Tobias, André Koch, Hartkopf Andreas, Brucker Sara, Latifa Zekri, Melanie Märklin. IgG based B7-H3xCD3 bispecific antibody for treatment of gynecological tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6707.

Abstract 3055: Characterizing the role of HNF4α isoforms in human PDAC

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly and recalcitrant malignancy with a 5-year survival rate of 12%. Transcriptomic studies have classified PDAC into a classical or basal-like subtype. The classical subtype has a better prognosis, response to chemotherapy, and express higher levels of endodermal lineage specifiers compared to the basal-like subtype. However, the field lacks a comprehensive understanding of the key subtype-specific regulators. Functional analysis of transcription factors associated with each subtype are needed to elucidate their roles in regulation of PDAC subtypes and to identify therapeutically targetable vulnerabilities. Previous work in our lab demonstrated that HNF4α is a key regulator of the classical subtype. Using genetically engineered mouse models, our lab showed that loss of HNF4α leads to an increase in tumor burden, a shift from glandular to poorly differentiated histology, and a decrease in the classical subtype score. However, while murine PDAC only express one set of HNF4α isoforms, human PDAC express both sets of HNF4α isoforms, suggesting murine PDAC may not fully recapitulate human disease. There are 2 subsets of HNF4α isoforms driven by expression from 2 distinct promoters, P1 and P2. P1 and P2 isoforms are differentially expressed within the gastrointestinal (GI) tract and play dichotomous roles in GI malignancies. In HNF4α-positive human PDAC, P2 isoforms are always expressed but there is variable expression of P1 isoforms. Based on the differential role of HNF4α isoforms in both normal tissue and cancer, we hypothesize that P1 isoforms will restrain tumor growth and promote greater classical/GI differentiation compared to P2 isoforms. We utilized CRISPRi to selectively inhibit transcription at the P1 or P2 promoter in HNF4α-positive, human cell lines expressing both isoforms. To test for sufficiency, we exogenously expressed P1 or P2 isoforms in HNF4α-negative, human cell lines. We then performed Incucyte, CRISPRi competition, and anchorage-independent growth assays. We performed RNA-seq and ChIP-seq on both exogenous and endogenous HNF4α isoforms. Functional assays revealed that HNF4α isoforms regulated growth in a context dependent manner. Exogenous P1 isoforms significantly inhibited growth while loss of endogenous P1 isoforms was dispensable for growth. Exogenous P2 isoforms inhibited growth to a lesser degree while loss of endogenous P2 isoforms led to a significant reduction in growth. Despite ChIP-seq analysis revealing very similar binding profiles, RNAseq analysis revealed that P1 isoforms are significantly more transcriptionally active than P2 isoforms and are stronger inducers of GI differentiation. Taken together, our data demonstrates that P2 isoforms are more compatible with growth in PDAC compared to P1 isoforms, which promote a more differentiated cell state. Mechanistically, this may be due to the increased transcriptional activity of P1 isoforms. Citation Format: Pengshu Fang, Acramul Kabir, Gabriela Fort, Eric L. Snyder. Characterizing the role of HNF4α isoforms in human PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3055.

Abstract 1761: Comprehensive profiling of the FAT3-associated gene signature in deciphering immunophenotypes of gastrointestinal cancers: Analysis of institutional cohort and TCGA dataset

Abstract Gastrointestinal (GI) cancers are among the most prevalent cancers affecting the US population. Anatomically, GI cancer includes cancers of the organs in the digestive tract, from the esophagus to the rectum. Advances in molecular oncology have started to transform the therapeutic landscape and offer tremendous promise for patients across diverse lineages. However, the equitable benefit of this approach has been hampered due to tumor heterogeneity and the lack of accurate, tumor-agnostic biomarkers with prognosis and predictive utility. Thus, there is a need to identify novel biomarkers that affect gastrointestinal malignancies to improve the management of cancer patients. This study analyzed a single institution's whole genome sequencing dataset to explore the genomic variation in GI cancers. Between 2020 and 2022, 302 AU patients underwent molecular profiling, including whole-exome sequencing (WES) profiling at Caris Life Sciences. WES is an NGS assay that analyzes the DNA sequences of all protein-coding exons in the genome, representing approximately 1-2% of the human genome with coverage of over 22,000 genes. We analyzed the TCGA dataset for comparative analysis, which included cancer data from &amp;gt;1800 GI cancer patients. In addition, survival and network analyses were performed to identify a 6-gene FAT3-related signature for GI cancers. In our cohort, we identified FAT3 (Fat atypical cadherin 3) as the most frequently mutated gene after TP53, APC, and KRAS. FAT3 encodes a cadherin protein involved in cell-cell interactions and adhesion. In the institutional cohort, FAT3 was found to be mutated in 16% of all GI cases. Further analysis of TCGA datasets comprising 1808 GI cancer patients revealed FAT3 mutations in 12% of the cases. To identify additional prognostic biomarkers associated with FAT3, we performed network analysis and identified a 6-gene FAT3-related signature (FAT3, RYK, FAT2, EGFLAM, NTRK3, IGSF9, and HMGA2) that significantly stratified GI cancer patients based on overall survival, progression-free survival, and disease-specific survival. The perturbation profile of the 6-gene signature was associated with 509 patients or 28% of total GI patients. Further, immune deconvolution analysis of stratified patients revealed increased infiltration of immune cells with immunosuppressive phenotypic properties in GI cancer patients with higher expression of the FAT3-related gene signature. In summary, this analysis reveals the distribution of FAT3 mutational profiles in GI patients and identifies a gene signature that stratifies patients based on survival outcomes. This analysis can provide new tools for patient stratification and therapy implementation, leading to better outcomes for cancer patients. Citation Format: Pankaj Kumar Ahluwalia, Tiffanie Leeman, Ashis Mondal, Ashutosh Vashisht, Harmanpreet Singh, Ravindra Kolhe. Comprehensive profiling of the FAT3-associated gene signature in deciphering immunophenotypes of gastrointestinal cancers: Analysis of institutional cohort and TCGA dataset [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1761.

A new strategy for immunotherapy of microsatellite-stable (MSS)-type advanced colorectal cancer: Multi-pathway combination therapy with PD-1/PD-L1 inhibitors.

Colorectal cancer (CRC) is a frequent gastrointestinal malignancy with high rates of morbidity and mortality; 85% of these tumours are proficient mismatch repair (pMMR)-microsatellite instability-low (MSI-L)/microsatellite stable (MSS) CRC known as 'cold' tumours that are resistant to immunosuppressive drugs. Monotherapy with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors is ineffective for treating MSS CRC, making immunotherapy for MSS CRC a bottleneck. Recent studies have found that the multi-pathway regimens combined with PD-1/PD-L1 inhibitors can enhance the efficacy of anti-PD-1/PD-L1 in MSS CRC by increasing the number of CD8+ T cells, upregulating PD-L1 expression and improving the tumour microenvironment. This paper reviews the research progress of PD-1/PD-L1 inhibitors in combination with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, oncolytic virus, intestinal flora, antiangiogenic agents, chemotherapy, radiotherapy and epigenetic drugs for the treatment of pMMR-MSI-L/MSS CRC.

RACGAP1 drives proliferation, migration and invasion and suppresses autophagy of gastric cancer cells via inhibiting SIRT1/Mfn2.

Gastric cancer is the most frequent gastrointestinal malignancy with a poor prognosis. Rac GTPase activation protein 1 (RACGAP1) is a novel tumor promotor, whose detailed effect on gastric cancer remains to be further elucidated. Hence, this study identifies the action of RACGAP1 on gastric cancer and investigates the potential mechanism. RACGAP1 expression in gastric cancer was analyzed based on the data of The Cancer Genome Atlas (TCGA) database. Cell proliferation was measured by CCK-8 and colony formation assay. Cell migration and invasion were evaluated by transwell assay. Cell apoptosis was assessed by flow cytometry. Cell autophagy was evaluated via determining LC3. RACGAP1 presented at high level in gastric cancer cells. Overexpressed RACGAP1 potentiated gastric cancer cell proliferation, migration, and invasion. Besides, silenced RACGAP1 induced cell apoptosis and autophagy. Furthermore, RACGAP1 suppressed the expression of SIRT1 and Mfn2. RACGAP1 was overexpressed in gastric cancer. RACGAP1 potentiated aggressive behaviors of gastric cancer, and suppressed cell apoptosis and autophagy via modulating SIRT1/Mfn2. RACGAP1 may be a valuable target in the treatment of gastric cancer.

Racial differences in body composition and survival among older adults with gastrointestinal malignancies

IntroductionMuscle and adipose tissue measures can be quantified from routinely obtained computed tomography (CT) images and are predictors of chemotherapy-related toxicities and survival among patients with gastrointestinal (GI) malignancies. Most studies to date have consisted of predominantly White patients, and the role of body composition among minoritized racial groups is unknown. We examined racial differences in body composition and survival among patients with GI malignancies. Materials and MethodsThis was a prospective cohort study of patients with GI malignancies. Single slices of axial CT images from L3 segments were analyzed using Slice-O-Matic software. The skeletal muscle area (cm2) was divided by height to obtain the skeletal muscle index (SMI, cm2/m2). Skeletal muscle radiodensity (SMD) in Hounsfield units (HU) was used for muscle composition. We compared body composition parameters between non-Hispanic (NH)-White and NH-Black participants. Cox models were used to examine the impact of body composition on survival. We proposed new race-specific cutoffs for body composition using optimal stratification. ResultsFive hundred forty patients were included, of which 24% were NH-Black. In Cox models stratified by race, each 5 cm2/m2 decrease in SMI was associated with increase in risk of all-cause mortality in NH-Black patients (hazard ratio [HR] 1.25; 95% confidence interval [CI] 1.04–1.49 p = 0.02). With the existing cut points, neither sarcopenia nor myosteatosis was associated with worse survival. Using a new cutoff for sarcopenia in NH-Black patients, NH-Black patients with sarcopenia (HR 2.31 95%CI 1.10–4.88 p = 0.03) and myosteatosis (HR 2.63 95% CI 1.25–5.53 p = 0.01) had worse survival. DiscussionNH-Black older patients with GI cancers and sarcopenia or myosteatosis have worse overall survival.

Competitive endogenous RNA networks: Decoding the role of long non-coding RNAs and circular RNAs in colorectal cancer chemoresistance.

Colorectal cancer (CRC) is recognized as one of the most common gastrointestinal malignancies across the globe. Despite significant progress in designing novel treatments for CRC, there is a pressing need for more effective therapeutic approaches. Unfortunately, many patients undergoing chemotherapy develop drug resistance, posing a significant challenge for cancer treatment. Non-coding RNAs (ncRNAs) have been found to play crucial roles in CRC development and its response to chemotherapy. However, there are still gaps in our understanding of interactions among various ncRNAs, such as long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs). These ncRNAs can act as either oncogenes or tumour suppressors, affecting numerous biological functions in different cancers including CRC. A class of ncRNA molecules known as competitive endogenous RNAs (ceRNAs) has emerged as a key player in various cellular processes. These molecules form networks through lncRNA/miRNA/mRNA and circRNA/miRNA/mRNA interactions. In CRC, dysregulation of ceRNA networks has been observed across various cellular processes, including proliferation, apoptosis and angiogenesis. These dysregulations are believed to play a significant role in the progression of CRC and, in certain instances, may contribute to the development of chemoresistance. Enriching our knowledge of these dysregulations holds promise for advancing the field of diagnostic and therapeutic modalities for CRC. In this review, we discuss lncRNA- and circRNA-associated ceRNA networks implicated in the emergence and advancement of drug resistance in colorectal carcinogenesis.

An Uncommon Tumor in Stomach in A Young Girl

Introduction: Gastrointestinal stromal tumours (GIST) are rare tumours of the Gastrointestinal tract. They are the most common mesenchymal tumour of the gastrointestinal tract. All GISTs are malignant.Among all Gastrointestinal tract malignancies GIST Comprises 0.1- 3%. The most common location is stomach. They are usually found in elderly and they are not common in pediatric age group. Case Report: A girl aged 16 years presented with the history of melena, hematemesis with dyspepsia. Physical examination revealed mild tenderness over right hypochondrium. On examination, multiple hypopigmented patches noted over both upper limbs. CECT abdomen showed a well-defined heterogeneously enhancing predominantly exophytic necrotic soft tissue SOL over the greater curvature of the proximal body of the stomach with intraluminal extension. Her complete blood count and routine biochemical tests were within normal limits. Endoscopic biopsy from the polyploid lesion along the greater curvature show fragmented bits of gastric mucosa involved by a tumour composed of sheets and fascicles of round to oval cells having eosinophilic to vacuolated cytoplasm and a few spindle cells. Histopathological examination revealed a mesenchymal neoplasm favouring GIST.. Then wide local excision of the stomach was done and sent for histopathological examination. The stomach mass was diagnosed as Epithelioid GIST which was confirmed by immunohistochemistry. Conclusion: GISTs are most common mesenchymal tumours of GI tract. They are malignant in nature. The primary treatment of choice is surgery followed by chemotherapy.

LncRNA LUESCC promotes esophageal squamous cell carcinoma by targeting the miR-6785-5p/NRSN2 axis

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent gastrointestinal malignancies with high mortality worldwide. Emerging evidence indicates that long noncoding RNAs (lncRNAs) are involved in human cancers, including ESCC. However, the detailed mechanisms of lncRNAs in the regulation of ESCC progression remain incompletely understood. LUESCC was upregulated in ESCC tissues compared with adjacent normal tissues, which was associated with gender, deep invasion, lymph node metastasis, and poor prognosis of ESCC patients. LUESCC was mainly localized in the cytoplasm of ESCC cells. Knockdown of LUESCC inhibited cell proliferation, colony formation, migration, and invasion in vitro and suppressed tumor growth in vivo. Mechanistic investigation indicated that LUESCC functions as a ceRNA by sponging miR-6785-5p to enhance NRSN2 expression, which is critical for the malignant behaviors of ESCC. Furthermore, ASO targeting LUESCC substantially suppressed ESCC both in vitro and in vivo. Collectively, these data demonstrate that LUESCC may exerts its oncogenic role by sponging miR-6785-5p to promote NRSN2 expression in ESCC, providing a potential diagnostic marker and therapeutic target for ESCC patients.

Myeloid-Derived Suppressor Cells: Therapeutic Target for Gastrointestinal Cancers.

Gastrointestinal cancers represent one of the more challenging cancers to treat. Current strategies to cure and control gastrointestinal (GI) cancers like surgery, radiation, chemotherapy, and immunotherapy have met with limited success, and research has turned towards further characterizing the tumor microenvironment to develop novel therapeutics. Myeloid-derived suppressor cells (MDSCs) have emerged as crucial drivers of pathogenesis and progression within the tumor microenvironment in GI malignancies. Many MDSCs clinical targets have been defined in preclinical models, that potentially play an integral role in blocking recruitment and expansion, promoting MDSC differentiation into mature myeloid cells, depleting existing MDSCs, altering MDSC metabolic pathways, and directly inhibiting MDSC function. This review article analyzes the role of MDSCs in GI cancers as viable therapeutic targets for gastrointestinal malignancies and reviews the existing clinical trial landscape of recently completed and ongoing clinical studies testing novel therapeutics in GI cancers.