NgR1 is an NK cell inhibitory receptor that destabilizes the immunological synapse.

The formation of an immunological synapse (IS) is essential for natural killer (NK) cells to eliminate target cells. Despite an advanced understanding of the characteristics of the IS and its formation processes, the mechanisms that regulate its stability via the cytoskeleton are unclear. Here, we show that Nogo receptor 1 (NgR1) has an important function in modulating NK cell-mediated killing by destabilization of IS formation. NgR1 deficiency or blockade resulted in improved tumor control of NK cells by enhancing NK-to-target cell contact stability and regulating F-actin dynamics during IS formation. Patients with tumors expressing abundant NgR1 ligand had poor prognosis despite high levels of NK cell infiltration. Thus, our study identifies NgR1 as an immune checkpoint in IS formation and indicates a potential approach to improve the cytolytic function of NK cells in cancer immunotherapy.

Bintrafusp alfa and chemotherapy as first-line treatment in biliary tract cancer: A randomized phase 2/3 trial.

BACKGROUND AND AIMS: We compared the safety and efficacy of bintrafusp alfa (BA) in combination with gemcitabine+cisplatin (GemCis), to those of GemCis alone, in patients with biliary tract cancer. APPROACH AND RESULTS: This randomized, double-blind, placebo-controlled, adaptive design phase 2/3 trial (NCT04066491) included adults who are treatment-naive with locally advanced/metastatic biliary tract cancer. Patients (N = 297) were randomized to receive an IV infusion of BA (2400 mg once/3 wk) plus GemCis (gemcitabine 1000 mg/m 2 +cisplatin 25 mg/m 2 on days 1 and 8/3 wk; 8 cycles) (BA group, n = 148) or placebo+GemCis (placebo group, n = 149). The primary end point was overall survival (OS). For adaptation analysis (phase 2-phase 3; data cutoff: May 20, 2021), efficacy was assessed in the first 150 patients who were antibiotic-naive when 80 progression-free survival events had occurred and ≥ 19 weeks of follow-up had been completed (BA, n = 73; placebo, n = 77). Median OS (95% CI) for the BA (11.5 mo [9.3-not estimable]) and placebo (11.5 mo [10.0-not estimable]) groups was comparable (hazard ration 1.23 [95% CI 0.66-2.28]; p = 0.7394); OS data maturity was 27.2% (41 events/151 patients). The most common grade ≥3 treatment-related adverse event was anemia (BA, 26.0%; placebo, 22.8%). Bleeding adverse events were reported more frequently in the BA group (28.8%) versus the placebo group (7.4%). Deaths within 60 days of the first dose were reported in 7.5% and 1.3% of patients in the BA and placebo groups, respectively. CONCLUSIONS: BA+GemCis did not provide a clinically meaningful benefit compared with GemCis alone as first-line treatment for biliary tract cancer, and the study was discontinued early (terminated: August 20, 2021).

Genome-wide association study identifies high-impact susceptibility loci for HCC in North America.

BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

FTO negatively regulates the cytotoxic activity of natural killer cells.

N6 -Methyladenosine (m6 A) is the most abundant epitranscriptomic mark and plays a fundamental role in almost every aspect of mRNA metabolism. Although m6 A writers and readers have been widely studied, the roles of m6 A erasers are not well-understood. Here, we investigate the role of FTO, one of the m6 A erasers, in natural killer (NK) cell immunity. We observe that FTO-deficient NK cells are hyperactivated. Fto knockout (Fto-/- ) mouse NK cells prevent melanoma metastasis in vivo, and FTO-deficient human NK cells enhance the antitumor response against leukemia in vitro. We find that FTO negatively regulates IL-2/15-driven JAK/STAT signaling by increasing the mRNA stability of suppressor of cytokine signaling protein (SOCS) family genes. Our results suggest that FTO is an essential modulator of NK cell immunity, providing a new immunotherapeutic strategy for allogeneic NK cell therapies.

Convergent MAPK pathway alterations mediate acquired resistance to FGFR inhibitors in FGFR2 fusion-positive cholangiocarcinoma.

BACKGROUND & AIMS: There is a knowledge gap in understanding mechanisms of resistance to fibroblast growth factor receptor (FGFR) inhibitors (FGFRi) and a need for novel therapeutic strategies to overcome it. We investigated mechanisms of acquired resistance to FGFRi in patients with FGFR2-fusion-positive cholangiocarcinoma (CCA). METHODS: A retrospective analysis of patients who received FGFRi therapy and underwent tumor and/or cell-free DNA analysis, before and after treatment, was performed. Longitudinal circulating tumor DNA samples from a cohort of patients in the phase I trial of futibatinib (NCT02052778) were assessed. FGFR2-BICC1 fusion cell lines were developed and secondary acquired resistance mutations in the mitogen-activated protein kinase (MAPK) pathway were introduced to assess their effect on sensitivity to FGFRi in vitro. RESULTS: On retrospective analysis of 17 patients with repeat sequencing following FGFRi treatment, new FGFR2 mutations were detected in 11 (64.7%) and new alterations in MAPK pathway genes in nine (52.9%) patients, with seven (41.2%) patients developing new alterations in both the FGFR2 and MAPK pathways. In serially collected plasma samples, a patient treated with an irreversible FGFRi tested positive for previously undetected BRAF V600E, NRAS Q61K, NRAS G12C, NRAS G13D and KRAS G12K mutations upon progression. Introduction of a FGFR2-BICC1 fusion into biliary tract cells in vitro sensitized the cells to FGFRi, while concomitant KRAS G12D or BRAF V600E conferred resistance. MEK inhibition was synergistic with FGFRi in vitro. In an in vivo animal model, the combination had antitumor activity in FGFR2 fusions but was not able to overcome KRAS-mediated FGFRi resistance. CONCLUSIONS: These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi. CLINICAL TRIAL NUMBER: NCT02052778. IMPACT AND IMPLICATIONS: We evaluated tumors and plasma from patients who previously received inhibitors of fibroblast growth factor receptor (FGFR), an important receptor that plays a role in cancer cell growth, especially in tumors with abnormalities in this gene, such as FGFR fusions, where the FGFR gene is fused to another gene, leading to activation of cancer cell growth. We found that patients treated with FGFR inhibitors may develop mutations in other genes such as KRAS, and this can confer resistance to FGFR inhibitors. These findings have several implications for patients with FGFR2 fusion-positive tumors and provide mechanistic insight into emerging MAPK pathway alterations which may serve as a therapeutic vulnerability in the setting of acquired resistance to FGFRi.

Δ133p53 coordinates ECM-driven morphogenesis and gene expression in three-dimensional mammary epithelial acini.

Growing evidence indicates that p53 (encoded by TP53) has a crucial role in normal tissue development. The role of the canonical p53 (p53α) and its 12 isoforms in development and homeostasis of healthy tissue remains poorly understood. Here, we demonstrate that the Δ133p53 isoforms, the three short isoforms of p53, respond specifically to laminin-111 and play an important regulatory role in formation of mammary organoids in concert with p53α. We demonstrate that down-modulation of Δ133p53 isoforms leads to changes in gene expression of the extracellular matrix molecules fibronectin (FN), EDA+-FN, laminin α5 and laminin α3 in human breast epithelial cells. These changes resulted in increased actin stress fibers and enhanced migratory behavior of cells in two-dimensional culture. We found that α5ß1-integrin coupled with the extracellularly deposited EDA+-FN activates the Akt signaling pathway in three-dimensional (3D) culture when Δ133p53 is dysregulated. Cells that do not express detectable Δ133p53 isoforms or express low levels of these isoforms failed to form polarized structures in 3D. These results uncover that Δ133p53 isoforms coordinate expression and deposition of organ-specific ECM molecules that are critical for maintenance of tissue architecture and function.

Development of a Novel Comprehensive Hepatocellular Carcinoma Outcome Prognostic Scoring System With Integration of Imaging Features.

BACKGROUND: Accurate prognostic stratification of hepatocellular carcinoma (HCC) is vital for clinical trial enrollment and treatment allocation. Multiple scoring systems have been created to predict patient survival, but no standardized scoring systems account for radiologic tumor features. We sought to create a generalizable scoring system for HCC which incorporates standardized radiologic tumor features and more accurately predicts overall survival (OS) than established systems. METHODS: Clinicopathologic parameters were collected from a prospectively collected cohort of patients with HCC treated at a single institution. Imaging studies were evaluated for tumor characteristics. Patients were randomly divided into a training set for identification of covariates that impacted OS and a validation set. Cox models were used to determine the association of various factors with OS and a scoring system was created. RESULTS: We identified 383 patients with HCC with imaging and survival outcomes, n = 255 in the training set and 128 in the validation cohort. Factors associated with OS on multivariate analysis included: tumor margin appearance on CT or MRI (hazard ratio [HR] 1.37, 95% CI, 1.01-1.88) with infiltrative margins portending worse outcomes than encapsulated margins, massive tumor morphology (HR 1.64, 95% CI, 1.06-2.54); >2 lesions (HR 2.06, 95% CI, 1.46-2.88), Child-Turcotte-Pugh class C (HR 3.7, 95% CI, 2.23-6.16), and portal vein thrombus (HR 2.41, 95% CI, 1.71-3.39). A new scoring system was developed and more predictive of OS than other well-established systems. CONCLUSIONS: Incorporation of standardized imaging characteristics to established clinical and lab predictors of outcome resulted in an improved predictive scoring system for patients with HCC.

Revisiting the Malignant Masquerade at the Liver Hilum: Have We Made Progress?

BACKGROUND: Distinguishing malignant from benign causes of obstruction at the liver hilum can pose a diagnostic dilemma. This study aimed to determine factors that predict benign causes of hilar obstruction and long-term outcomes after resection. METHODS: Consecutive patients who underwent surgery for hilar obstruction at a single institution between 1997 and 2022 were retrospectively analyzed. Median follow-up was 26 months (range 0-281 months). RESULTS: Among 182 patients who underwent surgery for hilar obstruction, 25 (14%) patients were found to have benign disease. Median CA19-9 level after normalization of serum bilirubin was 80 U/mL (range 1-5779) and 21 U/mL (range 1-681) among patients with malignant and benign strictures, respectively (p = 0.001). Cross-sectional imaging features associated with malignancy were lobar atrophy, soft tissue mass/infiltration, and vascular involvement (all p < 0.05). Factors not correlated with malignancy were jaundice upon presentation, peak serum bilirubin, sex, and race. Preoperative bile duct brushing or biopsy had sensitivity and specificity rates of 82% and 55%, respectively. Among patients who underwent resection with curative intent, grade 3-4 complications occurred in 55% and 29% of patients with malignant and benign strictures, respectively (p = 0.028). Postoperative long-term complications of chronic portal hypertension and recurrent cholangitis occurred in ≥ 10% of patients with both benign and malignant disease (p = non-significant). CONCLUSIONS: Strictures at the liver hilum continue to present diagnostic and management challenges. Postoperative complications and long-term sequelae of portal hypertension and recurrent cholangitis develop in a significant number of patients after resection of both benign and malignant strictures.

Intraindividual comparison of prognostic imaging features of HCCs between MRIs with extracellular and hepatobiliary contrast agents.

BACKGROUND & AIMS: Accumulating evidence suggests that certain imaging features of hepatocellular carcinoma (HCC) may have prognostic implications. This study aimed to intraindividually compare MRIs with extracellular contrast agent (ECA-MRI) and hepatobiliary agent (HBA-MRI) for prognostic imaging features of HCC and to compare the prediction of microvascular invasion (MVI) and early recurrence between the two MRIs. METHODS: The present study included 102 prospectively enrolled at-risk patients (median age, 61.0 years; 83 men) with surgically resected single HCC with both preoperative ECA-MRI and HBA-MRI between July 2019 and June 2023. The McNemar test was used to compare each prognostic imaging feature between the two MRIs. Significant imaging features associated with MVI were identified by multivariable logistic regression analysis, and early recurrence rates (<2 years) were compared between the two MRIs. RESULTS: The frequencies of prognostic imaging features were not significantly different between the two MRIs (p = .07 to >.99). Non-smooth tumour margin (ECA-MRI, odds ratio [OR] = 5.30; HBA-MRI, OR = 7.07) and peritumoral arterial phase hyperenhancement (ECA-MRI, OR = 4.26; HBA-MRI, OR = 4.43) were independent factors significantly associated with MVI on both MRIs. Two-trait predictor of venous invasion (presence of internal arteries and absence of hypoattenuating halo) on ECA-MRI (OR = 11.24) and peritumoral HBP hypointensity on HBA-MRI (OR = 20.42) were other predictors of MVI. Early recurrence rates of any two or more significant imaging features (49.8% on ECA-MRI vs 51.3% on HBA-MRI, p = .75) were not significantly different between the two MRIs. CONCLUSION: Prognostic imaging features of HCC may be comparable between ECA-MRI and HBA-MRI.

Performance of LI-RADS category 5 vs combined categories 4 and 5: a systemic review and meta-analysis.

OBJECTIVE: Computed tomography (CT)/magnetic resonance imaging (MRI) Liver Imaging Reporting and Data System (LI-RADS, LR) category 5 has high specificity and modest sensitivity for diagnosis of hepatocellular carcinoma (HCC). The purpose of this study was to compare the diagnostic performance of LR-5 vs combined LR-4 and LR-5 (LR-4/5) for HCC diagnosis. METHODS: MEDLINE and EMBASE databases through January 03, 2023 were searched for studies reporting the performance of LR-5 and combined LR-4/5 for HCC diagnosis, using CT/MRI LI-RADS version 2014, 2017, or 2018. A bivariate random-effects model was used to calculate the pooled per-observation diagnostic performance. Subgroup analysis was performed based on imaging modalities and type of MRI contrast material. RESULTS: Sixty-nine studies (15,108 observations, 9928 (65.7%) HCCs) were included. Compared to LR-5, combined LR-4/5 showed significantly higher pooled sensitivity (83.0% (95% CI [80.3-85.8%]) vs 65.7% (95% CI [62.4-69.1%]); p < 0.001), lower pooled specificity (75.0% (95% CI [70.5-79.6%]) vs 91.7% (95% CI [90.2-93.1%]); p < 0.001), lower pooled positive likelihood ratio (3.60 (95% CI [3.06-4.23]) vs 6.18 (95% CI [5.35-7.14]); p < 0.001), and lower pooled negative likelihood ratio (0.22 (95% CI [0.19-0.25]) vs 0.38 (95% CI [0.35-0.41]) vs; p < 0.001). Similar results were seen in all subgroups. CONCLUSIONS: Our meta-analysis showed that combining LR-4 and LR-5 would increase sensitivity but decrease specificity, positive likelihood ratio, and negative likelihood ratio. These findings may inform management guidelines and individualized management. CLINICAL RELEVANCE STATEMENT: This meta-analysis estimated the magnitude of changes in the sensitivity and specificity of imaging criteria when LI-RADS categories 4 and 5 were combined; these findings can inform management guidelines and individualized management. KEY POINTS: There is no single worldwide reporting system for liver imaging, partly due to regional needs. Combining LI-RADS categories 4 and 5 increased sensitivity and decreased specificity and positive and negative likelihood ratios. Changes in the sensitivity and specificity of imaging criteria can inform management guidelines and individualized management.

Liver Imaging Reporting and Data System version 2018 category 5 for diagnosing hepatocellular carcinoma: an updated meta-analysis.

OBJECTIVE: We performed an updated meta-analysis to determine the diagnostic performance of Liver Imaging Reporting and Data System (LI-RADS, LR) 5 category for hepatocellular carcinoma (HCC) using LI-RADS version 2018 (v2018), and to evaluate differences by imaging modalities and type of MRI contrast material. METHODS: The MEDLINE and Embase databases were searched for studies reporting the performance of LR-5 using v2018 for diagnosing HCC. A bivariate random-effects model was used to calculate the pooled per-observation sensitivity and specificity. Subgroup analysis was performed based on imaging modalities and type of MRI contrast material. RESULTS: Forty-eight studies qualified for the meta-analysis, comprising 9031 patients, 10,547 observations, and 7216 HCCs. The pooled per-observation sensitivity and specificity of LR-5 for diagnosing HCC were 66% (95% CI, 61-70%) and 91% (95% CI, 89-93%), respectively. In the subgroup analysis, MRI with extracellular agent (ECA-MRI) showed significantly higher pooled sensitivity (77% [95% CI, 70-82%]) than CT (66% [95% CI, 58-73%]; p = 0.023) or MRI with gadoxetate (Gx-MRI) (65% [95% CI, 60-70%]; p = 0.001), but there was no significant difference between ECA-MRI and MRI with gadobenate (gadobenate-MRI) (73% [95% CI, 61-82%]; p = 0.495). Pooled specificities were 88% (95% CI, 80-93%) for CT, 92% (95% CI, 86-95%) for ECA-MRI, 93% (95% CI, 91-95%) for Gx-MRI, and 91% (95% CI, 84-95%) for gadobenate-MRI without significant differences (p = 0.084-0.803). CONCLUSIONS: LI-RADS v2018 LR-5 provides high specificity for HCC diagnosis regardless of modality or contrast material, while ECA-MRI showed higher sensitivity than CT or Gx-MRI. CLINICAL RELEVANCE STATEMENT: Refinement of the criteria for improving sensitivity while maintaining high specificity of LR-5 for HCC diagnosis may be an essential future direction. KEY POINTS: • The pooled per-observation sensitivity and specificity of LR-5 for diagnosing HCC using LI-RADSv2018 were 66% and 91%, respectively. • ECA-MRI showed higher sensitivity than CT (77% vs 66%, p = 0.023) or Gx-MRI (77% vs 65%, p = 0.001). • LI-RADS v2018 LR-5 provides high specificity (88-93%) for HCC diagnosis regardless of modality or contrast material type.

Imaging classification of pancreatic ductal adenocarcinoma with histological large duct pattern.

OBJECTIVES: To investigate the imaging features of pancreatic ductal adenocarcinoma (PDAC) with histological large duct pattern. METHODS: Our study included 37 patients (mean age, 66.5 years; 22 women) with surgically proven PDAC with histological large duct pattern, whose imaging features were classified into four types: Type I, solid mass; Type II, predominantly cystic mass with intracystic solid components; Type III, predominantly solid mass with intratumoral cysts; and Type IV, solid mass with peritumoral retention cysts or pseudocysts. Two radiologists independently analyzed both CT and MRI images for the morphological type, presence of abrupt main pancreatic duct (MPD) cutoff, adjacent vascular invasion, diffusion restriction, and reached consensus. RESULTS: On CT, 26 patients (70.3%) had Type I tumors, five (13.5%) had Type II, three (8.1%) had Type III, and three (8.1%) had Type IV. Among the 26 patients with Type I tumors on CT, 16 had tumors with multiple intratumoral cysts within the solid mass on MRI and were subsequently classified as Type III. Accordingly, 10 patients (27.0%) were classified as Type I, five (13.5%) as Type II, 19 (51.7%) as Type III, and three (8.1%) as Type IV on MRI. Of the 37 patients, 27 (73.0%) had an abrupt MPD cutoff, 15 (40.5%) had adjacent vascular invasion, and 25 (67.6%) had diffusion restriction on MRI. CONCLUSIONS: Predominantly solid pancreatic masses with small intratumoral cysts visualized on MRI may be a characteristic imaging finding of PDAC with histological large duct pattern, and differentiate it from conventional PDAC or other cystic pancreatic tumors. CLINICAL RELEVANCE STATEMENT: Radiologists should be familiar with the various imaging features of PDAC with histological large duct pattern and should be aware that it may mimic other solid or cystic tumors of the pancreas. KEY POINTS: Imaging features of pancreatic ductal adenocarcinoma with histological large duct pattern can be classified into four types. This pathology more frequently appears as a predominantly solid mass with intratumoral cysts on MRI than on CT. Adding MRI to CT may help identify pancreatic ductal adenocarcinoma with histological large duct pattern.

Prediction of tumor recurrence after surgical resection of ampullary adenocarcinoma using magnetic resonance imaging.

OBJECTIVES: To predict tumor recurrence in patients who underwent surgical resection of ampullary adenocarcinoma using preoperative magnetic resonance (MR) imaging findings combined with clinical findings. METHODS: In this multicenter study, a total of 113 patients (mean age, 62.9 ± 9.8 years; 58 men and 55 women) with ampullary adenocarcinoma who underwent preoperative MR imaging and surgery with margin-negative resection between 2006 and 2017 were retrospectively included. The MR imaging findings were evaluated by two radiologists. Preoperative clinical findings were obtained. Cox proportional regression analyses were used to identify the independent prognostic factors for recurrence-free survival (RFS). A nomogram was created based on the multivariable analysis and was internally validated. RESULTS: Multivariable analysis revealed that presence of infiltrative tumor margin (hazard ratio [HR]: 2.18, p = 0.019), adjacent organ invasion (HR: 3.31, p = 0.006), adjacent vessel invasion (HR: 5.42, p = 0.041), peripancreatic lymph node enlargement (HR: 2.1, p = 0.019), and jaundice (HR: 1.93, p = 0.043) were significantly associated with worse RFS of ampullary adenocarcinoma after surgical resection. These MR imaging and clinical findings were used to construct a nomogram. On internal validation, the calibration plots showed excellent agreement between the predicted probabilities and the actual rates of tumor recurrence, with Harrell's c-index of 0.746. CONCLUSIONS: Combination of preoperative MR imaging and clinical findings can be useful for predicting tumor recurrence after surgical resection of ampullary adenocarcinoma. Identifying these features before surgery may aid in better treatment planning and management of these patients. CLINICAL RELEVANCE STATEMENT: A predictive nomogram using preoperative MR imaging and clinical findings can be useful in estimating the recurrence-free survival after surgical resection of ampullary adenocarcinoma. KEY POINTS: • Presently, tumor size on imaging is the only non-invasive factor that correlates with recurrence-free survival from ampullary adenocarcinoma; other factors are obtained postoperatively. • Infiltrative tumor margin, adjacent organ invasion, adjacent vessel invasion, peripancreatic lymph node enlargement on MRI, and jaundice are significant predictors for recurrence. • A nomogram incorporating significant MR imaging and clinical findings showed good performance in predicting recurrence-free survival, which can help in treatment planning.

Comparison between the GastroPanel test and the serum pepsinogen assay interpreted with the ABC method-A prospective study.

BACKGROUND AND AIMS: This study aimed to validate Helicobacter pylori serological and pepsinogen (PG) assays for detecting infection and gastric neoplasm. METHODS: Individuals who underwent serum Chorus H. pylori and HBI PG assays were included from May to September 2023. The GastroPanel test was performed using the same blood sample. HBI assay findings were interpreted with the ABC method using the criteria of corpus atrophy (PG I ≤ 70 ng/mL & I/II ≤3) and advanced corpus atrophy (PG I ≤ 30 ng/mL & I/II ≤2). RESULTS: A total of 144 H. pylori-infected and 184 non-infected Koreans were analyzed. The Chorus test (sensitivity 97.2%, specificity 89.1%) showed higher area under the curve (0.993 vs. 0.972, p = 0.003) than the GastroPanel test (sensitivity 95.8%, specificity 86.4%). Using the GastroSoft application, the incidence of gastric neoplasms was highest in the corpus atrophy group (50%), followed by the low acid-output (25.8%), H. pylori infection (11.6%), and antral atrophy (9.1%) groups. There were no gastric neoplasms in the normal and high acid output groups. Using the ABC method, the incidence of gastric neoplasms was highest in the corpus atrophy groups (23.8% in Groups C and D), followed by Group B (12.3%) and Group A (2.4%). Corpus atrophy interpreted with the GastroSoft showed poor agreement (k = 0.225) with corpus atrophy interpreted with the ABC method, whereas it showed excellent agreement (k = 0.854) with advanced corpus atrophy. CONCLUSIONS: Although the Chorus test was more accurate than the GastroPanel test, both assays discriminated high-risk individuals by detecting atrophy or infection. There were no gastric neoplasms in the normal or high acid-output groups (GastroSoft application), and gastric neoplasm incidence was lowest in Group A (ABC method). Corpus atrophy determined by GastroSoft application is more consistent with advanced corpus atrophy determined by the ABC method than is corpus atrophy.

Current Status of Diagnosis and Treatment of Colorectal Cancer in Asian Countries: A Questionnaire Survey.

INTRODUCTION: Diagnostic and therapeutic methods for colorectal cancer (CRC) have advanced; however, they may be inaccessible worldwide, and their widespread use is challenging. This questionnaire survey investigates the current status of diagnosis and treatment of early-stage CRC in Asian countries. METHODS: Responses to the questionnaire were obtained from 213 doctors at different institutions in 8 countries and regions. The questionnaire consisted of 39 questions on the following four topics: noninvasive diagnosis other than endoscopy (6 questions), diagnosis by magnification and image-enhanced endoscopy (IEE) including artificial intelligence (AI) (10 questions), endoscopic submucosal dissection (ESD), proper use among other therapeutic methods (11 questions), and pathologic diagnosis and surveillance (12 questions). RESULTS: Although 101 of 213 respondents were affiliated with academic hospitals, there were disparities among countries and regions in the dissemination of advanced technologies, such as IEE, AI, and ESD. The NICE classification is widely used for the diagnosis of colorectal tumors using IEE, while the JNET classification with magnification was used in countries such as Japan (65/70, 92.9%) and China (16/22, 72.7%). Of the 211 respondents, 208 (98.6%) assumed that en bloc resection should be achieved for carcinomas, and 180 of 212 (84.9%) believed that ESD was the most suitable in cases with a diameter larger than 2 cm. However, colorectal ESD is not widespread in countries such as Thailand, the Philippines, and Indonesia. CONCLUSION: The promotion of advanced technologies and education should be continual to enable more people to benefit from them.

Exploring the impact of excluding intrahepatic segmental vessels on liver stiffness measurement and advanced fibrosis diagnosis using magnetic resonance elastography.

BACKGROUND: The impact of excluding intrahepatic segmental vessels from regions of interest (ROIs) on liver stiffness measurement (LSM) via magnetic resonance elastography (MRE) remains uncertain. PURPOSE: To determine the effect of excluding intrahepatic segmental vessels from ROIs on LSM obtained from MRE. MATERIAL AND METHODS: This retrospective analysis included 95 participants who underwent successful two-dimensional gradient recalled-echo MRE before hepatic tumor resection (n = 49) or living liver donation (n = 46). The conventional LSM was determined by manually drawing ROIs on the elastogram within the 95% confidence region, staying 1 cm within the liver capsule and excluding large hilar vessels, the gallbladder, hepatic lesions, and artifacts. In addition, the modified LSM was determined by excluding intrahepatic segmental vessels. LSMs obtained by the two methods were compared with paired sample signed-rank test. Diagnostic performance for advanced fibrosis was calculated and compared using McNemar's test and Delong's test. The stage of hepatic fibrosis was assessed using surgical specimens by the METAVIR system. RESULTS: The modified LSM was larger than the conventional LSM (2.4 kPa vs. 2.2 kPa in reader 1; 2.7 kPa vs. 2.4 kPa in reader 2; P < 0.001). The modified LSM showed superior sensitivity (0.841 vs. 0.659 in reader 1; 0.864 vs. 0.705 in reader 2; P < 0.05) and area under the curve (0.901 vs. 0.820 in reader 1; 0.912 vs. 0.843 in reader 2; P < 0.05) for detecting advanced fibrosis (≥F3) than conventional LSM. CONCLUSION: The exclusion of intrahepatic segmental vessels from ROIs in MRE affected the LSM and enhanced diagnostic performance for advanced fibrosis.

MMP-9 facilitates selective proteolysis of the histone H3 tail at genes necessary for proficient osteoclastogenesis.

Although limited proteolysis of the histone H3 N-terminal tail (H3NT) is frequently observed during mammalian differentiation, the specific genomic sites targeted for H3NT proteolysis and the functional significance of H3NT cleavage remain largely unknown. Here we report the first method to identify and examine H3NT-cleaved regions in mammals, called chromatin immunoprecipitation (ChIP) of acetylated chromatin (ChIPac). By applying ChIPac combined with deep sequencing (ChIPac-seq) to an established cell model of osteoclast differentiation, we discovered that H3NT proteolysis is selectively targeted near transcription start sites of a small group of genes and that most H3NT-cleaved genes displayed significant expression changes during osteoclastogenesis. We also discovered that the principal H3NT protease of osteoclastogenesis is matrix metalloproteinase 9 (MMP-9). In contrast to other known H3NT proteases, MMP-9 primarily cleaved H3K18-Q19 in vitro and in cells. Furthermore, our results support CBP/p300-mediated acetylation of H3K18 as a central regulator of MMP-9 H3NT protease activity both in vitro and at H3NT cleavage sites during osteoclastogenesis. Importantly, we found that abrogation of H3NT proteolysis impaired osteoclastogenic gene activation concomitant with defective osteoclast differentiation. Our collective results support the necessity of MMP-9-dependent H3NT proteolysis in regulating gene pathways required for proficient osteoclastogenesis.

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients with Cancer and Viral Hepatitis: The MD Anderson Cancer Center Experience.

BACKGROUND: Despite the clinical benefit of immune checkpoint inhibitors (ICIs), patients with a viral hepatitis have been excluded from clinical trials because of safety concerns. The purpose of this study was to determine the incidence rate of adverse events (AEs) in patients with viral hepatitis who received ICIs for cancer treatment. MATERIALS AND METHODS: We conducted a retrospective study in patients with cancer and concurrent hepatitis B or C, who had undergone treatment with ICI at MD Anderson Cancer Center from January 1, 2010 to December 31, 2019. RESULTS: Of the 1076 patients screened, we identified 33 with concurrent hepatitis. All 10 patients with HBV underwent concomitant antiviral therapy during ICI treatment. Sixteen of the 23 patients with HCV received it before the initiation of ICI. The median follow-up time was 33 months (95% CI, 23-45) and the median duration of ICI therapy was 3 months (IQR, 1.9-6.6). Of the 33 patients, 12 (39%) experienced irAEs (immune-related adverse events) of any grade, with 2 (6%) having grade 3 or higher. None of the patients developed hepatitis toxicities. CONCLUSION: ICIs may be a therapeutic option with an acceptable safety profile in patients with cancer and advanced liver disease.

Brain Metastases from Biliary Tract Cancer: Case Series and Clinicogenomic Analysis.

BACKGROUND: Limited data from small series have suggested that brain metastases from biliary tract cancers (BrM-BTC) affect ≤2% of patients with BTC. We sought to review our experience with patients with BrM-BTC and to identify associations of tumor-related molecular alterations with outcomes. MATERIALS AND METHODS: A retrospective review of patients with BTC seen at a tertiary referral center from 2005 to 2021 was performed; patients with BrM-BTC were identified, and clinical and molecular data were collected. RESULTS: Twenty-one of 823 patients with BTC (2.6%) developed BrM. For patients with BrM-BTC, median follow-up time was 27.9 months after primary BTC diagnosis and 3.1 months after BrM diagnosis. Median time from primary diagnosis to diagnosis of BrM was 14.4 [range, 1.1-66.0] months. Median overall survival (OS) from primary diagnosis was 31.5 [2.9-99.8] months and median OS from BrM diagnosis was 4.2 [0.2-33.8] months. Patients who underwent BrM-directed therapy trended toward longer OS following BrM diagnosis than patients receiving supportive care only (median 6.5 vs 0.8 months, P = .060). The BrM-BTC cohort was enriched for BRAF (30%), PIK3CA (25%), and GNAS (20%) mutations. patients with BrM-BTC with BRAF mutations trended toward longer OS following BrM diagnosis (median 13.1 vs 4.2 months, P = .131). CONCLUSION: This is the largest series of patients with BrM-BTC to date and provides molecular characterization of this rare subgroup of patients with BTC. Patients with BrM-BTC may be more likely to have BRAF mutations. With advances in targeted therapy for patients with BTC with actionable mutations, continued examination of shifting patterns of failure, with emphasis on BrM, is warranted.

O-RADS US: A Systematic Review and Meta-Analysis of Category-specific Malignancy Rates.

Background Ovarian-Adnexal Reporting and Data System (O-RADS) US provides a standardized method with which to stratify lesions into risk of malignancy categories, which is crucial for proper management. Purpose To perform a systematic review and meta-analysis to estimate malignancy rates for each O-RADS US score and evaluate the diagnostic performance of combined O-RADS US scores 4 and 5 in the diagnosis of malignancy. Materials and Methods A systematic literature search from the inception of the MEDLINE, EMBASE, and Web of Science databases through January 27, 2023, was performed for articles that reported using the O-RADS US stratification system and included malignancy rates per each O-RADS score. Bivariate random-effects models were used to determine the pooled malignancy rates for each O-RADS US score and to obtain summary estimates of the diagnostic performance of combined O-RADS US scores 4 and 5 in the diagnosis of malignant lesions. Results The final analysis included 18 studies consisting of 11 605 patients and 11 818 ovarian-adnexal lesions, with 2996 malignant (25.4%) and 8822 benign (74.6%) lesions. No malignant lesions were reported in O-RADS 1 category. The pooled percentages of malignancy were 0.6% (95% CI: 0.3, 1.0) for O-RADS 2, 3.9% (95% CI: 2.5, 5.4) for O-RADS 3, 43.5% (95% CI: 33.8, 53.2) for O-RADS 4, and 87.3% (95% CI: 83.0, 91.7) for O-RADS 5. The pooled sensitivity and specificity of combined O-RADS scores 4 and 5 in the diagnosis of malignant lesions were 95.6% (95% CI: 94.0, 97.2) and 76.6% (95% CI: 70.4, 82.7), respectively. Conclusion Each O-RADS US score provided the intended probability of malignant lesions as outlined by the O-RADS risk stratification system. When O-RADS US scores 4 and 5 were combined as a predictor for malignancy, O-RADS US showed a high sensitivity and moderate specificity. Clinical trial registration no. CRD42022352166 © RSNA, 2023 Supplemental material is available for this article.