bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating tumor DNA for predicting radiographic and pathologic response to total neoadjuvant therapy in locally advanced rectal cancer: ENSEMBLE-1.
Authors: Kagawa Yoshinori , Watanabe Jun , Uemura Mamoru , Ando Koji , Inoue Akira , Nishizawa Yujiro , Suwa Yusuke , Chida Keigo , Hata Tsuyoshi , Sekido Yuki , Nakanishi Ryota , Okuya Koichi , Miyo Masaaki , Oba Koji , Laliotis George , Nakamura Yoshiaki , Bando Hideaki , Yoshino Takayuki , Takemasa Ichiro , Oki Eiji 
Published: August 2024

71 Background: Total neoadjuvant therapy (TNT) has dramatically shifted the treatment paradigm for locally advanced rectal cancer (LARC), prolonging survival with high rates of pathologic complete response (pCR) and introducing opportunities for nonoperative management (NOM). However, there is a need for robust predictive biomarkers of TNT efficacy, local cancer regrowth in NOM, and overall prognosis. Circulating tumor DNA (ctDNA) is a minimally invasive biomarker used to detect molecular residual disease (MRD) and predict recurrence in colorectal cancer after curative resection. The effectiveness of ctDNA MRD status specifically as a predictive biomarker for TNT was evaluated in the Phase II TNT study, ENSEMBLE-1 (jRCTs051200113), conducted in Japan. Methods: Patients with LARC undergoing TNT were enrolled in ENSEMBLE-1. Protocol treatment was defined as short-course radiotherapy (SCRT: 25Gy) followed by six cycles of CAPOX and total mesorectal excision (TME). NOM was allowed if a clinical complete response (cCR) was achieved after TNT. ctDNA was measured by SignateraTM (Natera, Inc.) at the following time points: baseline (pre-treatment), after SCRT, after 4 cycles of CAPOX, before TME, and post operatively at 4w, 12w, 24, 36 and 48w in the GALAXY trial (UMIN000039205). Results: A total of 30 patients were enrolled in the study. After completing TNT, TME and NOM were performed in 20 and 7 patients, respectively. ctDNA was measured in 26 patients (TME: 19 patients, NOM: 7 patients). ctDNA was detected in 100% (25/25) at baseline, 81% (21/26) after SCRT, 31% (8/26) after 4 cycles of CAPOX, and 45% (9/20) after TNT. The attached table shows the results of statistical analyses of the correlation between ctDNA status, clinical response, TME or NOM, and pathologic complete response (pCR). It was found that ctDNA status after SCRT and after 4 cycles of CAPOX was associated with cCR or non cCR (p=0.007 and p=0.007, respectively). Additionally, ctDNA status after TNT was associated with pCR or non pCR (p=0.029). Conclusions: Our study demonstrates that ctDNA-based MRD may predict TNT response in LARC patients. Negative ctDNA during treatment correlates with favorable responses and may be an aid in NOM decision making. Clinical trial information: jRCTs051200113 . [Table: see text]
Effect of pancreatobiliary reflux on macrophage-secreted IL-8, PI3K/NFκB pathway, and promotion of cholangiocarcinoma progression.
Authors: Wu Tingting , Gao Ruiqian , Wang Xiaowei , Guo Dong , Xie Yuwei , Dong Bingzi , Hao Xiwei , Zhu Chengzhan 
Published: August 2024

73 Background: Persistent pancreaticobiliary reflux (PBR) is associated with a high risk of biliary malignancy. This study aimed to evaluate the proportion of PBR in biliary tract diseases and mechanisms by which PBR promoted cholangiocarcinoma progression. Methods: Overall, 227 consecutive patients with primary biliary tract disease participated in this study. The amylase levels in the collected bile were analyzed. The mechanisms underlying the effect of high-amylase bile on bile duct epithelial and cholangiocarcinoma cells progression were analyzed. The source of interleukin-8 (IL-8) and its effects on the biological functions of cholangiocarcinoma cells were investigated. Results: The bile amylase levels in 148 of 227 patients were higher than the upper serum amylase limit of 135 IU/L. PBR was significantly correlated with sex, pyrexia, and serum gamma-glutamyl transferase (GGT) levels in the patient cohort. High-amylase bile-induced DNA damage and genetic differences in the transcript levels of the gallbladder mucosa and facilitated the proliferation and migration of bile duct cancer cells (HUCCT1 and QBC939 cells). The concentration of many cytokines increased in high-amylase bile. IL-8 is secreted primarily by macrophages via the mitogen-activated protein kinase pathway and partially by bile duct epithelial cells. IL-8 promotes the progression of HUCCT1 and QBC939 cells by regulating the expression of epithelial-mesenchymal transition-associated proteins and activating the phosphatidylinositol 3-kinase/nuclear factor kappa-B pathway. Conclusions: PBR is one of the primary causes of biliary disease. IL-8 secreted by macrophages or bile duct epithelial cells stimulated by high-amylase bile promotes cholangiocarcinoma progression.
Comparative analysis of mortality and hospital expenditure in patients with gastroenterological cancer: Thailand and United States.
Authors: Suenghataiphorn Thanathip , Laohavinij Wasin , Lohawatcharagul Tuntanut 
Published: August 2024

79 Background: Concerns about rising health care cost and quality of care has been a major health issue worldwide. Gastrointestinal (GI) cancer accounts for one-quarter of the global cancer incidence. However, there are limited evidence, which demonstrates the differences in clinical outcome and economic burden of GI cancer when comparing between health care setting of developed and developing countries. Methods: Two data sources were analyzed: (i) The 2020 U.S. National Inpatient Sample (NIS) involving patients that were primarily discharged with gastroenterological cancer, and (ii) data at tertiary care center in Thailand used for this comparative study, with similar period and conditions. Participants were identified using relevant ICD-10 CM codes. Adjusted odds ratios (aORs) for specified outcomes were calculated through multivariate logistic and linear regression analyses. Participants are divided into those who experienced mortality and those who survived. We report crude mortality rates and expenditure outcomes. Statistical significance was established at a p-value of 0.05. Results: We identified 9,299 Thai records and estimated 216,859 US records with a primary diagnosis of GI cancer at discharge. Of these, 2.15% (200/9,299) of the Thai records and 3.82% (8,285/216,859) of the US records died. In a multivariate analysis, death during hospitalization is associated with higher length of stay (Thai: b = 18.10, 95% CI (16.71, 19.49), p < 0.001), (US: b = 3.38, 95% CI 3.38 (2.14, 4.63), p < 0.001) and higher hospitalization charges (Thai: b = 155,530.02 THB, 95% CI (141,805.10, 169,254.80), p < 0.001), (US: b = 46,882.44 USD, 95% CI (31,629.51, 62,135.37), p <0.001). Subpopulation analysis revealed similar significant results. We observed higher increased length of stay in Thailand, whereas higher crude mortality rate and hospitalization charges was observed in the United States. Conclusions: In both Thailand and United States, mortality in patient with GI cancer is associated with increase in length of stay and higher hospitalization expenses. However, the magnitude of difference in each outcome differs between two countries. Future studies investigating health care costs, cultural role and clinical outcomes may provide insights for cost-reduction strategies, while maintaining or improving the current standard of care in this population group. [Table: see text]
The prognosis of pancreatic neuroendocrine tumors according to the WHO 2017 classification: The multi-center experience in Taiwan.
Authors: Ho Wei-Pang 
Published: August 2024

87 Background: The occurrence of pancreatic neuroendocrine tumors (PanNETs) remains infrequent, there is an upward trend in their diagnosis. Our retrospective study, conducted in Taiwan, focuses on exploring the interplay between clinical characteristics, treatment modalities, and prognosis in PanNET cases. Particularly, we aim to assess the implications of the updated WHO classification system on prognosis. Methods: We conducted a retrospective analysis of 176 PanNET cases from Chang Gung Medical Foundation, encompassing Linkou, Taoyuan, and Tucheng Hospitals, spanning the years 2009 to 2022. Pathology reports for all cases were reevaluated by pathologists according to the WHO 2017 classifications. Clinical features and overall survival outcomes were documented. Additionally, we examined the prognosis of distinct subgroups categorized by the WHO 2017 classification and their respective treatments. Results: The 5-year survival rate for all patients in the cohort stood at 58.7%. Among these, individuals diagnosed with NET G1 exhibited the highest survival rate (n = 78, 83.1%), followed by those with NET G2 (n = 57, 55.0%), NET G3 (n = 25, 14.6%), and NEC (n = 16, 9.4%). Univariate analysis highlighted several significant prognostic factors, including age, absence of symptoms at diagnosis, tumor size, lymph node involvement, distant metastasis, higher Ki-67 index, and cellular morphology. Comparative analysis between the WHO 2017 and WHO 2010 classifications revealed both systems as significant independent predictors of overall survival in PanNET cases. Notably, the 95% confidence interval for the WHO 2017 classification (2.892–9.703) showed a slight improvement in prognostic precision compared to the WHO 2010 classification (3.696–10.067). Under the WHO 2010 classification, NET G3 and NEC were combined, with NEC presenting higher rates of distant metastases, lymph node involvement, and Ki-67 index. Further investigation revealed that patients receiving somatostatin analogs, chemotherapy, or targeted therapy exhibited improved survival rates, particularly notable in NET G3 and NEC subgroups. Furthermore, NEC patients displayed extended treatment durations and higher objective response rates to first-line chemotherapy compared to the NET G3 group. Conclusions: Our retrospective analysis has illuminated the interrelation between prognostic factors and the overall survival rate. Furthermore, the updated WHO 2017 classification elucidates the distinctions between G3 and NEC, thus influencing the selection of clinical interventions.
Investigation of a tamoxifen-RACK7/KDM5C-IFN-I axis for ER+ breast cancer immunomodulation.
Authors: Aberin Marvin Angelo Esteban , Singh Saurabh , Lee Yu-Ling , Lin Kun-Yuan , Chang Yao-Ming , Guha Chandan , Wang Shu-Ping 
Published: August 2024

9 Background: ER+ breast cancer patients generally have good prognosis. However, significant relapse rates (i.e., hormone drugs, Tamoxifen/TMX) and the poor response to immune checkpoint blockade (ICB) remain critical issues to be addressed. Thus, exploration of anti-ICB resistant mechanisms and alternative targets is needed to improve therapeutic efficacy. Methods: To investigate potential cross-resistant mechanisms between hormone and ICB therapy, ER+ cell lines T47D and MCF7 cells were chronically-treated with TMX for 6 months, and subjected to RNA-Seq and pathway enrichment analysis. Dysregulation of identified factors were validated via western blotting, RT-qPCR, and flow cytometry. Target factors were then inhibited or depleted by shRNA knockdown (KD) or small-compound inhibition. Identified ICB resistance mechanisms were further elaborated by in vitro co-culture assays, syngeneic mouse models, and immune-profiling of tumor microenvironment (TME). Results: Chronic exposure to TMX activates Type I interferon (IFN-I) signaling, induces IFN I-stimulated gene (ISG) expression, and downregulates the H3K4 demethylase and ISG repressor complex known as RACK7/KDM5C. Chronic TMX also upregulates CEACAM1, a well-known ligand for the immune checkpoint receptor TIM3. Results prompt us to evaluate whether loss of RACK7 combined with TMX treatment may modulate a lymphocyte-attractive (via IFN-I), but T-cell exhaustive (via CEACAM1-TIM3) TME. Indeed, in vitro treatment of TMX under RACK7-KD conditions triggers STING upregulation, TBK1 hyperphosphorylation, and a more pronounced activation of ISGs and CEACAM1. In vivo, TMX combined with RACK7-KD enhances tumor growth in the TS/A (ER+) syngeneic mouse model, while immune-profiling reveal that this combination promotes lymphocyte infiltration with a higher population of terminally exhausted CD8+ T-cells in the TME. Conclusions: Our data demonstrate that the TMX-induced activation of cGAS/STING pathway and RACK7 downregulation coordinately shape the IFN-I and immune checkpoint signaling axes in ER+ breast cancer. This TMX–RACK7–IFN-I regulatory network promotes a lymphocyte-attractive TME via IFN-I signaling activation, whereas induction of inhibitory ligands renders T-cells to be terminally-exhausted and unable to kill tumors. These findings highlight the potential use of TMX’s STING-agonistic effect in re-shaping the “cold” breast cancer TME, and the use of combined TMX and anti-TIM3 or anti-CEACAM1 blockade to improve ICB therapy.
A potent and selective pan-RAS inhibitor, ADT-1004, targeting complex KRAS mutations for pancreatic cancer.
Authors: Piazza Gary , Bandi Reddy DS , Foote Jeremy B , Keeton Adam B , Mattox Tyler Ernest , Chen Xi , Maxuitenko Yulia , Manne Upender , Boyd Michael R , Buchsbaum Donald J , El-Rayes Bassel F. 
Published: August 2024

90 Background: Pancreatic ductal adenocarcinoma (PDAC) is a challenging cancer with a 5-year survival rate of under 12%. More than 90% of PDAC cases involve KRAS mutations. KRASG12C inhibitors recently developed have limited use because only 3% of PDAC express this mutation, highlighting the urgent need for pan-RAS inhibitors to address the complex mutation landscape in PDAC while avoiding resistance mechanisms. We synthesized and evaluated a novel pan-RAS inhibitor, ADT-1004, in mouse tumor models transplanted with mouse PDAC cell lines or patient-derived xenografts. ADT-1004 is an orally bioavailable prodrug of ADT-007, a highly potent and selective pan-RAS inhibitor (doi.org/10.1101/2023.05.17.541233). Methods: Human and mouse PDAC cell lines were utilized to evaluate in vitro growth inhibitory potency and selectivity of ADT-007. For in vivo experiments, KPC-Luc (1 × 105) and 2838C3-Luc (1.5 × 105) PDAC cells harboring the KRASG12D mutation were injected into the pancreas of C57BL/6J mice. After one week, the mice were randomly divided into treatment groups (n = 7 per group) and received oral ADT-1004 at a dose of 40mg/kg body weight five times a week for 4 weeks. Tumor burden was assessed weekly by monitoring bioluminescence signals using the IVIS Xenogen imaging system. Four patient-derived xenografts from PDAC patients with KRASG12C, KRASG12D, KRASG12V, KRASG13Q mutations were subcutaneously implanted in NSG mice by a small incision in the right flank. A week later, when the tumors reached a size of 100mm3 mice were randomized (n=7 per group) and treated orally with 40mg/kg of ADT-1004 five times a week for 6 weeks. Body weight and tumor size were measured twice weekly. Results: ADT-007 potently and selectively inhibited the growth of human and mouse PDAC cell lines. For example, the IC50 value pf ADT-007 for KRASG12C MIA PaCA-2 PDAC cells was as low as 2 nM compared to 2500 nM for RASWT BxPC3 PDAC cells. Growth inhibition was dependent on activated RAS and associated with reduced GTP-RAS levels and MAPK/AKT signaling. ADT-1004 was well tolerated in mice at a dose up to 175 mg/kg bid orally with sustained plasma levels of ADT-007 far exceeding growth IC50 values. When administered orally at 40 mg/kg body weight, ADT-1004 displayed robust antitumor activity in mouse tumor models using patient or mouse derived PDAC cell lines with G12D, G12V, G12C, or G13Q KRAS mutations, causing significant inhibitory effects on ERK phosphorylation. Conclusions: ADT-1004 inhibited tumor growth of KRAS mutant PDA tumors by targeting activated RAS to disrupt downstream MAPK/AKT signaling. The results highlight the promise of ADT-1004 as a novel pan-RAS inhibitor and open new strategies for addressing the complex genetic landscape of PDAC and other RAS driven cancers.
Efficacy assessment of a novel pan-RAS inhibitor in KRAS-mutant and wild type colorectal 3D bioprinted organoid tumor tissue.
Authors: Ahirwar Parmanand , Charania Areesha A. , Zuaiter Dana , Eiler Logan C. , Nizamuddin Alyssa , Crawford Chelsea L. , Maxuitenko Yulia Y. , Piazza Gary , Budhwani Karim I. 
Published: August 2024

91 Background: Colorectal cancer (CRC) is the third leading type of cancer worldwide, with ~150,000 new cases in the US annually and a grim 14% 5-year survival for patients diagnosed at a late stage. A lack of treatment options leads to persistently poor prognosis for patients with advanced stage disease. KRAS mutations are well known drivers of CRC and other GI cancers. Multiple KRAS mutations occur in CRC, including G12D (34%), G12V (21%), G13D (20%), G12C (8%), and others (18%). Existing KRAS-targeted therapies have limited use in CRC, underscoring the need for pan-RAS inhibitors in treating CRC and other RAS driven cancers. Objective: Assess activity of ADT-007, our pan-RAS inhibitor, on wild-type (WT) and KRAS-mutant 3D bioprinted organoid tumor (BOT) tissue using our high-throughput ex vivo platform. Methods: Using previously established bioprinting protocols, WT and mutant BOTs were printed with HT29 and HCT116 cells, respectively. HT29 is an established human WT CRC cell line with known sensitivity to proteosome and survivin inhibitors. HCT116 is a KRASG13D mutant human CRC cell line. 3 sets of BOTs were generated and acclimated for 24h. One set was treated for 72h with proteosome inhibitor Bortezomib, another with survivin inhibitor YM155, and the third with our novel pan-RAS inhibitor ADT-007. Dose response curves were generated from both conventional ATP luminescence readouts and high-content imaging. Results: BOT tissue microarchitecture was validated and >200 µm diffusion in BOTs was confirmed using high-content imaging. Differential response was quantified using Cell TiterGlo endpoint assay as well as advanced image processing of high-content live/dead nuclear stained images captured at multiple z-plains. ADT-007 IC50 was found to be substantially lower for mutant HCT116 compared to that for WT HT29 cell line BOTs, which was consistent with separately conducted in vitro and in vivo studies. Conclusions: A pan-RAS inhibitor, such as ADT-007 with high selectivity for cancer cells with activated RAS that is not limited to a specific KRAS mutant allele or RAS isozyme, could have broader use for CRC and other RAS-driven cancers. Further, due to their potential to replicate biophysical characteristics of a tumor and its microenvironment, BOT based precision and personalized medicine platforms can provide more accurate drug efficacy readout compared to in vitro cancer models.
Observational study examining the feasibility of generating real-world evidence (RWE) for new drug applications from the clinical trials database (DB; RELIASE study).
Authors: Bando Hideaki , Misumi Toshihiro , Sakamoto Yasutoshi , Takeda Yuriko , Nakamura Yoshiaki , Mizuguchi Kazuya , Aoyagi Yoshihiro , Miki Izumi , Yoshino Takayuki , Ohtsu Atsushi 
Published: August 2024

TPS100 Background: The extraction of the data that contributes to regulatory approval from real-world data (RWD) are difficult due to the lack of standardized data format as well as the extraction methodology. In addition, when RWE is used as an external control group, the similarity between internal and external control data has not been evaluated. Methods: In our ‘REALISE’ study, we will investigate the data extraction methodology as external control data of rare molecular subtype. We also elucidate the 'quality' and 'reliability' of RWD/RWE necessary for regulatory submissions. In addition, as most databases are not designed for regulatory use in the creation phase, we will investigate the retrospective methodologies to ensure reliability of RWD/RWE. We compare ‘data quality’ and ‘data reliability’ of ARCAD global DB (N=45,224), SCRUM-Japan registry (N=546), SCRUM-Japan observational study (N=14,325), and the Flatiron health RWD in Japan (N=650) and statistically analyze the differences and similarities among 4 databases. All analyses will be summarized descriptively. Similarity of patient characteristics and efficacy endpoints such as response rate, progression-free survival, overall survival, and all available endpoints will be evaluated by cancer type, treatment line, and standard treatment. For colorectal cancer, data extracted from the SCRUM-Japan registry, SCRUM-Japan observational study, and the Flatiron health RWD will be compared with data extracted from randomized controlled trials in the ARCAD global DB to examine the availability as an external control of RWD. The Kaplan-Meier method will be applied to estimate the survival distribution of time-to-event data. No imputation method for missing data will be used, and the frequency of missing data will also be summarized. We will also examine the methodology for extracting data with sufficient quality from the SCRUM-Japan observational study. In addition, if the reliability of RWD/RWE does not reach the required level, we will also examine the methodologies to retrospectively assure the reliability of the SCRUM-Japan observational study for regulatory submissions. [Table: see text]