bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-tumor effect of zartoprofen, a non-steroidal anti-inflammatory drug, targeting PPARγ (peroxisome proliferator-activated receptor gamma) on chondrosarcoma.
Authors: Higuchi Takashi , Takeuchi Akihiko , Miwa Shinji , Hayashi Katsuhiro , Yamamoto Norio , Tsuchiya Hiroyuki
Published: August 2024

232

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) plays a central role in the differentiation of adipocytes. Anti-tumor effects by activating PPARγ have been reported on chondrosarcoma. We revealed that zaltoprofen, a non-steroidal anti-inflammatory drug (NSAID), could activate and induce PPARγ in chondrosarcoma cells. We report antitumor effects of zaltoprofen targeting PPARγ on chondrosarcoma. Methods: PPARγ activation by zaltoprofen was assessed with luciferase assay. Human chondrosarcoma cells and PPARγ-silencing cells established with shRNA were subjected to the anti-tumor analyses, western blotting, RT-PCR, and zymography. For in vivo study, chondrosarcoma cells were subcutaneously inoculated into nude mice. Zaltoprofen was administered to mice (30 mg/kg/day). Tumors were pathologically assessed. We obtained tumor tissue specimens from a patient who underwent several surgeries for recurrent spinal chondrosarcoma. The patient was administered zaltoprofen as a therapeutic agent for algia the tumor remained stable for more than 2 years. Pathological analyses were performed on the specimen before and after administration of zaltoprofen). Results: Zaltoprofen significantly increased PPARg activation (EC50 47.3 uM). Treatment with 200–400 uM zaltoprofen significantly inhibited cell viability and induced PPARγ protein and mRNA expression in chondrosarcoma cells. Zaltoprofen (400 uM) significantly decreased the cell proliferation, migration, invasion, and MMP2 expression in control cells, whereas these were significantly increased in PPARγ-silencing cells. Also, zaltoprofen (400 uM) induced p21, p27, and p53 expression in control cells, whereas these effects were canceled in PPARg-silencing cells. Upregulation of KROX20 followed by CEBP-α and –β, all of which were reported to induce PPARγ in normal adipose tissue, were detected after zaltoprofen administration. Tumor growth was significantly inhibited in mice administered zaltoprofen. Apoptotic indices in the TUNEL-labeled area were significantly larger and Ki-67 positive cells were significantly lower in tumor specimens from mice administered zaltoprofen. Patient’s specimens revealed that PPARγ expression was stronger and MMP2 expression was weaker in post-administration specimens. Conclusions: Zaltoprofen suppressed tumor progression by inhibiting cell proliferation, migration, and invasion with induction of PPARγ expression in chondrosarcoma cells. The suppressing effect on tumor progression by zaltoprofen was also observed in vivo. Zaltoprofen induced PPARγ expression and MMP2 downregulation in clinical specimens with expected antitumor effects. This is the first study demonstrating that one of the NSAIDs, zaltoprofen, may act as an antitumor agent by targeting PPARγ for chondrosarcoma.
Potential for boron neutron capture therapy (BNCT) with ASCT2-targeted boron agents.
Authors: Eza Kenichiro , Tsujino Kohei , Kawabata Shinji , Fujikawa Yoshiki , Kashiwagi Hideki , Hutamura Gen , Hiramastu Ryo , Miyatake Sinichi , Tanaka Hiroki , Suzuki Minoru , Wanibuchi Masahiko , Nakamura Hiroyuki , Araki Tomoyuki , Morita Taiki
Published: August 2024

233

Background: Boron Neutron Capture Therapy (BNCT) is a cutting-edge particle irradiation technique that utilizes the nuclear reaction triggered by the irradiation of non-radioactive boron-10 with thermal neutrons, selectively annihilating tumor cells that have incorporated boron. In the clinical arena, Boronophenylalanine (BPA), a phenylalanine compound targeting amino acid receptors, has been the cornerstone of BNCT. While BNCT has been effective against malignant gliomas, its dependency on BPA uptake has illuminated the existence of inherent resistance within specific cells, tissues, and cancer types. This study pivots towards the Alanine-serine-cysteine transporter 2 (ASCT2)—a transporter distinct from LAT1—investigating its potential as a gateway for the development of innovative boron carriers, with the aim of expanding the clinical applicability and effectiveness of BNCT. Methods: This research embarked on in vitro investigations to evaluate boron accumulation in F98 and C6 rat glioma cells, and 9L rat gliosarcoma, following 24 hours of exposure to BPA and GluB-2 (10 μg B/ml each). Complementary in vivo studies involved the intravenous administration of these compounds to an F98 rat brain tumor model, with the subsequent measurement of boron distribution at 2.5, 6, and 24 hours post-administration. The efficacy of these treatments was then ascertained through neutron irradiation experiments, gauging therapeutic outcomes via the survival periods of the subjects. Results: In vitro findings highlighted that GluB-2 facilitated a significantly higher intracellular boron concentration compared to BPA in F98 cells (p=0.02, Student's t-test). In vivo results indicated that the apex of boron biodistribution in tumors was achieved at 2.5 hours post-BPA treatment and at 6 hours post-GluB-2 treatment, with GluB-2 securing a superior maximum intratumor boron concentration. Survival analysis revealed a mean survival of 28.0±2.5 days for the neutron alone group, 37.7±5.0 days for the group receiving BPA IV + BNCT at 2.5 hours, 55.1±19.9 days for the group treated with GluB-2 IV + BNCT at 6 hours, and 25.3±1.4 days for the untreated group. Remarkably, the group treated with GluB-2 demonstrated significantly prolonged survival compared to the BPA-treated group (p<0.001, log-rank test). Conclusions: Combining BNCT with GluB-2 showed superior efficacy over BPA. Further research is needed to optimize boron concentration timing and ASCT2 expression levels, yet GluB-2 presents a promising advancement in BNCT, potentially transforming malignant brain tumor treatment.
Exploratory study of PD-1 inhibitors for recurrent meningioma.
Authors: Wang Yali , Chen Feng , Wu Zhen , Li Wenbin
Published: August 2024

26

Background: Meningiomas are the most common primary intracranial tumor. Some patients still have poorly controlled conditions after multiple surgeries and radiotherapies. More effective treatment methods are urgently needed. Previous studies have suggested that meningioma may shape an inhibitory tumor immune microenvironment and achieve immune escape by expressing programmed cell death ligand 1 (PD-L1) and other factors. Immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors have shown promising efficacy in cases, but large-sample studies are needed to confirm these findings. Methods: Recurrent meningioma patients were included and treated with PD-1 inhibitors until tumor progression or intolerance occurred. The efficacy evaluation of enrolled patients used the Response Assessment in Neuro-Oncology (RANO) criteria. The primary endpoint was progression-free survival at 6 months (PFS-6), and secondary endpoints were progression-free survival at 12 months (PFS-12) and overall survival (OS). Adverse events were also recorded. Regular imaging follow-ups were conducted, and clinical characteristics were collected for survival analysis. Peripheral blood lymphocyte subsets and cytokines were detected before and after treatment, and tumor paraffin sections were used for immunohistochemical detection of relevant molecular markers. Results: A total of 35 recurrent meningioma patients (10 grade I, 14 grade II, 11 grade III) were included. Among all grades of patients, the median PFS was 9 months, PFS-6 was 63.6%, and PFS-12 was 47.6%. In grade I patients, the median PFS was 14 months, PFS-6 was 83%, and PFS-12 was 67%. In grade II/III patients, the median PFS was 9 months, PFS-6 was 58.9%, and PFS-12 was 42%. Among all grades of meningioma patients, PFS was significantly correlated with Ki-67 index (P = 0.021) and tumor progression times (P = 0.019). In grade II/III meningioma patients, PFS was only correlated with tumor progression times (P = 0.012). Twenty-five patients had stable disease, and seven patients had disease progression, with no patient achieving partial or complete remission. There was no significant correlation between tumor mutation burden (TMB) and PFS. Further immunohistochemical analysis of tumor tissues in three recurrent high-grade patients revealed varying degrees of increase in local CD3+, CD4+, CD8+ and PD-1+ T lymphocytes after treatment compared to baseline. Conclusions: Our study suggests that PD-1 inhibitors may prolong PFS in recurrent meningioma patients (especially high-grade) with good drug safety, warranting further exploration. Recurrent meningiomas have an immunosuppressive tumor microenvironment, and PD-1 inhibitors may improve the immune status of tumor microenvironments. Clinical trial information: NCT04728568 .
In-hospital outcome of central nervous system malignancy with COVID-19 infection: Analysis from National Inpatient Sample (NIS).
Authors: Suenghataiphorn Thanathip , Wattanachayakul Phuuwadith , Srikulmontri Thitiphan , Saowapa Sakditad , Buasri Kochakorn , Kulthamrongsri Narathorn
Published: August 2024

29

Background: Previous research highlights central nervous system (CNS) malignancy as significant contributors to disability-adjusted life-years. However, there's a lack of information on the impact of COVID-19 infection in hospitalized CNS malignancy patients. Methods: Using the 2020 U.S. National Inpatient Sample (NIS), we investigated the impact of COVID-19 infection affected patients primarily hospitalized for CNS malignancy. We calculated adjusted odds ratios (aORs) for specific outcomes using multivariable logistic and linear regression analyses. The primary outcome was inpatient mortality, with secondary outcomes including system-based complications. Results: We identified 37,385 patients diagnosed with CNS malignancy, averaging 53.6 years old, with 57.76% being female. Among them, 0.84% (315/37,385) were also diagnosed with COVID-19. After adjusting for patient and hospital factors, COVID-19 infection was linked to higher in-hospital mortality (aOR 4.12, 95% CI: 1.55, 10.89, p = 0.004), longer stays (Beta-coefficient 6.06, 95% CI: 2.97, 9.14, p < 0.001), increased total hospital costs (Beta-coefficient 11,855, 95% CI: 1,410, 22,301, p = 0.026), elevated risks of shock (aOR 3.96, 95% CI 1.03, 15.10, p = 0.018), acute respiratory failure (aOR 4.33, 95% CI: 1.83, 10.22, p = 0.001), and sepsis (aOR 3.96, 95% CI: 1.03, 15.10, p = 0.044). Conclusions: Our study reveals that COVID-19 infection is associated with higher in-hospital mortality and multiple adverse outcomes in patients hospitalized for CNS malignancy. Further longitudinal studies are necessary to thoroughly investigate the causality of these clinical outcomes in this population.
An artificial intelligence system for early prediction of breast cancer regression pattern during neoadjuvant chemotherapy.
Authors: Huang Yuhong , Zhu Teng , Wang Kun
Published: August 2024

3

Background: Breast cancer exhibits diverse tumor regression patterns (TRP) following neoadjuvant chemotherapy (NAC). We aims to develop an artificial intelligence (AI) system utilizing longitudinal magnetic resonance imaging (MRI) for precise TRP prediction. Methods: This retrospective study involved 2249 breast cancer patients from 12 institutions. The dataset comprised a training cohort (n=1006) from institutions I and II, and an external validation cohort (n=1243) from institutions III-XII. We utilized a 3D U-Net model for automated tumor delineation, incorporating spatial habitat analysis and 3D ResNet-50 model for extracting imaging featur, to develop an AI system. Results: The 3D U-Net model showed significant accuracy, with Dice coefficients of 0.875 in the validation cohort. The AI system achieved areas under the curve of 0.912. It demonstrated robust performance across diverse molecular subtypes (accuracies: 80·68% to 87·87%) and tumor stages (accuracies: 80·16% to 84·98%) in the validation cohorts. Conclusions: Our study provides a noninvasive AI system for early TRP prediction in breast cancer, potentially assisting clinicians in adjusting NAC regimens and planning breast-conserving surgery.
Reduced cardiovascular disease risk after gastrectomy for gastric cancer: Unexpected treatment benefits.
Authors: Kwon Yeongkeun , Kim Dohyang
Published: August 2024

51

Background: The relationship between gastrectomy for gastric cancer and subsequent cardiovascular risk modifications has been noted, yet the direct consequences of such surgeries on cardiovascular incidences are not fully established. This study evaluated cardiovascular event rates among patients who received gastrectomy versus a matched general cohort. Methods: In a nationwide retrospective cohort analysis, we examined individuals diagnosed with gastric cancer who underwent gastrectomy (n=18,698), and a control group matched for demographics (n=81,787) from 2004 to 2008. Criteria for inclusion were patients devoid of any previous cancer diagnosis (except gastric cancer), myocardial infarction, or ischemic stroke. The primary outcome was the incidence of major adverse cardiovascular events (MACE) such as acute myocardial infarction (MI) or acute ischemic stroke, in patients with gastric cancer. Results: Within a seven-year observational window, 2.7% of the gastrectomy group (or 4.29 events per 1000 person-years) experienced new MAC). The gastrectomy group showed a significantly lower incidence rate of MACE compared to the matched control subjects (hazard ratio [HR] 0.65; 95% confidence interval [CI] 0.63–0.71; P<0.001), MI (HR, 0.68; 95% CI, 0.60–0.78; P < 0.001), and stroke (HR, 0.73; 95% CI, 0.66–0.79; P<0.001). In the subgroup analyses, no significant interactions were identified between the study groups and baseline variables. Conclusions: The study indicates a decreased risk of developing cardiovascular diseases post-gastrectomy for gastric cancer, as opposed to the general population. Beyond their significance for public health strategies aimed at cardiovascular risk management in gastric cancer patients, these findings empower both patients and healthcare providers with enhanced knowledge for making decisions about gastric cancer surgical options. Furthermore, this study lays the groundwork for future investigations into the metabolic effects of gastric cancer surgeries, notably their potential in lowering cardiovascular risk.
Deciphering the prognostic value of FGFR2b/2c isoform expression levels in advanced esophagogastric cancer through whole-transcriptome sequencing.
Authors: Hashimoto Tadayoshi , Iida Naoko , Nakamura Yoshiaki , Mishima Saori , Kotani Daisuke , Kawazoe Akihito , Nakayama Izuma , Kuboki Yasutoshi , Shibuki Taro , Imai Mitsuho , Fujisawa Takao , Bando Hideaki , Yoshino Takayuki , Shitara Kohei
Published: August 2024

53

Background: Fibroblast growth factor receptor (FGFR) isoform switching from FGFR2b to FGFR2c has been implicated in epithelial-to-mesenchymal transition and enhanced invasive potential in various malignancies and potentially be involved in resistance mechanisms to FGFR2b targeted therapy (e.g., bemarituzumab). This study sought to investigate the potential of respective FGFR2 isoform expression evaluation utilizing whole-transcriptome sequencing (WTS) and its correlation with therapeutic efficacy and clinical outcomes in patients with advanced G/GEJ cancer. Methods: Patients with advanced G/GEJ cancer who received systemic therapy at the National Cancer Center Hospital East between May 2021 and September 2023, and were enrolled in the immunological profiling study (UMIN000019129) and MONSTAR-SCREEN-2 (UMIN000043899) were included. FGFR2 protein and RNA expression were assessed via immunohistochemistry (IHC) and WTS with Caris MI Profile, respectively. FGFR2b and FGFR2c isoforms were distinguished by the detection of their respective splice junctions using WTS data. The FGFR2b/(2b+2c) ratio was stratified into FGFR2b-dominat and -containing subtypes using the median value. The log-rank test was used to discern differences in overall survival (OS). Results: Among the 129 patients, 21 (16.3%) exhibited FGFR2-positivity by IHC (staining intensity 2+ or 3+≥1% membranous staining of tumor cells), and a significant correlation was observed between FGFR2 IHC status and RNA expression levels (TPM: transcript per million) in WTS (FGFR2-positive, median TPM=11.1; FGFR2-negative, median TPM=4.7; P=0.002). The distribution of FGFR2b/(2b+2c) ratio (median, 0.89) was: 10.9% (0≤x<0.2), 5.4% (0.2≤x<0.4), 7.0% (0.4≤x<0.6), 12.4% (0.6≤x<0.8), 43.4% (0.8≤x<1.0), and 20.9% (x=1.0). Among 58 patients treated with 1st line therapy, no significant difference in treatment response was observed between the FGFR2b-dominat (67.9%) and FGFR2c-containing subtypes (53.3%) (P=0.259). Overall, the FGFR2c-containing subtype was associated with significantly shorter OS compared to the FGFR2b-dominat subtype (median OS, 10.1 vs. 17.9 months; hazard ratio, 1.72; 95% confidence interval, 1.03-2.86; log-rank P=0.037). Conclusions: Our findings underscore the substantial concordance between IHC and WTS analysis of FGFR2, the feasibility of distinguishing FGFR2 isoforms using WTS, and the prognostic implications of FGFR2c isoform in patients with advanced G/GEJ cancer. Further analysis is warranted in patients receiving FGFR2b targeted treatment.
Effect of deconvoluting single-cell transcriptomics on cellular programs regulated by cell-cell communication in colorectal cancer.
Authors: Chen Lujia , Zhang Han , Lu Binfeng , Cooper Gregory F. , Saeed Anwaar , Lu Xinghua
Published: August 2024

59

Background: Colorectal cancer (CRC) is the 3rd most common cancer. The consensus molecular subtypes among CRC tumors reflects the heterogeneity of composition and functional states of cells in the tumor microenvironments (TME), which in turn may underlie diverse behaviors of disease progression and responses to anticancer treatments. Cells within a TME communicate through intricate cell-cell communication (CCC) networks. The altered state of one cell can influence the states of other cells through ligand-receptor-mediated signal transduction. Gaining insight into the cellular states of cells and understanding their complex communications in a TME is vital for uncovering the heterogeneous mechanisms governing tumor growth, immune evasion, and therapy resistance. Methods: In this meta-analysis of eight single-cell cohorts encompassing 153 patients and 279 samples with more than 600,000 cells, we advance the understanding of CCC networks in CRC through a novel analytical framework. Employing hierarchical language modeling, we identify gene expression modules (GEMs) that mirror single-cell signaling states, crucial for deciphering the complexity of intercellular interactions. By applying causal discovery methods, we systematically uncover GEMs likely regulated by ligand-receptor signaling and cross-cell-type communication. We further validate the discovered CCC using spatial transcriptomic data by testing the spatial co-localization. Results: This analysis reveals nine cross-cell-type CCC programs, marked by highly correlated GEMs across various cell types, shedding light on the intricate CCC networks within the TME. The discovered CCC programs include malignant program, proliferation program, stromal interactions, stromal-myeloid interactions, innate immunity interactions, regulatory interactions, epithelial-lymphocyte interactions and exhaustion program. Each program is composed of GEMs from various cell types. Spatial transcriptomics further validate these findings by demonstrating the co-localization of GEMs within CCC programs in distinct spatial domains, emphasizing the spatial dynamics of tumor intercellular communication. We successfully construct the CCC subnetworks connected by ligand-receptor signaling. Our interactive website and analytical framework equip researchers with powerful tools to explore complex mechanisms, potentially uncovering novel drug targets and refining strategies for precision immunotherapies. Conclusions: This study provides an in-depth analysis of colorectal cancer by: 1) Cataloging GEMs that precisely depict the transcriptomic processes unique to individual cell clusters or shared among multiple cell clusters. 2) Presenting the CCC networks driven by ligand-receptor interactions within the TME supported by both single-cell RNA-seq data and spatial transcriptomic data.
Predicting chemotherapy response in patients with advanced or metastatic pancreatic cancer using machine learning.
Authors: Kim Moonho , Choi Gyucheol , Koo Jamin
Published: August 2024

60

Background: When determining the initial chemotherapy regimen for advanced or metastatic pancreatic cancer, various factors must be evaluated. The decision between FOLFIRINOX and Gemcitabine/Nab-paclitaxel (GnP) is challenging, as patient survival hinges on the efficacy and toxicity profiles of these treatments, alongside individual patient characteristics and vulnerabilities.This study aims to guide the selection of an appropriate first-line chemotherapy regimen for advanced or metastatic pancreatic cancer by leveraging machine learning (ML) methods to predict survival outcomes. Methods: We conducted a retrospective analysis involving a cohort of 151 patients who underwent systemic chemotherapy for advanced or metastatic pancreatic cancer at Gangneung Asan Hospital in South Korea between 2019 and 2023. The initial data consisted of 17 types of demographic and clinical characteristics, as well as time-course of response and survival outcomes. The ML models predicting overall survival (OS) were developed using the XGBoost method. The minimal set of covariates resulting in the highest predictive performance during 5-fold cross validation were chosen as inputs to each model. Results: The median age of the patients was 66 years, with 62.3% being male. The ML models achieved the ROC-AUC of 0.81 when predicting OS after 12 months following the initial administration of FOLFIRINOX (n=61) or GnP (n=47). Five (peritoneal metastases, other metastases, bilirubin level, white blood cell counts, and retroperitoneal lymph node metastases) or four (age, tumor location, sex, and metastatic status) covariates were used to achieve the predictive accuracy for the two regimens, respectively. The median OS of the high versus low risk groups of FOLFIRINOX predicted by the ML models were significantly different (7 vs 18 months, P < 0.01), recording the hazard ratio (HR) of 2.79 (95% CI, 1.47-5.26). Similarly, the median OS of the high and low risk groups of GnP were significantly different (8 vs 16 months, P < 0.001, HR 3.50, 95% CI, 1.60-7.66). Conclusions: We developed the ML models that can compute the probability of OS based on the routinely collected data from patients with advanced or metastatic pancreatic cancer. To the best of our knowledge, this is the first ML solution aimed at aiding clinicians in the selection of the first-line chemotherapy regimen for pancreatic cancer.
The dynamic changes of circulating myeloid-derived suppressor cells (MDSCs) subsets in patients with colorectal cancer undergoing oxaliplatin-based chemotherapy.
Authors: Fauza Dilafitria , Manuel RALPH G , Sudoyo Aru Wisaksono , Steven Ricci , Gultom Fajar Lamhot , Basir Ibrahim , Kurniawan Dicky , Budiyati Akterono Dwi
Published: August 2024

62

Background: Increased level of circulating myeloid-derived suppressor cells (MDSCs) have been associated with higher tumor stage, poorer survival, and poorer response to therapeutic agents in colorectal cancer (CRC). It has been reported that the common first-line chemotherapy involving combination with oxaliplatin mediated MDSCs depletion via induction of cell death. However, this phenomenon is yet to be further investigated since it only occurred in polymophonuclear MDSC (PMN-MDSC) subset, not in monocytic MDSC (M-MDSC). The present study aims to learn deeper on the dynamic changes of circulating MDSCs in response to oxaliplatin-based treatment in CRC patients. Methods: This was a prospective study that recruited 30 treatment-naïve patients with varying stage of CRC who were scheduled to receive oxaliplatin-based chemotherapy. Blood sampling was conducted prior and at several time points during and after chemotherapy. Multicolor flow cytometry assay was used to analyze the proportion of HLA-DR-, CD33+, and CD15+ (PMN-MDSC) and CD14+ (M-MDSC) cells within peripheral blood mononuclear cells (PBMCs). Other essential tumor biomarkers such as carcinoembryonic antigen (CEA) and tumor infiltrating lymphocytes (TILs) were assessed as well. As control, 14 healthy subjects were recruited. Results: Our result showed that circulating PMN-MDSCs was significantly higher in CRC patients compared to healthy subjects (p=0.003), whilst insignificant result was shown by M-MDSCs (p=0.890). Following chemotherapy, MDSCs level showed dynamic changes. Interestingly, a subgroup of CRC patients with decreased in both PMN- and M-MDSCs levels on D-14 chemotherapy were consistently showed a significant decreased of MDSCs level during and after therapy completion compared to baseline (p=0.0078). Conclusions: Circulating MDSCs level, particularly PMN-MDSCs in CRC patients was significantly higher compared to healthy subjects. Changes in both circulating PMN- and M-MDSCs levels at D-14 chemotherapy might have prognostic value in oxaliplatin-based chemotherapy.
i-Biomarker CaDx: A circulating miRNA-based multi-cancer detection test with generative and explainable AI for colorectal cancer.
Authors: Floares Alexandru , Sarghie Larisa , Zety Adrian Vasile , Androutsos Lampros , Oliveira Rafael , Calin George , Floares Carmen , Manolache Florin
Published: August 2024

64

Background: Colorectal cancer (CRC), the second most deadly cancer, underscores the critical need for early detection to significantly improve treatment outcomes and survival rates. Colonoscopy, flexible sigmoidoscopy, and the fecal immunochemical tests (FIT), often fail to capture early disease, significantly decreasing the survival chance. Circulating miRNA is a promising non-invasive biomarker for various cancers, including CRC. The i-Biomarker CaDx (patent pending) is an innovative multi-cancer early detection and diagnosis platform, covering 32 cancer types with an impressive accuracy rate of 99-100%. This study focuses on the effectiveness of i-Biomarker CaDx for CRC, employing significant data collection and leveraging insights from Generative AI (GenAI) and Explainable Artificial Intelligence (XAI). Methods: We collected various available datasets (e.g. GSE106817, etc.) encompassing 305 colorectal cancer patients and a matching number of healthy controls. Microarray was employed to profile circulating miRNAs. We used various classification paradigms, e.g., decision trees, neural networks, etc. Hyperparameter optimization was conducted, and the best-performing classifiers were amalgamated in the final model, weighted by their respective efficacies. We assessed i-Biomarker CaDx's performance through cross-validation and independent test sets. The XAI provided detailed insights into miRNA variations associated with personalized diagnostic. GenAI integrated the test into the screening and early detection best practice workflows and performs Functional Analysis. Results: i-Biomarker CaDx shows exceptional diagnostic accuracy of 99-100%, surpassing conventional colorectal cancer diagnostic methods like colonoscopy, flexible sigmoidoscopy, and FIT. It can also be used for personalized treatment response monitoring. I-Biomarker effectively deciphers intricate miRNA relationships relevant to colorectal cancer using XAI. Thus, our analyses shed light on miRNA patterns and their associations with colorectal cancer, enhancing the understanding of the underlying molecular complexities of the disease. It goes further by explaining the personalized cellular and molecular mechanisms involved, and it will be integrated into the corresponding medical workflows. Conclusions: Our AI-powered multi-cancer early diagnostic platform demonstrates outstanding performance in detecting CRC, surpassing traditional diagnostic methods like colonoscopy, flexible sigmoidoscopy, and FIT. XAI allows for in-depth exploration of miRNA alterations and their impact on CRC, enriching our interpretations at both the population and individual levels. These findings underscore the substantial potential of i-Biomarker CaDx as a transformative, non-invasive diagnostic tool for CRC.
Perioperative FLOT + immunotherapy for resectable gastric and gastroesophageal junction cancer: A systematic review and meta-analysis.
Authors: Revillas Lorenz Fort Estrada , Lalusis John Kelvin , Dy Carlos
Published: August 2024

66

Background: The current standard of care for resectable gastric and GEJ cancers is perioperative chemotherapy with FLOT.Although its benefits in improving rates of pathologic complete response, increasing prospects of R0 resection, and improving survival have been proven, efforts to find novel strategies which can improve on its gains continue.The addition of an immune checkpoint inhibitor to FLOT has been a focal point of research in this field. This meta-analysis evaluated high-quality data from clinical trials to determine the efficacy of this chemoimmunotherapy combination. Methods: A systematic search of English-language articles on PubMed, Cochrane and Google scholar was done to identify randomized trials investigating the use of perioperative FLOT and immune checkpoint inhibitors in the treatment of resectable gastric and GEJ cancer. Quality of studies was assessed using the Revised Cochrane risk-of-bias tool for randomized trials. Inverse variance was the statistical method used with random effects as the analysis model in the production of the Forest plot and calculation of odds ratio at 95% CI. Results: Three RCTs (N = 1446), each with two arms, were included in the meta-analysis. The Phase II Dante Trial (N= 295)compared perioperative FLOT alone with perioperative atezolizumab + FLOT. The Phase III Keynote 585 trial(N=203) and the phase III Matterhorn trial (N=948) compared perioperative placebo + FLOT with perioperative pembrolizumab + FLOT, and perioperative Durvalumab + FLOT, respectively. Risk of bias and heterogeneity were low. Pooled results showed that in patients given perioperative FLOT + immunotherapy, there is statistically significant improvement in the rate of pathologic complete response (OR 2.60 95% CI 1.88-3.61, p <0.0001). In terms of rate of R0 resection, there was no statistically significant difference between the two groups (OR 1.02 95% CI 0.75-1.38,p= 0.92). Conclusions: This analysis shows that adding immunotherapy to FLOT improves the rate of pathologic complete response, and maintains the high rate of R0 resection, in resectable gastric and GEJ cancers. Favorable results of pending survival outcomes from these trials may help re-shape the current standard of care in this field.
Multimodal analysis of methylation and fragmentomic profiles in plasma cell free DNA for differentiation of benign and malignant breast tumors.
Authors: Van Thi Tuong Vi , Nguyen Hanh Thi-Hue , Nguyen Thien-Chi Van Van , Vo Dac Ho , Tran Trung Hieu , Nguyen Trong Hieu , Doan Nhu Nhat Tan , Huynh Le Anh Khoa , Nguyen Xuan Vinh , Giang Hoa , Phan Minh-Duy , Nguyen Hoai Nghia , Tran Le Son
Published: August 2024

7

Background: Breast cancer ranks as the second leading cause of cancer-related mortality among women globally. Early detection of breast cancer is crucial for improving patient outcomes and reducing mortality rates. Liquid biopsy, which relies on circulating tumor DNA (ctDNA) shed by breast tumors into the bloodstream, presents a promising non-invasive approach for early breast cancer detection. However, accurately distinguishing between benign breast abnormalities and malignant tumors remains a significant clinical challenge, as misdiagnosis can lead to unnecessary invasive procedures. Methods: Herein, we employed a multimodal analysis approach, namely SPOT-MAS (Screen for the Presence of Tumor by DNA Methylation and Size), to profile alterations in methylation and fragment length patterns of cell-free DNA (cfDNA) from 169 breast cancer-confirmed patients and 99 patients diagnosed with benign breast lumps including cysts, fibroadenomas, and fibrocystic changes. A robust machine learning model was constructed using these signatures to differentiate between breast cancer patients and individuals with benign lesions. Results: Our genome-wide analyses identified distinct profiles of methylation changes, copy number alterations, and end motifs in cfDNA, enabling discrimination between breast cancer patients and individuals with benign conditions. Notably, we observed a significant enrichment of Thymine and Adenine at cfDNA cleavage sites in breast cancer patients. Moreover, our target sequencing analyses uncovered distinct methylation patterns in the regulatory regions of multiple genes, including hypermethylation in GPR126 or hypomethylation in TOP1 or MAFB in breast cancer cfDNA. Our multi-featured model achieved an AUC of 0.92 (95% CI: 0.88–0.97), a specificity of 97.44% and sensitivities of 57.14% and 61.70% for stage I and stage II–III patients, respectively. Furthermore, our multimodal assay effectively differentiated multiple molecular subtypes of breast tumors from benign lesions, achieving the highest sensitivity of 71.43% with Luminal A, followed by Luminal B, Triple Negative Breast Cancer (TNBC), Luminal B-HER2, and HER2 with sensitivities of 66.67%, 60%, 58.33% and 55.56%, respectively. Conclusions: Our findings demonstrate the potential of cancer-specific methylation and fragmentomic patterns in plasma cfDNA as novel biomarkers for accurately discriminating between breast cancer and benign lesions. This capability reduces the false-positive rate and helps avoid unnecessary biopsies in current clinical practice.
Clinical characteristics and outcomes in patients with early-onset locally advanced rectal cancer.
Authors: Pretta Andrea , Ziranu Pina , Giampieri Riccardo , Donisi Clelia , Randon Giovanni , Moledda Giusy , Morano Federica , Spanu Dario , Cadoni Andrea , Cimbro Erika , Dell'Utri Veronica , Rizzo Daiana , Codipietro Claudia , Semonella Francesca , Puzzoni Marco , Pusceddu Valeria , Zorcolo Luigi , Berardi Rossana , Pietrantonio Filippo , Scartozzi Mario
Published: August 2024

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Background: Despite a reduction in both the incidence and mortality of CRC in the elderly population, recent studies have highlighted an increase in the incidence of early-onset CRC (EO-CRC). Clinical and prognostic data in this context are limited and conflicting. The aim of our study was to evaluate the clinical differences and outcomes of patients with early onset locally advanced rectal cancer. Methods: We retrospectively collected data from 305 patients affected by LARC treated in Italy at the Medical Oncology Units of the University Hospital of Cagliari, Istituto Nazionale dei Tumori Milan, and AOU Ospedali Riuniti Ancona. All patients underwent neoadjuvant chemoradiotherapy. The primary objective was overall survival (OS) while while secondary objectives were overall response rate (ORR) and major TRG. Results: Twenty five (8,2%) pts were EO-RC and 280 (91,8%) were LO-RC. In EO-RC the locations were distributed as follows: 9 (36%) lower rectum, 13 (52%) medium rectum, and 3 (12%) upper rectum. Pathologic responses were as follows: 3 (12%) TRG-0, 6 (24%) TRG-1, 10 (40%) TRG-2, and 6 (24%) TRG-3. While the radiological responses were as follows: 2 (8%) CR, 15 (60%) PR, 7 (28%) SD, and 1 (4%) PD. In LO-RC the locations were: 78 (27,8%) lower rectum, 153 (54,6%) medium rectum, and 49 (17,6%) upper rectum. Pathologic responses were as follows: 29 (10,4%) TRG-0, 60 (21,4%) TRG-1, 159 (56,8%) TRG-2, and 32 (11,4%) TRG-3. Radiological responses were as follows: 25 (8,9%) CR, 155 (61,4%) PR, 64 (22,9%) SD, and 19 (6,8%) PD. The 10 year overall survival was significantly higher in LO-RC patients compared to EO-CRC patients: 92.54% versus 70.83% (p = 0.0005). Conclusions: Compared to LO-RCs, EO-RC patients had more frequent low rectal tumors and higher rates of major pathological responses. Despite this, 10-year OS was found to be inferior in EO-RC. Further studies and insights will be necessary to better understand the biological and clinical characteristics of early-onset tumors.
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

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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

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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

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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

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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.