bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammation gene signature to predict survival outcomes in hepatocellular carcinoma (HCC): A machine-learning approach.
Authors: Al-Bzour Nour , Sahin Ibrahim Halil , Cavalcante Ludimila , Singh Meghana , Al-Bzour Ayah N. , Saeed Azhar , Saeed Anwaar
Published: January 2024

551

Background: Inflammation is closely associated with HCC tumorigenesis. Understanding transcriptomic features of inflammatory response will elucidate potential therapeutic targets that could improve survival outcomes. Herein, we study the association between inflammation-based genes and survival outcomes in early-stage HCC. Methods: Transcriptomic and clinical data of 249 patients with resectable stage I and II HCC were obtained from The Cancer Genome Atlas. 132 genes associated with acute and chronic inflammatory response were identified from the molecular signature database. Those were then used in a principal component analysis (PCA) to cluster patients into high and low inflammation groups using the median of the first PCA. Inflammation related differentially expressed genes (DEGs) between the two groups were then identified & were fit in Least Absolute Shrinkage and Selection Operator model to reduce the multicollinearity. Uni- and multi-variate Cox proportional hazard model was used to find the independent predictors of survival. PCA was applied to significant genes to calculate the inflammation score (IS) and the optimal cut-off point was chosen based on survival. Log-rank test and Kaplan Meier curves were used to correlate the IS with overall survival (OS) & disease-free survival (DFS). Pearson’s Chi-squared, Wilcoxon rank sum, and Fisher’s exact tests were used to correlate the inflammation groups with clinical variables. Gene set variation analysis was performed to investigate enriched pathways between groups using the cancer hallmark gene sets. Results: We identified 6 inflammation-related DEGs associated with survival including: ADAM8, CCR7, FFAR3, S100A9, TNF, and TREM1. Two of those were independent predictors of survival: TREM1 & FFAR3. Based on IS cut off of 0.29 we have grouped patients into inflammation high (n=91) and inflammation low (n=158) groups. The low-inflammation group had significantly better OS & DFS (P=0.00039, P=0.039) respectively. No significant association was found between the inflammation groups and multiple variables including hepatitis B and C, alcohol and non-alcohol fatty liver disease. Stage I HCC patients had low-inflammation scores and better survival outcomes compared to stage II, indicative of an association between inflammation and HCC evolution. Pathway enrichment analysis notably showed significant enrichment in signal transduction pathways in the high inflammation group including Wnt/β-catenin, Notch, PI3K-AKT-mTOR, Hedgehog, TGFβ and upregulated KRAS signaling. Conclusions: Findings from this analysis highlight the close association between inflammation and survival outcomes in early-stage HCC and support the utility of an inflammation-based gene signature to predict survival in this disease setting. Our work also sheds light on potentially targetable pathways linked to IS that deserve further exploration.
Serologic, radiographic, and tissue-based markers associated with major pathologic response after treatment with neoadjuvant immunotherapy in patients with resectable hepatocellular carcinoma.
Authors: LaPelusa Michael Brian , Chamseddine Shadi , Xiao Lianchun , Hasanov Elshad , Bhosale Priya , Abugabal Yehia I. , Gok Yavuz Betul , Yadav Shalini S. , Tran Cao Hop Sanderson , Xu Li , Hu Zishuo Ian , Lee Sunyoung S. , Sakamuri Divya , Curran Michael A. , Jindal Sonali , Duda Gabriel Dan , Sharma Padmanee , Qayyum Aliya , Kaseb Ahmed Omar
Published: January 2024

561

Background: Neoadjuvant immunotherapy can induce a major pathologic response (MPR) in patients with resectable hepatocellular carcinoma (HCC), which may be associated with prolonged recurrence-free survival. This study aimed to understand which variables correlate with achieving an MPR. Methods: Patients with resectable HCC who received either neoadjuvant nivolumab plus ipilimumab or nivolumab alone and underwent surgery were included. 18 patients had baseline and post-treatment computed tomography, alpha-fetoprotein (AFP), and elastography. 17 of these patients had baseline and post-treatment tissue available for immunohistochemistry. Patients were classified into two groups: MPR, defined as necrosis of >70%, and no MPR. Data was summarized using descriptive statistics and compared using Wilcoxon rank sum test. P value <0.05 was considered statistically significant. Results: Statistically significant differences in objective response (OR) and changes in CD8, Granzyme B, and PD-1 expression were identified upon comparison of patients with an MPR to those without an MPR (Table 1). Additionally, numerical differences in baseline tumor size, change in AFP, and both non-tumor and tumor liver fibrosis (at baseline, after treatment, and interim change) were identified upon comparison of patients with an MPR to those without an MPR. Conclusions: Our data show that large baseline tumor size, greater OR, reduction in AFP, increase in liver and tumor fibrosis, and increase in CD8, Granzyme B, and PD-1 expression after receipt of neoadjuvant immunotherapy are associated with achieving an MPR in patients with resectable HCC. [Table: see text]
Epidemiological characteristics of patients with cholangiocarcinoma with and without ulcerative colitis: A retrospective cohort study.
Authors: Nieto Dominguez Alejandro , Eichinger Sarah Elizabeth , Olafimihan Ayobami Gbenga , Guifarro Rivera Daniel
Published: January 2024

564

Background: Ulcerative colitis (UC) is correlated with gastrointestinal cancer. While the exact mechanism is unknown, it is thought that a chronic inflammatory state may result in the development of malignancies including cholangiocarcinoma. Patients with UC that develop cholangiocarcinoma usually have a poor prognosis and early detection is key to improve survival. Methods: We used the 2016-2019 National Inpatient Sample (NIS) database, the largest all-payer inpatient care database in the United States, to stratify all patients admitted with a diagnosis of cholangiocarcinoma with and without ulcerative colitis, to further characterize their epidemiological characteristics. Results: There were at total of 46,001 patients with a diagnosis of cholangiocarcinoma studied. Of these patients with cholangiocarcinoma, 401 had concomitant UC (0.87%). Individuals with UC in the database had an increased association with cholangiocarcinoma (OR=7.67, 95% CI 6.96-8.46) compared to those without UC. Patients with cholangiocarcinoma and UC tended to be younger (57.8 vs. 67.9 years old without UC), male (69.51% vs. 53.23% without UC), with private insurance (57.5%) vs. patients without UC who predominately had Medicare (59.46%). Patients with cholangiocarcinoma and UC had on average fewer Charleston Comorbidities (64.63% with 3 comorbidities) vs. patients without UC (74.52% with 3 comorbidities). Of patients with cholangiocarcinoma and UC, 65.85% were Caucasian (vs. 64.85% without UC), 6.1% were Black (vs. 10.09% without UC), 3.66% were Hispanic (vs. 12.37% without), and 24.39% were Asian or Pacific Islander (vs 12.79% without). Conclusions: In the population studied, there was a significant correlation between UC and cholangiocarcinoma. Patients with cholangiocarcinoma and UC tended to be younger with fewer comorbidities than their counterparts without. There were nearly double the percentage of Asian patients with cholangiocarcinoma and UC as compared to Asian patients without UC. Understanding the characteristics of patients with UC who develop cholangiocarcinoma is important as it could inform future best practices in potential screening and early detection of carcinomas in patients with UC. [Table: see text]
Association of congestive heart failure (CHF) with incidence rates of enteric infections and gram-negative sepsis (GNS) in patients with hepato-pancreatico-biliary cancers (HPBCs).
Authors: Mahadevia Himil , Modi Karnav , Vodnala Deepthi , Roth Marc Thomas
Published: January 2024

567

Background: ChronicCHF leads to volume overload and can cause bowel wall edema. This may compromise local immune defense and promote increased translocation of gut bacteria into the blood.HPBCs can cause biliary tract obstruction which is also associated with bacteremia. Additionally, cancer treatments are associated with an increased risk of clostridium difficile infection (CDI), regardless of antibiotic exposure. While associations between cancer and increased infection rates are well-established, we questioned whether concomitant CHF increases this risk further in the HPBC population. We therefore investigated whether concomitant CHF and HPBC influenced CDI, other infectious gastroenteritis (IGE), GNS rates or all-cause-hospital mortality. Methods: A retrospective study was conducted by obtaining patients with HPBC through the application of specific ICD 10 codes from the National Inpatient Sample 2020, a large publicly available database of inpatient hospital stays incorporating data from hospitals across 48 U.S. states. Among this cohort, patients with chronic CHF were further identified by applying all CHF-specific ICD 10 codes. All patients with HPBC were divided into two groups, one with CHF (group A) and the other without CHF (group B). Outcomes were compared between the two groups using multivariate regression analysis (MVRA) adjusting for demographic factors, hospital-specific characteristics like location, bed size, etc., comorbidities including obesity, diabetes, hypertension, prior cardiovascular events, HIV, CKD, OSA, etc., prior coronary intervention/surgery as well as alcohol, smoking or substance use. Results: 211,790 patients were identified with HPBC. 40.55% were female. 18,955 patients (9.95%) were found to have chronic CHF. The incidence of GNS was higher in group A compared to group B in the MVRA (Adjusted (Ad) OR: 1.4, CI 1.07-1.95, p=0.015). However, there was no difference in the incidence rate of CDI between groups A and B (Ad OR: 1.0, CI 0.71-1.50, p=0.86). Similarly, the two groups had no difference in other IGE (Ad OR: 1.0, CI 0.71-1.37, p=0.96). All-cause hospital mortality was slightly higher in group A than group B but failed to reach statistical significance (Ad OR: 1.1, CI: 0.99-1.29, p=0.069). Conclusions: GNS was more common in patients with HPBC who also had comorbid chronic CHF. Future investigations may focus on the effect of increased GNS on outcomes beyond hospitalization, correlation between the severity of CHF and GNS as well as primary site of HPBC and infection risk. Based on this signal-finding analysis, it is postulated that early inter-disciplinary collaboration between oncology and cardio-oncology/cardiology may have special significance in the management of patients with chronic CHF and HPBCs, the latter of which already carries a dismal prognosis.
Repeat peptide receptor radionuclide therapy in neuroendocrine neoplasms: A NET Center of Excellence experience.
Authors: Grewal Udhayvir Singh , Paschke Alexander , Dillon Joseph S. , Chandrasekharan Chandrikha
Published: January 2024

590

Background: Lu177 DOTATATE Peptide Receptor Radionucleotide Therapy (PRRT) was FDA approved in the United States in 2018 however this treatment modality has been widely available in European nations since early 2000s. Therefore, the data for the safety and efficacy of repeat PRRT are almost exclusively from European centers. We present a real-world experience with repeat PRRT in a cohort of US patients. Methods: We used our single-center longitudinal IRB approved neuroendocrine tumor (NET) registry to identify patients who had been previously treated with at least 1 dose of PRRT (PRRT 1, either Lu 177 DOTATATE or Y90 DOTATOC) and following disease progression were retreated with a second course of PRRT (PRRT 2). Patients who received alpha PRRT were not included. We reviewed patient, tumor and treatment characteristics, time to progression after PRRT 1 and PRRT 2 and toxicity. Results: A total of 153 patients received at least 1 dose of Lu-177 DOTATATE PRRT at our institution post FDA approval, out of which, 13/153 (8.5%) patients received repeat PRRT .2/13 patients were excluded due to lack of adequate follow up. All patients included were white (11/11, 100%). Median age of the participants was 65 years (IQR 63, 67) and 54.5% (6/11) patients were females. Most patients had grade 2 (9/11,81.8%) followed by grade 1 NET (2/11, 18.2%) and all except one patient included had a gastroenteropancreatic origin NET (10,11, 90.9%). 45.5% (5/11) patients received Lu-177 DOTATATE PRRT only both for PRRT1 and PRRT 2, while 54.5% (6/11) patients received Y90 DOTATOC PRRT for PRRT1. Median number of lines therapies before PRRT1 and PRRT were 2 (IQR 2,5) and 1 (IQR 1,2) respectively. Patients received a median of 3 (IQR 2, 4) and 3 (IQR 1,4) cycles for PRRT1 and PRRT2 respectively. At first restaging scan after PRRT1 (3-6 months), 54.5% and 45.5% patients had partial response (PR) and stable disease (SD) respectively. At first restaging scan after PRRT2 (3-6 months), 45.5%, 27.3% and 9.1% patients had SD, progressive disease (PD) and PR respectively; 2/11 patients (18.2%) died before first restaging scan. Median PFS for PRRT1 (n=11) was 22.5 months (IQR 12.7, 30.7). Median PFS (n=5) for PRRT2 was 10.9 months (IQR 10.05, 25.7). PFS was not reached for 1 patient after PRRT2. 1 (9.1%) patient each developed grade 2 nephrotoxicity and grade 3 thrombocytopenia after PRRT2. Conclusions: To our knowledge, this is the first of its kind analysis describing the safety and effectiveness of repeat PRRT in a US cohort. We show that repeat PRRT may benefit select patients and has an acceptable safety profile. Larger prospective clinical studies are required to identify patient groups that are more likely to benefit from repeat PRRT.
A novel early cancer detection approach for pancreatic cancer.
Authors: Bijlsma Maarten F. , Strasser Patrick Christian , Schneider Maximilian Christoph , Thumfart Norbert
Published: January 2024

613

Background: Pancreatic adenocarcinoma (PDAC) is commonly diagnosed at advanced stages, leading to high mortality rates. Earlier detection of PDAC is associated with improved long-term survival, but effective population-level screening is not available. There is therefore an urgent need to improve early detection of PDAC. Wholomics has developed a PDAC-specific proprietary early detection test, using cancer-specific molecular signatures in peripheral blood. Methods: We conducted a retrospective analysis of serum samples from the Amsterdam UMC Liquid Biopsy Center. Three cohorts were included in this study: 1) A cohort of healthy control subjects, 2) patients with a histopathologically confirmed diagnosis of PDAC spanning stages I through IV, and 3) patients with a confirmed diagnosis of chronic pancreatitis. Peripheral blood samples of cancer patients were taken before treatment or surgery. Wholomics used its proprietary technology to quantitatively analyse all serum specimens. Disease-specific molecular signatures were identified and used to develop computational biomarkers specific to both pancreatic pathologies (chronic pancreatitis and pancreatic cancer) and to pancreatic cancer individually. A comparative analysis was conducted employing multiple machine learning algorithms, which were subjected to a 10-fold cross-validation procedure. The accuracy, specificity and sensitivity of the best-performing algorithm is reported. Results: This retrospective study included 50 healthy controls, 12 patients with chronic pancreatitis, and 42 patients with pancreatic cancer (12 stage I, 15 stage II, 9 stage III, 6 stage IV). Applying Wholomics´ technology, an accuracy of 99.1% in differentiating the chronic pancreatitis and pancreatic cancer patients from the healthy controls was achieved. A specificity of 98.0% and a sensitivity of 100.0% were reached. Furthermore, pancreatic cancer patients and chronic pancreatitis patients were differentiated with 95.2% accuracy. Wholomics was also capable of differentiating between early stage (stages I and II) and late-stage (stages III and IV) pancreatic cancer with an accuracy of 100%. Conclusions: Taken together, this study demonstrates that disease-specific molecular signatures in peripheral blood can distinguish patients with PDAC from healthy individuals and patients with pancreatitis with very high accuracy. If validated in additional cohorts, this method could be evaluated as a screening test for PDAC to allow for early detection and improve patient outcomes.
In-hospital outcomes of acute pulmonary embolism in patients with gastrointestinal cancer: A nationwide study.
Authors: POUDEL SAJANA , Ghimire Manoj , Ghimire Kalpana , Poudel Ayusha , Shrestha Karun , Subedi Prakriti , Karki Sandesh , Adhikari Anurag , Garzon_Siatoya Wendy Tatiana , Batool Humera , Elfert Khaled , Ibrahim Muhammad Bilal
Published: January 2024

624

Background: Cancer is a well-established risk factor for the development of pulmonary embolism (PE), especially the. gastrointestinal (GI) cancers. While multiple studies have reported the burden of PE in cancer patients, recent data comparing in-hospital outcomes among different types of cancer patients are lacking. This study aimed to investigate the clinical and healthcare utilization outcomes of hospitalized patients with acute PE in the context of gastrointestinal (GI) cancers. Methods: A cross-sectional study was conducted using data from the National Inpatient Sample (2016-2020). International Statistical Classification of Diseases (ICD-10) codes were employed to identify hospitalized patients admitted with primary diagnosis acute PE. Data regarding GI cancer diagnosis along with demographic information, baseline clinical characteristics, and outcome variables, including mortality, hospital length of stay, total hospital charges, complications and risk factors were collected and analyzed. Statistical analysis was performed using the survey procedures function in STATA v.17, with statistical significance defined by the t-test at a significance level of p < 0.05. Results: Among the 181,060 patients admitted with primary diagnosis of acute pulmonary embolism, 550 (0.3%) had underlying gastric cancer, 1,790 (0.98%) had pancreatic cancer, 875 (0.48%) had hepatobiliary cancer, and 2,600 (1.61%) had small intestine and colorectal cancer. Mortality was found to be significantly higher in all types of GI cancer, with gastric cancer demonstrating the highest mortality rate (10%). After adjusting for age, sex, race, payment category, comorbidities, and risk factors of PE, gastric cancer (OR 2.6; 95% CI: 1.1-6.2) and pancreatic cancer (OR 2.2; 95% CI: 1.4-3.4) were found as independent risk factors for mortality. There was no significant difference in mean length of hospital stays and mean total hospital charges in patients with or without cancer. Similarly, no significant differences were observed in complications such as requirement for mechanical ventilation, arrhythmia, cardiac arrest, need for vasopressor and thrombolysis. Conclusions: In-hospital mortality in patients with acute pulmonary embolism is significantly higher in all types of GI cancer, however; there is no significant differences in hospital length of stay and total hospital charges in patients with or without cancer.
Frequency and oncologic outcomes of KRAS mutations in circulating tumor DNA of patients with pancreatic ductal adenocarcinoma.
Authors: Yousef Mahmoud M.G. , Hurd Mark W. , Yousef Abdelrahman M.G. , Snyder Rebecca A , Knafl Mark , Fanaeian Mohammad Mahdi , Chacko Ray , Peterson Jennifer , Smaglo Brandon George , Wolff Robert A. , Pant Shubham , Lee Michael Sangmin , Overman Michael J. , Tzeng Ching-Wei D. , Katz Matthew H. G. , Wang Huamin , Maitra Anirban , Ludmir Ethan B. , Shen John Paul Y.C. , Zhao Dan
Published: January 2024

636

Background: KRAS genetic alterations have been reported in more than 90% of pancreatic ductal adenocarcinoma (PDAC). The association of KRAS mutation subtypes detected in circulating tumor DNA (ct-DNA) with survival remains unclear. We investigated the rate of liquid biopsy detected KRAS mutation subtypes, and their association with overall survival (OS) in patients with PDAC. Methods: The Foundry software platform was used to retrospectively query a single-institution Electronic Health Records to identify patients with PDAC who underwent ct-DNA liquid biopsy from 2018 to 2023 and extract their oncologic outcomes. Results: Liquid biopsies were performed for 313 patients with PDAC; 58% (n=181) were diagnosed with stage IV disease. The median follow-up was 25 months, with median OS 24 months (95%CI=21-29). Overall, 52% (n=162) tested positive for KRAS mutations. Among patients with metastatic disease at diagnosis (n=181), 66.7% (n= 120) tested positive for KRAS mutations. In contrast, only 31.8% (n= 42) of patients with stage I to III disease at diagnosis (n=132) tested positive. Among patients with metastatic disease, those with KRAS positive disease had significantly shorter OS (median OS 13 vs 27 months, HR=2.7, 95%CI=1.7-4.3, P<0.0001). In patients with non-metastatic disease, the median OS was 28 vs 43 months, respectively (HR=1.7, 95%CI=0.97-2.8, P=0.064). The most frequent KRAS mutation was G12D (n=66, 40.7% of KRAS mutations) followed by G12V (n=58, 35.8%), G12R (n=15, 9.3%), and Q61H (n=10, 6.2%). Among KRAS mutations allelic subtypes, KRAS G12D and Q61 mutations had significantly worse OS with median OS 13 and 10 months respectively (P <0.001). The most frequently co-occurring mutations detected in KRAS positive patients were TP53 (n=126, 77.8%), CDKN2A (n=34, 21%), SMAD4 (n=33, 20.4%), and ARID1A (n=12, 7.4%). Examining the prognostic significance of co-occurring mutations among patients with metastatic disease, only detection of co-occurring CDKN2A mutation was associated with worse OS as compared to patients with KRAS mutations without co-occurring CDKN2A mutations (median OS 8 vs 14 months, HR=2, 95%CI=1.1-3.5, P value=0.015). Conclusions: Detection of KRAS mutation in liquid biopsies of patients with metastatic PDAC is associated with worse OS. KRAS G12D/Q61 alterations detection is associated with worse OS compared to other KRAS mutation subtypes. Ct-DNA detection of co-occurring CDKN2A mutation is associated with worse OS in patients with KRAS positive metastatic disease.
Survival of patients with microsatellite instability-high and Lynch syndrome-associated pancreatic ductal adenocarcinomas.
Authors: Nasar Naaz , Eikenboom Ellis , Seier Kenneth , Gonen Mithat , Wagner Anja , Jarnagin William R. , Drebin Jeffrey A. , D'Angelica Michael Ian , Kingham T. Peter , Balachandran Vinod P. , Soares Kevin , Spaander Manon C.W. , Wei Alice Chia-Chi
Published: January 2024

640

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease due to its aggressive nature, late-stage diagnosis, and limited treatment options. There is an increased interest in cancers which harbor microsatellite instability (MSI) due to their susceptibility to immune checkpoint inhibitors. MSI in PDAC is rare, and little is known about survival in this subtype of pancreas cancers. Our aim was to assess overall survival in surgically resected high microsatellite instability (MSI-H), mismatch repair deficient (MMRd), and Lynch Syndrome (LS) associated PDACs treated in our center. Methods: Patients with surgically resected PDACs from 1990 to 2023 were identified. A total of 936 cases were sequenced utilizing MSK-IMPACT, a targeted next generation sequencing platform. Patients with germline or sporadic pathogenic variants or likely pathogenic variants in one of the DNA MMR genes MLH1, MSH2, MSH6, PMS2, or 3’ end of EpCAM were identified. MSI-H, MMRd, and LS-associated cases were matched to patients with microsatellite stable or MMR proficient, non-LS-associated PDAC in a 1:2 ratio with a direct match on age (±5 years), gender, and year of surgery (±3 years). Kaplan-Meier curves were used to visualize the data. A generalized estimating equation (GEE) cox model with robust sandwich estimator was used to compare matched cohorts. Results: 17 patients with MSI-H, MMRd or LS-associated surgically resected PDACs were identified. Five patients were classified as MSI-H, 3 patients were MSI-indeterminate, and 9 patients were microsatellite stable. Eight patients were found to have pathogenic germline variants in LS-associated genes. The remaining nine patients had sporadic pathogenic DNA MMR gene variants ( MLH1 n=3, MSH6 n=6). Median age at surgery was 66 (interquartile range (IQR) 60-77), 41% of the patients were female, and median year of surgery was 2014. MSI-H, MMRd or LS-associated PDACs were matched to 34 control patients. The median survival time of the cases was 12 years vs. 1.9 years in the control group. Five-year survival rate was 81% (IQR 60-100%) and 18% (7.4%-43%), respectively. LS-associated, MSI-H or MMRd status in resectable PDAC was a strong predictor of good prognosis (hazard ratio 0.17, 95% CI 0.07-0.38, p value <0.001). Conclusions: MSI-H, MMRd or LS-associated PDACs displayed significantly better survival compared to their MSI-stable, MMR proficient, non-LS-associated counterparts, in the era before routine use of immunotherapy. It is expected that survival will be increased further with more frequent availability of immunotherapy.
The interim analysis of a single-arm, open-label, phase II study investigating ALLEN regimen (durvalumab plus albumin paclitaxel and lenvatinib) in patients with metastatic pancreatic cancer (mPC).
Authors: Chen Meixia , Li Zhifang , Ming Qianyi , Zhang Yan , Feng Kaichao , Mei Qian , Liu Yang , Han Weidong
Published: January 2024

658

Background: Metastatic pancreatic cancer is a leading cause of cancer death worldwide with limited treatment options. Durvalumab, the anti- PD-L1 inhibitor has revealed remarkable efficacy in solid malignancies including hepatobiliary cancers. We conducted a study to evaluate the efficacy and safety of a combination therapy of Durvalumab, Albumin paclitaxel and Lenvatinib (ALLEN Regimen) in patients with mPC. Methods: This open-label, single-center, single-arm, phase Ⅱ clinical trial investigated patients with metastatic pancreatic cancer. Durvalumab (1000mg IV, q3w), albumin paclitaxel(180-220 mg/m2 IV q3w) and lenvatinib (8mg PO QD) were given regularly until disease progression. The primary endpoint was objective response rate (ORR) evaluated by investigators according to RECIST 1.1. The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAEs). Results: Between September 2021 and September 2023, seventeen patients with ECOG score 0-2 were enrolled, including 8 patients (47%) who were refractory to at least one systemic chemotherapy.The median follow-up was 6.0 months (95% CI 4.0, 8.4). 17 patients were evaluable, with a median age of 58 years. 9 patients (52.9%) were male. The ORR and DCR were 64.7% and 94.1%, respectively. The median PFS was 7.8 months (95% CI 3.1, 11.4), and the median OS was 8.1 months (95% CI 4.7, 13.5). TRAEs (all grades) occurred in 16 (94.1%) patients. The most common grade 1-2 TRAEs were nausea 8 (47.1%), diarrhoea 5(29.4%), peripheral sensory neuropathy 3 (17. 6% ) and hypertension 3(17.6% ). No grade 3 or higher TRAEs occurred. Conclusions: The ALLEN regimen demonstrated promising antitumor activity and well acceptable toxicity in metastatic pancreatic cancer. Further randomized controlled studies will be required in a larger patient population. Clinical trial information: NCT05327582 .
Does metformin use effect overall survival for patients with pancreatic cancer?
Authors: Ramjeesingh Ravi , Nazarali Samina , Sheridan Margaret , Sun Peiran , Popovacki Aimee
Published: January 2024

660

Background: In Canada, the incidence of pancreatic cancer ranks 11th amongst all cancers but has resulted in the third highest mortality. Despite advancements in both diagnostics and therapeutics, the 5-year overall survival rate of pancreatic adenocarcinoma (PDAC) remains under 10%. Emerging studies have begun to examine the role of the hypoglycemic medication metformin, in improving outcomes of patients with PDAC. In cell cultures, metformin has been shown to have direct growth-inhibitory actions on malignant cells, and previous retrospective studies have suggested a potential association between metformin use and increased overall survival in breast and prostate cancer. To identify if metformin plays a role in improving PDAC outcomes, we have conducted a retrospective review of PDAC in Nova Scotia, Canada. Methods: We conduced a retrospective study of 630 patients diagnosed with PDAC treated at the Halifax Infirmary (Halifax, Nova Scotia). Records of patients were reviewed and information regarding patient demographics, cancer staging, metformin use, date of diagnosis, and date of death were collected. Statistical analysis using the log rank method was done to determine if there was a statistically significant difference in overall survival between groups. Results: Among the 630 patients identified, there were 337 males and 293 females. The average age at time of diagnosis was 74.02 years. There was no significant difference found in overall survival of patients on metformin (n=132, mean overall survival (mOS) 6.68 months), compared to those not on metformin (n=498, average survival 7.44 months), p=0.989. Further subgroup analysis based on cancer staging showed that patients with resectable pancreatic cancer (AJCC stage I-IIA, n=140), who did not use metformin (n=106) had a mOS of 12.98 months compared to 9.71 months for metformin users (n=34), p=0.438. For patients with locally advanced disease (AJCC stage IIB-III, n=125), the average mOS of non-metformin users (n=103) was 11.10 months compared to 10.73 months for metformin users (n=22), p=0.803. For patients with metastatic disease (AJCC stage IV, n=365), the average survival of non-metformin users (n=289) was 3.48 months compared to 4.26 months for metformin users (n=76), p=0.803. Diabetic patients (n=195) on metformin (n=132) compared to those not on metformin (n=63), did not show significant survival difference (mOS 6.68 months vs 6.61 months respectively, p =0.602). Conclusions: Despite suggestion that metformin use may improve survival in some cancers, we found no statistical improvement in mOS for metformin use in PDAC patients. Future research including a prospective study should be undertaken to confirm these results in a larger sample size.
Mucin 5 AC (MUC5AC) to predict pathologic treatment response (TR) to neoadjuvant chemotherapy (NAT) in resected-pancreatic ductal adenocarcinoma (R-PDA).
Authors: Manne Ashish , Sheel Ankur , Sara Amir , Noonan Anne M. , Yu Lianbo , Yang Wancai , Hays John L. , Mittra Arjun , Malalur Pannaga G. , Rahman Shafia , Roychowdhury Sameek , Elkatib Rifat , Jin Ning , Cloyd Jordan M. , Dillhoff Mary , Ejaz Aslam , Esnakula Ashwini K.
Published: January 2024

690

Background: MUC5AC is a gel-forming glycoprotein that exists in two major glycoforms in PDA. We studied the differential expression and predictive value of heavily glycosylated mature MUC5AC (MM) detected in the apical (Ap) and/or extracellular region (EC) and less-glycosylated immature MUC5AC (IM) detected only in the cytoplasm (Cy) in R-PDA. Methods: R-PDA formalin-fixed paraffin-embedded tissue blocks from January 2010 to June 2021 were obtained from the Ohio State University biorepository. Immunohistochemistry was performed to study the expression for MM and IM using monoclonal antibodies 45M1 and CLH2, respectively, and H-scores were calculated. Analysis of variance (ANOVA), t-tests, and Wilcoxon tests were used for statistical analysis. Results: Tissue samples from 100 R-PDA (43 received NAT and 57 had upfront surgery (UpS)) were available for testing. The median age of diagnosis was 65 years, and 50% were females. MM and IM were positive in 96% R-PDA (MM-95% Ap and 72% EC).In the NAT group, 89% (n=38) had 5-fluorouracil (5FU) based (36 FOLFIRINOX and 2 FOLFOX), and the rest received gemcitabine (Gem)-based therapy; patients received a median of 6 cycles of NAT; 37% (16) had preoperative chemoradiation (CRT) after NAT; 63% (27) had adjuvant systemic therapy (AST); pathologic objective response (OR = near complete or partial) and no response (NR) to NAT was reported in 63% (27) and 37% (16), respectively. In UpS group, 92% and 4% had AST (48 Gem-based, 4 5FU-based) and adjuvant CRT, respectively. The median time to recurrence (mTTR) and overall survival of the group was 15 and 33 months (m), respectively. NAT group had significantly (p<0.05) lower EC-positive MM (mean H-score 108 vs. 151), IM (mean H-score 122 vs. 162), and mTTR (11 vs 15 m) than UpS group. IM levels were directly proportional to the response (near complete (mean H-score 98) < partial (105) < NR (152) < UpS (162), p=0.04). Other TR results are discussed in the table. Conclusions: MUC5AC (IM > MM) is a potential predictive marker for TR among PDA patients, specifically among those receiving FOLFIRINOX. These associations must be validated in further prospective studies.[Table: see text]
Is lymph node metastasis an event indicating an advanced gastrointestinal stromal tumor?
Authors: Zhang Peng , Yang Weili , Fu Yingfeng , Zhang Jun , Feng Fan , Zhai Gang , Fu Yang , Wu Xin , Zhang Xinhua , Wu Xiao-Jun , Gao Zhidong , Liang Han , Zhou Yanbing , Liu Heli , Tao Kaixiong
Published: January 2024

754

Background: The clinicopathological features and prognosis of gastrointestinal stromal tumors (GISTs) with lymph node metastasis remain controversial owing to their low incidence. A multicenter retrospective cohort study was conducted to compare the clinicopathological features and oncologic outcomes of GIST with and without lymph node metastases. Methods: The medical records of patients with GISTs in 16 large medical centers in China from January 2014 to December 2020 were reviewed. Patients were divided into three groups: no metastasis, lymph node metastasis without distant metastasis, and distant metastasis without lymph node metastasis. Propensity score matching (PSM) was performed to reduce confounding factors. Results: A total of 1109 cases of primary GIST were included in this study, comprising 607 males (54.7%) and 502 females (45.3%), with a mean age of 56.6±11.9 years. There were 1024 patients (92.3%) with no lymph node metastasis after surgery, and 85 patients (7.7%) had lymph node metastasis. Compared to that in GIST without lymph node metastasis, the proportion of non-gastric GIST was higher in GIST with lymph node metastasis (52.9% vs. 40.7%) with a larger tumor diameter (>10 cm: 36.5% vs. 18.1%) and more patients with distant metastasis (11.8% vs. 3.5%). Tumor location not in the stomach, the largest tumor diameter, and distant metastasis were independent risk factors for GIST with lymph node metastasis (all P < 0.05). After PSM, 96, 48, 24 patients comprised no metastasis, lymph node metastasis without distant metastasis, and distant metastasis without lymph node metastasis, respectively. The relapse-free survival (RFS) of the lymph node metastasis group was comparable to that of the distant metastasis group without lymph node metastasis ( P = 0.368) and significantly inferior to that of no metastases ( P = 0.042). Conclusions: The prognosis of patients with GIST with lymph node metastasis was comparable to that of patients with distant metastasis and significantly worse than that of patients without metastasis. Lymph node metastasis may be an advanced event in GIST.
Clinical validation of Northstar Response, a novel methylated ctDNA therapy response monitoring assay in patients with advanced GI cancer undergoing active treatment.
Authors: Sahin Ilyas , Kahramangil Doga , Rogers Sherise C. , Ramnaraign Brian Hemendra , Manda Pravalika , Varga Matthew Gordon , Palmer Gary A. , Ye Patrick Peiyong , George Thomas J.
Published: January 2024

756

Background: ctDNA is a non-invasive way to holistically assess the tumor. Several assays developed for therapy response monitoring rely on variant allele frequencies to detect scarce somatic variants in the blood. In contrast, methylated ctDNA measurement has shown promise as a treatment monitoring biomarker without requiring a tumor biopsy, yet accuracy is limited in ability to precisely quantify the amount of methylation present in the ctDNA. The CLIA-approved Northstar Response assay (BillionToOne, Inc.) quantifies on average 90 methylated loci, a 10-fold increase in signal over the average tissue-informed assays. Methods: This prospective, observational study assesses the clinical validity of Northstar Response, a quantitative methylated ctDNA therapeutic response monitoring assay that does not require prior tumor tissue. A cohort of 100 advanced cancer patients with a variety of GI malignancies submit serial ctDNA measurements in a blinded fashion. Eligibility includes advanced GI cancer patients starting a new line of systemic therapy (IO, targeted, chemo or combination) who are not pregnant or s/p organ or bone marrow transplantation. Blood samples are collected at baseline, at the time of imaging, and at least two intermediate time points (~30 days and 60 days post tx initiation). The primary endpoint is to measure the concordance and temporal relationship between disease progression measured by ctDNA compared to RECISTv1.1, clinical confirmation, or death. A Cox proportional hazards model will be used to quantify the association between the change in tumor methylation score (TMS; total methylated tumor molecules per 1000 assayed genomic equivalents) and clinical progression. The cohort will be split equally between a training and validation set. Results: Enrollment began in June 2023 and continues. To date, 28 patients with a variety of advanced GI cancers (table) have been enrolled with 37 samples processed. All samples have passed established QC metrics with average turn-around-time from receipt of sample to final report of 9.1 days (95% were <15 days). TMS ranged from <120 to >160,000 across individual samples, indicating that the assay can detect a broad range of tumor load in blood. We detected a median of 69 methylated loci per sample (range 4-451). Out of 21 pts, 17 had at least one sample with TMS measured above the noise floor of 120. Conclusions: The Northstar Response assay can consistently detect ctDNA across a variety of advanced GI cancers. Enrollment continues with formal comparison to clinical progression planned. Additional data on the complete training set will be available at the meeting.[Table: see text]
Single cell transcriptomic profiling of appendiceal adenocarcinoma to identify rare tumor cells and a myeloid-enriched tumor microenvironment (TME).
Authors: Gunes Betul Beyza , Hornstein Nicholas James , Wang Mingshuang , Chowdhury Saikat , Yousef Mahmoud M.G. , Yousef Abdelrahman M.G. , Zeineddine Mohammad A. A. , White Michael , Shen John Paul Y.C.
Published: January 2024

760

Background: Appendiceal adenocarcinoma (AA) is a rare malignancy with distinct clinical and molecular characteristics compared to colorectal cancer (CRC). Currently there is little knowledge regarding how tumor cells from AA interact with the tumor microenvironment (TME). In this study, we performed single cell RNA sequencing (scRNAseq) on metastatic AA tumors taken from three patients undergoing curative intent surgical resection. Methods: After obtaining informed consent, tumor tissue from three patients with AA and one patient with CRC undergoing cytoreductive surgery at the MD Anderson Cancer Center (MDACC) was harvested and dissociated into single cell suspension for scRNAseq; libraries were prepared with ‘5 sequencing (10X Genomics). Bulk RNA sequencing from 19 additional patients with AA was available as a validation cohort. Results: scRNAseq analysis of a cohort of 3 patients with AA, 1 with CRC, and 12 healthy control samples identified 39,451 evaluable single cells after filtering and doublet removal. Separating cells into immune, stromal, and epithelial compartments identified that epithelial cells are rare in AA tumors. On average, AA constituted 62% stroma, 36% immune and only 2% epithelial cells, in contrast to healthy appendix (46% immune, 29% epithelial, 25% stroma). Sub-classification of immune cells revealed enrichment of myeloid cells in AA tumors (67% myeloid, 27% T, 5% B and 1% plasma B cells). This is in contrast to healthy appendix tissue (44% T, 26% plasma B, 22% B, 6% myeloid and 2% mast cells). In CRC, the majority of immune cells from the CRC sample were T cells (69%). These single cell data were used to improve deconvolution of bulk RNAseq, allowing for evaluation of TME contribution to transcription using bulk RNAseq data. Analysis of tumors from 19 patients with AA confirmed myeloid predominance in AA tumors. We performed pseudobulk differential expression analysis between compartments comparing CRC and AA which identified significant differences between compartments. Gene set enrichment analysis enabled identification of organized compartment specific changes. Conclusions: Findings from this study provide new insights into AA's biological distinctions from CRC and represent a crucial step toward better understanding this rare malignancy. Myeloid cells need further investigation in AA to develop specialized management approaches and improve patient outcomes.
The impact of multidisciplinary care for locally advanced rectal cancer referrals: A systems perspective.
Authors: Lo Victor , Mallick Ranjeeta , Goodwin Rachel Anne , Gotfrit Joanna
Published: January 2024

85

Background: Locally advanced rectal cancer patients require multidisciplinary care for treatment planning. We sought to determine whether the order of surgical and radiation oncology consultation in relation to medical oncology consultation affects the time from cancer diagnosis to treatment initiation and the requirement for additional pre-treatment visits with medical oncology. Methods: We conducted a retrospective chart review of adult patients referred to The Ottawa Hospital with locally advanced rectal adenocarcinoma, seen in consultation by a surgical, radiation, and medical oncologist between January 2018 and December 2022. Results: Of 195 patients, the median time from diagnosis to treatment was 55 days (IQR: 45-68). Both surgical and radiation oncology consultation preceded medical oncology consultation in a minority of patients (72; 37%), and 48 (25%) patients required multidisciplinary cancer conference (MCC) discussion. However, the time from cancer diagnosis to treatment initiation was not significantly different between patients who were and were not seen by the surgeon and radiation oncologist prior to the medical oncologist (56 vs. 55 days respectively), nor if MCC discussions were or were not required (55 vs. 55 days). However, almost half of all patients (93; 48%) required an additional pre-treatment visit with their medical oncologist, and patients who saw both surgical and radiation oncology prior were significantly less likely to require additional pre-treatment visits with medical oncology (25% vs. 61%; p<0.0001). Conclusions: The time from cancer diagnosis to treatment initiation was not significantly impacted by the order of specialist consultations with the multidisciplinary team, nor if patients required MCC discussion or additional pre-treatment visits with medical oncology. However additional pre-treatment visits with medical oncology were significantly more likely to occur when patients were seen by medical oncology prior to surgical and/or radiation oncology, representing a logistical and financial inefficiency in the system, and a potential area for process improvement. [Table: see text]
NRG-GI008: Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-NORTH AMERICA).
Authors: Lieu Christopher Hanyoung , Yu Guan , Kopetz Scott , Puhalla Shannon L. , Lucas Peter C. , Sahin Ibrahim Halil , Deming Dustin A. , Philip Philip A. , Hong Theodore S. , Rojas-Khalil Yesenia , Loree Jonathan M. , Wolmark Norman , Yothers Greg , George Thomas J. , Dasari Arvind
Published: January 2024

TPS243

Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (SignateraÔ, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines vs. serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP+Ox vs. more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate vs. delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox vs FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Support: U10-CA-180868, -180822; UG1CA-189867; Natera, Inc. Clinical trial information: NCT05174169 .