Impact of alcohol consumption on metabolic dysfunction-associated fatty liver disease development and remission: A longitudinal cohort study.

BACKGROUND: The influence of alcohol intake on metabolic dysfunction-associated fatty liver disease (MAFLD) development and remission remains unclear; thus, we aimed to investigate their longitudinal associations. METHODS: This observational cohort study included 6349 patients who underwent more than two health check-ups over >2 years between April 2013 and March 2021. Generalized estimation equations were used to analyse the longitudinal associations between changes in alcohol intake and MAFLD according to repeated measures at baseline and the most recent stage. RESULTS: The MAFLD development and remission rates were 20.4 and 5.1 and 9.1 and 4.7% in men and women, respectively. Although alcohol consumption was not a significant factor for MAFLD development, consuming 0.1-69.9 g/week (odds ratio [OR]: 0.672, 95% confidence interval [CI]: 0.469-0.964, p < .05) and ≥280 g/week were significant factors for MAFLD development in males (OR: 1.796, 95% CI: 1.009-3.196, p < .05) and females (OR: 16.74, 95% CI: 3.877-72.24, p < .001). Regardless of quantity and frequency, alcohol consumption was not a significant factor for MAFLD remission. Several noninvasive liver fibrosis scores were significantly associated with alcohol intake quantity and frequency in males with MAFLD development and remission (p < .05). The nonalcoholic fatty liver disease fibrosis score differed significantly between males with and without reduced alcohol intake (p < .05) who showed MAFLD remission. CONCLUSIONS: Although the influence of alcohol intake on MAFLD development and remission differed, alcohol consumption was not beneficial for MAFLD remission in either sex. Alcohol intake reduction or cessation is recommended to prevent liver fibrosis, even in those who achieve MAFLD remission.

Gastric fundic gland polyposis and cancer development after eradication of Helicobacter pylori in patient with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS).

A 44-year-old woman with gastric cancer (GC) and fundic gland polyposis (FGPs) was referred to our hospital for further diagnosis and treatment. She successfully underwent eradication therapy for Helicobacter pylori (HP) 6 years ago, but did not exhibit FGPs at that time. When she underwent an esophagogastroduodenoscopy 2, 4, and 5 years after the eradication of HP, her imaging results revealed the existence of FGPs which gradually increased in her gastric fundus and body. Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) was suspected and a mutational analysis was performed, revealing an APC promoter 1B variant c.-191T > C. A robotic total gastrectomy with lymphadenectomy was performed. Histopathological analysis of the surgical specimens revealed GC with no lymph node metastasis. GAPPS is characterized by GC and FGPs. However, our case shows different gastric phenotypes that are dependent on the status of HP infection.

Association of metabolic dysfunction-associated steatotic liver disease with erosive esophagitis development: a longitudinal observational study.

BACKGROUND AND AIM: Although erosive esophagitis (EE) is associated with fatty liver and metabolic dysregulation, the association between EE and metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. Thus, this study aimed to investigate the longitudinal association between MASLD and EE. METHODS: We included 1578 patients without EE at baseline who underwent more than two health checkups over 2 years. Generalized estimation equations were used to analyze associations between MASLD and EE according to repeated measures at baseline and most recent stages. RESULTS: EE development rates in men and women were 14.5% and 7.2%, respectively. After adjusting for lifestyle habits, the odds ratios of MASLD for EE development in men and women were 1.907 (95% confidence interval [CI]: 1.289-2.832, P < 0.005) and 1.483 (95% CI: 0.783-2.811, P = 0.227), respectively. In the subgroup analysis, after adjusting for lifestyle habits, among men and women aged ≥50 years with more than three MASLD components, the odds ratios for EE development were 2.408 (95% CI: 1.505-3.855, P < 0.001) and 2.148 (95% CI: 1.093-4.221, P < 0.05), respectively. After adjusting for various factors, the significant risk factors for EE development were different between men and women. CONCLUSION: The influence of MASLD and other factors on EE development differed by sex and age. Particularly, patients aged ≥50 years with MASLD and with an increased number of MASLD components should be considered at increased risk for EE.

Association of metabolic dysfunction-associated fatty liver disease with gallstone development: A longitudinal study.

BACKGROUND AND AIM: The influence of metabolic dysfunction-associated fatty liver disease on gallstone development remains unclear. We aimed to investigate the longitudinal association between metabolic dysfunction-associated fatty liver disease and gallstone development in both men and women. METHODS: This observational cohort study included 5398 patients without gallstones who underwent > 2 health check-ups between April 1, 2014, and March 31, 2020. A generalized estimation equation model was used to analyze the association between metabolic dysfunction-associated fatty liver disease and gallstone development according to repeated measures at baseline and most recent stage. RESULTS: After adjustment, the odds ratios of metabolic dysfunction-associated fatty liver disease for gallstone development in men and women were 3.019 (95% confidence interval [CI]: 1.901-4.794) and 2.201 (95% CI: 1.321-3.667), respectively. Among patients aged ≥ 50 years, the odds ratio for gallstone development was significantly enhanced with increasing metabolic dysfunction-associated fatty liver disease component numbers in both sexes; however, no significance was observed in those aged < 50 years. Other significant risk factors for gallstone development were age (odds ratio: 1.093, 95% CI: 1.060-1.126) and waist circumference (odds ratio: 1.048, 95% CI: 1.018-1.079) in men and age (odds ratio: 1.035, 95% CI: 1.003-1.067) and current smoking (odd ratio: 5.465, 95% CI: 1.881-15.88) in women. CONCLUSION: Although the risk factors for gallstone development differed between sexes, metabolic dysfunction-associated fatty liver disease was common. Paying attention to an increase in the number of metabolic dysfunction-associated fatty liver disease components in patients aged ≥ 50 years is important for gallstone prevention.

Predictive modeling for the germline pathogenic variant of the APC gene in patients with adenomatous polyposis: proposing a new APC score.

BACKGROUND: The precise diagnosis and medical management of patients with suspected familial adenomatous polyposis should be based on genetic testing, which may not always be available. Therefore, establishing a new model for predicting the likelihood of a germline pathogenic variant (GPV) of APC based on its clinical manifestations could prove to be useful in clinical practice. METHODS: The presence of GPVs of APC gene was investigated in 162 patients with adenomatous polyposis (≥ 10 polyps) using a multigene panel or single-gene testing. To generate a predictive model for GPV of the APC gene, a logistic regression analysis was performed using the clinicopathological variables available at the time of the diagnosis of adenomatous polyposis. RESULTS: Ninety (55.6%) patients had GPV of the APC gene. According to a multivariate logistic regression analysis, age < 40 years, polyps ≥ 100, fundic gland polyposis, and a family history of colorectal polyposis were found to be independent predictors of the GPV of APC and were used to establish a formula for predicting the GPV of APC using the four predictors. The prediction model had an area under the curve of 0.91 (0.86-0.96) according to a receiver operating characteristic analysis. CONCLUSION: The model for predicting the GPV of APC will help patients with adenomatous polyposis and physicians make decisions about genetic testing.

Genotype-phenotype correlation for extracolonic aggressive phenotypes in patients with familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) patients develop various life-threatening extracolonic comorbidities that appear individually or within a family. This diversity can be explained by the localization of the adenomatous polyposis coli (APC) variant, but few reports provide definitive findings about genotype-phenotype correlations. Therefore, we investigated FAP patients and the association between the severe phenotypes and APC variants. Of 247 FAP patients, 126 patients from 85 families identified to have APC germline variant sites were extracted. These sites were divided into six groups (Regions A to F), and the frequency of severe comorbidities was compared among the patient phenotypes. Of the 126 patients, the proportions of patients with desmoid tumor stage ≥III, number of FGPs ≥1000, multiple gastric neoplasms, gastric neoplasm with high-grade dysplasia, and Spigelman stage ≥III were 3%, 16%, 21%, 12%, and 41%, respectively, while the corresponding rates were 30%, 50%, 70%, 50%, and 80% in patients with Region E (codons 1398-1580) variants. These latter rates were significantly higher than those for patients with variants in other regions. Moreover, the proportion of patients with all three indicators (desmoid tumor stage ≥III, number of FGPs ≥1000, and Spigelman stage ≥III) was 20% for those with variants in Region E and 0% for those with variants in other regions. Variants in Region E indicate aggressive phenotypes, and more intensive management is required.

Intensive endoscopic resection for downstaging of polyp burden in patients with familial adenomatous polyposis (J-FAPP Study III): a multicenter prospective interventional study.

BACKGROUND: Total colectomy is the standard treatment for familial adenomatous polyposis (FAP). Recently, an increasing number of young patients with FAP have requested the postponement of surgery or have refused to undergo surgery. We aimed to evaluate the effectiveness of intensive endoscopic removal for downstaging of polyp burden (IDP) in FAP. METHOD: A single-arm intervention study was conducted at 22 facilities. Participants were patients with FAP, aged ≥ 16 years, who had not undergone colectomy or who had undergone colectomy but had ≥ 10 cm of large intestine remaining. For IDP, colorectal polyps of ≥ 10 mm were removed, followed by polyps of ≥ 5 mm. The primary end point was the presence/absence of colectomy during a 5-year intervention period. RESULTS: 222 patients were eligible, of whom 166 had not undergone colectomy, 46 had undergone subtotal colectomy with ileorectal anastomosis, and 10 had undergone partial resection of the large intestine. During the intervention period, five patients (2.3 %, 95 % confidence interval [CI] 0.74 %-5.18 %) underwent colectomy, and three patients died. Completion of the 5-year intervention period without colectomy was confirmed in 150 /166 patients who had not undergone colectomy (90.4 %, 95 %CI 84.8 %-94.4 %) and in 47 /56 patients who had previously undergone colectomy (83.9 %, 95 %CI 71.7 %-92.4 %). CONCLUSION: IDP in patients with mild-to-moderate FAP could have the potential to be a useful means of preventing colorectal cancer without implementing colectomy. However, if the IDP protocol was proposed during a much longer term, it may not preclude the possibility that a large proportion of colectomies may still need to be performed.

Multicenter retrospective study of initial treatment outcome and feasibility of initiating dose reduction of cabozantinib in unresectable hepatocellular carcinoma.

AIM: Cabozantinib (CAB), a multiple kinase inhibitor, has been approved for use in patients with previously treated unresectable hepatocellular carcinoma (uHCC). However, real-world clinical data are lacking, particularly clinical data regarding dose modifications of CAB. We analyzed the clinical outcomes of CAB in uHCC and compared treatment outcomes between the full- and reduced-dose groups. METHODS: This multicenter, observational study included patients with uHCC who were treated with CAB from March 2021 to April 2022. Patient characteristics, efficacy, and safety were compared between the full- and reduced-dose groups. RESULTS: Twenty-six patients from eight institutes were analyzed. Cabozantinib was administered as a third-line or later treatment in 25 (96.2%) patients and postimmunotherapy in 21 (80.5%) patients. There were 15 patients in the full-dose group (60 mg CAB) and 11 in the reduced-dose group (40 or 20 mg CAB). The objective response rate (ORR) and disease control rate (DCR) were not significantly different between the two groups. The ORR was 6.7% for the full-dose group and 9.1% for the reduced-dose group, and the DCR was 53.4% and 81.8%, respectively. Progression-free survival analysis showed no significant differences between the two groups. The incidence of decreased appetite, fatigue, and diarrhea, and the rate of discontinuation and dose reduction, was significantly higher in the full-dose group. CONCLUSIONS: Our study suggests that the efficacy and safety of CAB in real-world clinical practice are comparable to those of the phase III trial (CELESTIAL), and that dose reduction of CAB may be a safer treatment option.

Progression of duodenal neoplasia to advanced adenoma in patients with familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) have a lifetime risk of developing duodenal adenomas approaching 100%, and the relative risk for duodenal cancer compared with the general population is high. We conducted a retrospective study to investigate the progression of non-ampullary duodenal adenomas (NADAs) and risk factors for advanced lesions in patients with FAP. METHODS: Of 248 patients with 139 pedigrees at 2 institutes, we assessed 151 patients with 100 pedigrees with a pathogenic germline variant in the adenomatous polyposis coli gene, excluding mosaic variants. We evaluated the prevalence of NADAs in patients with FAP, the progression of these adenomas to advanced adenoma during the observation period, and the risk factors for the lifetime development of high-grade dysplasia (HGD), large (≥ 10 mm) duodenal adenomas, and Spiegelman stage IV. RESULTS: During the median observation period of 7 years, the incidences of patients with NADAs, with more than 20 polyps, with polyps ≥ 10 mm, with HGD, and with stage IV at the last esophagogastroduodenoscopy were increased 1.6-fold, 1.7-fold, 5-fold, 22-fold, and 9-fold, respectively. Intramucosal cancer occurred in three patients (2%), but no patients developed invasive cancer during the observation period because we performed endoscopic intervention for advanced adenomas. Stage progression was observed in 71% of 113 patients. Stage IV was more common in women, patients with a history of colectomy, and those with a 3' side mutation in their adenomatous polyposis coli gene. CONCLUSIONS: NADAs in patients with FAP frequently become exacerbated. Our findings suggest that patients with FAP who develop duodenal adenomas should be surveyed to prevent the development of duodenal cancer.

A microRNA-based liquid biopsy signature for the early detection of esophageal squamous cell carcinoma: a retrospective, prospective and multicenter study.

BACKGROUND: Currently, there is no clinically relevant non-invasive biomarker for early detection of esophageal squamous cell carcinoma (ESCC). Herein, we established and evaluated a circulating microRNA (miRNA)-based signature for the early detection of ESCC using a systematic genome-wide miRNA expression profiling analysis. METHODS: We performed miRNA candidate discovery using three ESCC tissue miRNA datasets (n = 108, 238, and 216) and the candidate miRNAs were confirmed in tissue specimens (n = 64) by qRT-PCR. Using a serum training cohort (n = 408), we conducted multivariate logistic regression analysis to develop an ESCC circulating miRNA signature and the signature was subsequently validated in two independent retrospective and two prospective cohorts. RESULTS: We identified eighteen initial miRNA candidates from three miRNA expression datasets (n = 108, 238, and 216) and subsequently validated their expression in ESCC tissues. We thereafter confirmed the overexpression of 8 miRNAs (miR-103, miR-106b, miR-151, miR-17, miR-181a, miR-21, miR-25, and miR-93) in serum specimens. Using a serum training cohort, we developed a circulating miRNA signature (AUC:0.83 [95%CI:0.79-0.87]) and the diagnostic performance of the miRNA signature was confirmed in two independent validation cohorts (n = 126, AUC:0.80 [95%CI:0.69-0.91]; and n = 165, AUC:0.89 [95%CI:0.83-0.94]). Finally, we demonstrated the diagnostic performance of the 8-miRNA signature in two prospective cohorts (n = 185, AUC:0.92, [95%CI:0.87-0.96]); and (n = 188, AUC:0.93, [95%CI:0.88-0.97]). Importantly, the 8-miRNA signature was superior to current clinical serological markers in discriminating early stage ESCC patients from healthy controls (p < 0.001). CONCLUSIONS: We have developed a novel and robust circulating miRNA-based signature for early detection of ESCC, which was successfully validated in multiple retrospective and prospective multinational, multicenter cohorts.

Resveratrol inhibits development of colorectal adenoma via suppression of LEF1; comprehensive analysis with connectivity map.

Although many chemopreventive studies on colorectal tumors have been reported, no effective and safe preventive agent is currently available. We searched for candidate preventive compounds against colorectal tumor comprehensively from United States Food and Drug Administration (FDA)-approved compounds by using connectivity map (CMAP) analysis coupled with in vitro screening with colorectal adenoma (CRA) patient-derived organoids (PDOs). We generated CRA-specific gene signatures based on the DNA microarray analysis of CRA and normal epithelial specimens, applied them to CMAP analysis with 1309 FDA-approved compounds, and identified 121 candidate compounds that should cancel the gene signatures. We narrowed them down to 15 compounds, and evaluated their inhibitory effects on the growth of CRA-PDOs in vitro. We finally identified resveratrol, one of the polyphenolic phytochemicals, as a compound showing the strongest inhibitory effect on the growth of CRA-PDOs compared with normal epithelial PDOs. When resveratrol was administered to ApcMin/+ mice at 15 or 30 mg/kg, the number of polyps (adenomas) was significantly reduced in both groups compared with control mice. Similarly, the number of polyps (adenomas) was significantly reduced in azoxymethane-injected rats treated with 10 or 100 mg/resveratrol compared with control rats. Microarray analysis of adenomas from resveratrol-treated rats revealed the highest change (downregulation) in expression of LEF1, a key molecule in the Wnt signaling pathway. Treatment with resveratrol significantly downregulated the Wnt-target gene (MYC) in CRA-PDOs. Our data demonstrated that resveratrol can be the most effective compound for chemoprevention of colorectal tumors, the efficacy of which is mediated through suppression of LEF1 expression in the Wnt signaling pathway.

TIMP1 promotes cell proliferation and invasion capability of right-sided colon cancers via the FAK/Akt signaling pathway.

Although right-sided colorectal cancer (CRC) shows a worse prognosis than left-sided CRC, the underlying mechanism remains unclear. We established patient-derived organoids (PDOs) from left- and right-sided CRCs and directly compared cell proliferation and invasion capability between them. We then analyzed the expression of numerous genes in signal transduction pathways to clarify the mechanism of the differential prognosis. Cell proliferation activity and invasion capability in right-sided cancer PDOs were significantly higher than in left-sided cancer PDOs and normal PDOs, as revealed by Cell Titer Glo and transwell assays, respectively. We then used quantitative RT-PCR to compare 184 genes in 30 pathways among right-sided and left-sided cancer and normal PDOs and found that the TIMP1 mRNA level was highest in right-sided PDOs. TIMP1 protein levels were upregulated in right-sided PDOs compared with normal PDOs but was downregulated in left-sided PDOs. TIMP1 knockdown with shRNA significantly decreased cell proliferation activity and invasion capability in right-sided PDOs but not in left-sided PDOs. Moreover, TIMP1 knockdown significantly decreased pFAK and pAkt expression levels in right-sided PDOs but not in left-sided PDOs. A database analysis of The Cancer Genome Atlas revealed that TIMP1 expression in right-sided CRCs was significantly higher than in left-sided CRCs. Kaplan-Meier survival analysis showed significantly shorter overall survival in high-TIMP1 patients versus low-TIMP1 patients with right-sided CRCs but not left-sided CRCs. Our data suggest that TIMP1 is overexpressed in right-sided CRCs and promotes cell proliferation and invasion capability through the TIMP1/FAK/Akt pathway, leading to a poor prognosis. The TIMP1/FAK/Akt pathway can be a target for therapeutic agents in right-sided CRCs.

miR-144-3p/miR-451a promotes lymphovascular invasion through repression of PTEN/p19 in rectal neuroendocrine tumors.

BACKGROUND AND AIM: Although rectal neuroendocrine tumor (NET-G1) have potential metastatic capability, even among small tumors, no predictive biomarker for invasion and metastasis has been reported. We analyzed microRNA (miRNA) expression profiles in rectal NET-G1 tissues with and without lymphovascular invasion (LVI). Moreover, we then investigated their target genes to clarify the mechanism of invasion/metastasis in NET-G1. METHODS: miRNA array analysis was performed using seven rectal NET-G1 tissues with LVI and seven without LVI. miRNA expression was confirmed by quantitative real-time PCR. A NET cell line H727 was transfected with miRNA mimic or target gene small interfering RNA, and migration and invasion assays were performed. RESULTS: The expression levels of miR-144-3p and miR-451a were significantly higher in NET-G1 with LVI versus without LVI, as determined by miRNA array analysis and RT-qPCR. A significant correlation was observed between miR-144-3p and miR-451a expression levels, strongly suggesting miR144/451 cluster overexpression in NET-G1 with LVI. Bioinformatic analysis of target genes revealed that miR-144-3p and miR-451a directly interact with PTEN and p19 mRNA, respectively. Immunohistochemistry revealed significantly lower expression of PTEN and p19 in NET-G1 tissues with LVI than in those without LVI. The miR-144-3p and miR-451a mimic significantly increased cell migration/invasion capability, respectively. Knockdown of PTEN and p19 induced significant augmentation of cell invasion and migration capability, respectively. CONCLUSIONS: Our data suggest that overexpression of miR-144/miR-451 cluster promotes LVI via repression of PTEN and p19 in rectal NET-G1 cells. miR-144/451 cluster may be a novel biomarker for predicting invasion/metastasis in rectal NET-G1.

Cancer risk and genotype-phenotype correlation in Japanese patients with Cowden syndrome.

BACKGROUND: Cowden syndrome (CS) is an autosomal-dominant hereditary disorder caused by a germline PTEN variant and characterized by multiple hamartomas and a high risk of cancers. However, no detailed data on CS in Asian patients nor genotype-phenotype correlation have been reported. METHODS: We performed the first Japanese nationwide questionnaire survey on CS and obtained questionnaire response data on 49 CS patients. RESULTS: Patients included 26 females (median age 48 years). The incidence of breast, thyroid, endometrium, and colorectal cancer was 32.7%, 12.2%, 19.2% (among females), and 6.1%, respectively. The incidence of any cancers was relatively high among all patients (46.9%, 23/49), and particularly female patients (73.1%, 19/26), compared with previous reports from Western countries. Gastrointestinal (GI) polyps were more frequently found throughout the GI tract compared with previous studies. PTEN variants were detected in 95.6% (22/23) of patients; 12 in the N-terminal region (11 in phosphatase domain) and 10 in the C-terminal (C2 domain) region. The incidence of cancer in the C2 domain group was significantly higher than in the N-terminal region (phosphatase) group. All female patients with C2 domain variant had breast cancer. CONCLUSION: Our data suggest that Japanese patients with CS, particularly female patients and patients with C2 domain variant may have a high risk of cancers.

Implications of glutathione-S transferase P1 in MAPK signaling as a CRAF chaperone: In memory of Dr. Irving Listowsky.

Glutathione-S transferase P1 (GSTP1) is one of the glutathione-S transferase isozymes that belong to a family of phase II metabolic isozymes. The unique feature of GSTP1 compared with other GST isozymes is its relatively high expression in malignant tissues. Thus, clinically, GSTP1 serves as a tumor marker and as a refractory factor against certain types of anticancer drugs through its primary function as a detoxifying enzyme. Additionally, recent studies have identified a chaperone activity of GSTP1 involved in the regulation the function of various intracellular proteins, including factors of the growth signaling pathway. In this review, we will first describe the function of GSTP1 and then extend the details onto its role in the mitogen-activated protein kinase signal pathway, referring to the results of our recent study that proposed a novel autocrine signal loop formed by the CRAF/GSTP1 complex in mutated KRAS and BRAF cancers. Finally, the possibilities of new therapeutic approaches for these cancers by targeting this complex will be discussed.

[Gastric cancer genome profiling reveals HER2 false-negative status and informs a successful trastuzumab treatment strategy].

Intratumoral HER2 heterogeneity is a well-described gastric cancer feature and may explain many false-negative results related to this oncogene. An 81-year-old man was diagnosed at our hospital with stage IV gastric cancer with multiple lymph node metastases. Immunohistochemistry (IHC) analysis indicated that the primary tumor was HER2-negative. After a chemotherapy course, we submitted a pretreatment biopsy specimen for comprehensive cancer genome profiling (CGP) to determine the last-line therapy. This revealed HER2 amplification. The specimen was reevaluated using fluorescence in situ hybridization and IHC with deeper-cut specimens, which confirmed that the tumor was indeed HER2-positive. Therefore, the patient was treated with chemotherapy plus trastuzumab, which elicited tumor shrinkage and conferred long-term survival. Our current data underscore the CGP importance, which can provide more accurate tumor profilings and inform subsequent treatment decisions.

LAMC2 promotes cancer progression and gemcitabine resistance through modulation of EMT and ATP-binding cassette transporters in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis. Gemcitabine remains an effective option for the majority of PDAC patients. Unfortunately, currently no reliable prognostic and predictive biomarkers of therapeutic response are available for the patients with PDAC. Laminin γ2 (LAMC2) is overexpressed in several cancers, and its high expression facilitates cancer development and chemoresistance. However, its functional role in PDAC remains unclear, and a better understanding of this will likely help improve the prognosis of PDAC patients. This study aimed to elucidate the clinical and biological role of LAMC2 in PDAC. We first analyzed the expression levels of LAMC2 by real-time reverse transcription PCR in a cohort of 114 PDAC patients. Interestingly, higher expression of LAMC2 significantly correlated with poor survival in PDAC cohort. In addition, elevated LAMC2 expression served as a potential prognostic marker for survival. Subsequently, functional characterization for the role of LAMC2 in PDAC was performed by small interfering RNA knockdown in pancreatic cancer (PC) cell lines. Interestingly, inhibition of LAMC2 in PC cells enhanced the gemcitabine sensitivity and induction of apoptosis. Moreover, it inhibited colony formation ability, migration and invasion potential. Furthermore, LAMC2 regulated the expression of epithelial-mesenchymal transition (EMT) phenotype. In addition, LAMC2 significantly correlated with genes associated with the expression of ATP-binding cassette (ABC) transporters in PC cells and PDAC patients. In conclusion, these results suggest that LAMC2 regulates gemcitabine sensitivity through EMT and ABC transporters in PDAC and may be a novel therapeutic target in PDAC patients.

Gastric neoplasms in patients with familial adenomatous polyposis: endoscopic and clinicopathologic features.

BACKGROUND AND AIMS: Gastric neoplasms in patients with familial adenomatous polyposis (FAP) occur at a high rate and can cause death. The endoscopic findings of gastric neoplasms in these patients are characteristic but not well recognized. To identify the relevant characteristics to enable early detection, we retrospectively investigated endoscopic findings of gastric neoplasms in patients with FAP and then compared the clinical, histopathologic, and genetic features among subgroups. METHODS: Of 234 patients with 171 pedigrees at 2 institutes, 56 cases (24%, 133 gastric neoplasms) with 44 pedigrees were examined. Immunostaining was performed for histopathologic evaluation by 1 blinded pathologist. According to the endoscopic findings, gastric neoplasms were divided into 4 types based on location (L: antrum and pylorus, UM: the rest of the stomach) and color (W: white, T: translucent, R: reddish) and their clinicopathologic features examined. RESULTS: Of the cases, 93% could be classified into a single type. Among histologic phenotypes, high-grade dysplasia was present in 26% (type L), 41% (type UM-W), 0% (type UM-T), and 22% (type UM-R). The immunologic phenotype comprised the gastric type in 69% (93% in Type UM) and the intestinal phenotype, including the mixed type, in 31% (61% in type L). Moreover, 96% of patients had concurrent duodenal neoplasms. Adenomatous polyposis coli gene status was identified in 93% of patients; the pathogenic variant was detected in 98% but did not influence any endoscopic features. CONCLUSIONS: Gastric neoplasms in patients with FAP were stratified into 4 types according to their endoscopic findings. The endoscopic phenotype was related to the histopathologic phenotype but not to germline variants.

Comparison of therapeutic outcomes of sorafenib and lenvatinib as primary treatments for hepatocellular carcinoma with a focus on molecular-targeted agent sequential therapy: A propensity score-matched analysis.

AIM: The optimal choice between sorafenib (SOR) or lenvatinib (LEN) as the first-line treatment for unresectable hepatocellular carcinoma (u-HCC) remains debatable. Using propensity score matching, this study compares the outcomes of SOR and LEN in the molecular-targeted agent (MTA) sequential treatment of u-HCC patients. METHODS: This retrospective, multicenter, observational study recruited 137 u-HCC patients who underwent primary treatment with LEN (n = 52) or SOR (n = 85) between June 2017 and June 2020 after regorafenib was approved as the secondary treatment for u-HCC. Propensity score matching was used to reduce confounding, resulting in the selection of 104 patients (n = 52 for the SOR and LEN cohorts). RESULTS: The median overall survival was 21.8 months for LEN and 20.4 months for SOR. LEN exhibited significantly greater therapeutic efficacy as compared to SOR (objective response rate: 3.8% [SOR] vs. 42.3% [LEN], p < 0.01; progression-free survival: 10 months [LEN] vs. 5.1 months [SOR], p < 0.01). No significant intergroup differences were noted in the rate of transition to secondary MTA treatments (SOR: 58.7%; LEN: 48.4%), adverse events (SOR: 86%; LEN: 95%), and maintenance of the Child-Pugh (CP) score during treatment. Compared to non-MTA treatments, secondary MTA treatment achieved a greater improvement in survival (4.3  vs. 2.8 months, p = 0.0047). Multivariate analysis demonstrated that the CP score (p < 0.01) and alpha-fetoprotein level (p < 0.01) were independent prognostic factors. CONCLUSIONS: Both SOR and LEN treatments showed a clinically comparable therapeutic efficacy as the first-line treatments for u-HCC patients in an MTA sequential therapy.

Indocyanine green-labeled dasatinib as a new fluorescent probe for molecular imaging of gastrointestinal stromal tumors.

BACKGROUND AND AIM: It is difficult to differentiate gastrointestinal stromal tumors (GISTs) from other subepithelial lesions under gastrointestinal endoscopy. Because most GISTs express tyrosine kinase receptor c-KIT, fluorescence-labeled c-KIT-specific tyrosine kinase inhibitors seem to be useful agents for molecular imaging of GIST. We aimed to develop a near-infrared fluorescent imaging technology for GIST targeting c-KIT using the novel fluorescent probe indocyanine green-labeled dasatinib (ICG-dasatinib) and to investigate the antitumor effect of ICG-dasatinib on GIST cells. METHODS: Indocyanine green-labeled dasatinib was synthesized by labeling linker-induced dasatinib with ICG derivative 3-indocyanine-green-acyl-1,3-thiazolidine-2-thione. Human GIST cell lines GIST-T1 and GIST-882M were incubated with ICG-dasatinib and observed by fluorescent microscopy. GIST cells were incubated with ICG-dasatinib, unlabeled dasatinib, or imatinib, and cell viabilities were evaluated. Subcutaneous GIST model mice or orthotopic GIST model rats were intravenously injected with ICG-dasatinib and observed using an IVIS Spectrum. RESULTS: Strong fluorescent signals of ICG-dasatinib were observed in both GIST cell lines in vitro. IC50 values for ICG-dasatinib, unlabeled dasatinib, and imatinib were 13.9, 1.17, and 16.2 nM in GIST-T1 and 26.6, 3.63, and 47.6 nM in GIST-882M cells, respectively. ICG-dasatinib accumulated in subcutaneous xenografts in mice. Fluorescent signals were also observed in liver and gallbladder, indicating biliary excretion; however, fluorescence intensity of tumors was significantly higher than that of intestine after washing. Strong fluorescent signals were observed in orthotopic xenografts through the covering normal mucosa in rats. CONCLUSIONS: Indocyanine green-labeled dasatinib could visualize GIST cells and xenografted tumors. The antitumor effect of ICG-dasatinib was preserved to the same degree as imatinib.