Early detection of hypervascularization in hepatocellular carcinoma (≤2 cm) on hepatic arterial phase with virtual monochromatic imaging: Comparison with low-tube voltage CT.

This study aims to assess the diagnostic value of virtual monochromatic image (VMI) at low keV energy for early detection of small hepatocellular carcinoma (HCC) in hepatic arterial phase compared with low-tube voltage (80 kVp) CT generated from dual-energy CT (DE-CT). A total of 107 patients with 114 hypervascular HCCs (≤2 cm) underwent DE-CT, 140 kVp, blended 120 kVp, and 80 kVp images were generated, as well as 40 and 50 keV. CT numbers of HCCs and the standard deviation as image noise on psoas muscle were measured. The contrast-to-noise ratios (CNR) of HCC were compared among all techniques. Overall image quality and sensitivity for detecting HCC hypervascularity were qualitatively assessed by three readers. The mean CT numbers, CNR, and image noise were highest at 40 keV followed by 50 keV, 80 kVp, blended 120 kVp, and 140 kVp. Significant differences were found in all evaluating endpoints except for mean image noise of 50 keV and 80 kVp. Image quality of 40 keV was the lowest, but still it was considered acceptable for diagnostic purposes. The mean sensitivity for detecting lesion hypervascularity with 40 keV (92%) and 50 keV (84%) was higher than those with 80 kVp (56%). Low keV energy images were superior to 80 kVp in detecting hypervascularization of early HCC.

Postoperative Prognosis According to Pathologic Categorization of Desmoplastic Reaction in Patients with Extrahepatic Cholangiocarcinoma.

BACKGROUND: Recent studies have demonstrated the importance of desmoplastic reaction (DR) in predicting postoperative prognosis for patients with colorectal carcinoma. However, the impact of DR on the prognosis of extrahepatic cholangiocarcinomas (EHCCs) is not established. This study aimed to clarify the associations of pathologic DR categories with clinicopathologic factors and postoperative prognosis of perihilar cholangiocarcinoma (PHCC) and distal cholangiocarcinoma (DCC). METHODS: A pathologic review of 174 patients with PHCC and 109 patients with DCC who underwent surgical resection was performed. The patients were classified into three DR categories (immature, intermediate, and mature) based on the histologic features within the fibrotic stroma in the invasive front. The association between DR categories and the distribution of fibroblasts with anti-α-smooth muscle actin (SMA) expression, seeming to be tumor-promoting cancer-associated fibroblasts (CAFs), was evaluated in 191 tissue microarray specimens of EHCCs. RESULTS: Intermediate/immature DR categories were significantly associated with a more invasive nature, including higher pT and pN stages and more tumor buds than the mature category in both PHCC and DCC. The DR categories could stratify overall survival (OS) and relapse-free survival (RFS) in both PHCC and DCC patients. In the multivariate analysis, the DR category was an independent prognostic factor for OS and RFS in both PHCC and DCC (p < 0.001). The mature and immature DR categories were significantly associated respectively with the confined and pervasive distribution of fibroblasts with α-SMA expression. CONCLUSION: In patients with EHCCs, DR categorization was an independent prognostic factor reflecting the distribution of tumor-promoting CAFs in the invasive front.

CCR7 Mediates Cell Invasion and Migration in Extrahepatic Cholangiocarcinoma by Inducing Epithelial-Mesenchymal Transition.

The epithelial-mesenchymal transition (EMT) contributes to the metastatic cascade in various tumors. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine (C-C motif) ligand 19 (CCL19), to promote EMT. However, the association between EMT and CCR7 in extrahepatic cholangiocarcinoma (EHCC) remains unknown. This study aimed to elucidate the prognostic impact of CCR7 expression and its association with clinicopathological features and EMT in EHCC. The association between CCR7 expression and clinicopathological features and EMT status was examined via the immunohistochemical staining of tumor sections from 181 patients with perihilar cholangiocarcinoma. This association was then investigated in TFK-1 and EGI-1 EHCC cell lines. High-grade CCR7 expression was significantly associated with a large number of tumor buds, low E-cadherin expression, and poor overall survival. TFK-1 showed CCR7 expression, and Western blotting revealed E-cadherin downregulation and vimentin upregulation in response to CCL19 treatment. The wound healing and Transwell invasion assays revealed that the activation of CCR7 by CCL19 enhanced the migration and invasion of TFK-1 cells, which were abrogated by a CCR7 antagonist. These results suggest that a high CCR7 expression is associated with an adverse postoperative prognosis via EMT induction and that CCR7 may be a potential target for adjuvant therapy in EHCC.

Efficacy and Safety of Radium-223 for Castration-resistant Prostate Cancer With Bone Metastasis Before and After Docetaxel.

BACKGROUND/AIM: Radium-223 (Ra-223) therapy provides a survival benefit for castration-resistant prostate cancer (CRPC) patients with bone metastasis. The optimal timing of using Ra-223 has not been determined. We evaluated the efficacy and safety of Ra-223 before and after docetaxel (DOC) therapy. PATIENTS AND METHODS: We retrospectively reviewed 36 CRPC patients with bone metastasis who were treated with Ra-223 in our institution and satellite hospitals. Ra-223 was used before DOC (pre-DOC group) in 17 patients (47%) and after DOC (post-DOC group) in 19 patients (53%). The treatment completion rate of 6 cycles, progression-free survival (PFS), cause-specific survival (CSS) and occurrence rate of adverse events were compared between the groups. RESULTS: The median follow-up duration was 45 months. In the pre-DOC compared with the post-DOC group, treatment completion rate was significantly higher (94% vs. 52%, p<0.01), PFS was significantly longer (median: 8 vs. 5 months, p=0.024) and CSS was significantly longer (median: 32 vs. 15 months, p=0.028). The difference in CSS was significant in multivariate analysis. In the pre-DOC compared with the post-DOC group, the occurrence rate of grade ≥3 adverse events tended to be lower (6% vs. 36%, p=0.322), and the CSS tended to be longer (median: not reached vs. 45 months, p=0.208). CONCLUSION: Ra-223 could be used more safely and more effectively for CRPC patients with bone metastasis before than after DOC therapy.

Improved detection of early gastric cancer with linked color imaging using an ultrathin endoscope: a video-based analysis.

Background and study aims Ultrathin endoscopy causes a minimal gag reflex and has minimal effects on cardiopulmonary function. Linked color imaging (LCI) is useful for detection of malignancies in the digestive tract. The aim of this study was to clarify whether LCI with ultrathin endoscopy facilitates detection of early gastric cancer (EGC) despite its lower resolution compared with high-resolution white light imaging (WLI) with standard endoscopy. Patients and methods This was a retrospective analysis with prospectively collected video, including consecutive 166 cases of EGC or gastric atrophy alone. Ninety seconds of screening video was collected using standard and ultrathin endoscopes with both WLI and LCI for each case. Three expert endoscopists assessed each video and the sensitivity of detecting EGC calculated. Color difference calculations were performed. Results Sensitivities using ultrathin WLI, ultrathin LCI, standard WLI, and standard LCI for the identification of cancer were 66.0 %, 80.3 %, 69.9 %, and 84.0 %, respectively. The color difference between malignant lesions and surrounding mucosa with ultrathin LCI and standard LCI were significantly higher than using ultrathin WLI or standard WLI, supported subjectively by the visibility score. Ultrathin LCI color difference and visibility score were significantly higher than standard WLI. Conclusions LCI with a low-resolution ultrathin endoscope is superior to WLI with a high-resolution standard endoscope for gastric cancer screening. This suggests that the high color contrast between EGC and the surrounding mucosa is more important than high-resolution images.

Assessment of postoperative common bile duct stones after endoscopic extraction and subsequent cholecystectomy.

BACKGROUND: Common bile duct stones (CBDSs) occasionally cause serious diseases, and endoscopic extraction is the standard procedure for CBDS. To prevent biliary complications, cholecystectomy is recommended for patients who present with gallbladder (GB) stones after endoscopic CBDS extraction. However, CBDS can occasionally recur. To date, the occurrence of CBDS after endoscopic CBDS extraction and subsequent cholecystectomy is not fully understood. Hence, the current study aimed to evaluate the incidence of postoperative CBDSs. METHODS: This retrospective observational study included consecutive patients who underwent postoperative endoscopic retrograde cholangiography after endoscopic CBDS extraction and subsequent cholecystectomy between April 2012 and June 2021 at our institution. After endoscopic CBDS extraction, a biliary plastic stent was inserted to prevent obstructive cholangitis. Endoscopic retrograde cholangiography was performed to evaluate postoperative CBDSs after cholecystectomy until hospital discharge. The outcomes were the incidence of postoperative CBDSs and CBDSs/sludge. Moreover, the predictive factors for postoperative CBDSs were evaluated via univariate and multivariate analyses. RESULTS: Of eligible 204 patients, 52 patients (25.5%) presented with postoperative CBDSs. The incidence rate of CBDS/sludge was 36.8% (n = 75). Based on the univariate analysis, the significant predictive factors for postoperative CBDSs were ≥ 6 CBDSs, presence of cystic duct stones, and ≥ 10 GB stones (P < 0.05). Moreover, male sex and < 60-mm minor axis in GB might be predictive factors (P < 0.10). Based on the multivariate analysis, ≥ 6 CBDSs (odds ratio = 6.65, P < 0.01), presence of cystic duct stones (odds ratio = 4.39, P < 0.01), and ≥ 10 GB stones (odds ratio = 2.55, P = 0.01) were independent predictive factors for postoperative CBDSs. CONCLUSIONS: The incidence of postoperative CBDS was relatively high. Hence, patients with predictive factors for postoperative CBDS must undergo imaging tests or additional endoscopic procedure after cholecystectomy.

Usefulness of linked color imaging for the detection of obscure early gastric cancer: Multivariate analysis of 508 lesions.

OBJECTIVES: Early gastric cancers (EGCs) of the elevated type or with submucosal invasion are easily found by routine endoscopy. However, most early cancers are challenging to detect because of subtle morphological or color differences from surrounding atrophic mucosa and intestinal metaplasia. Linked color imaging (LCI) enhances mucosal color difference, making it easier to detect EGCs. The aim of this study is to clarify the advantages and possible disadvantages of LCI for screening for obscure EGC. METHODS: A total of 665 malignant gastric lesions resected using endoscopic submucosal dissection between January 2015 and April 2018 were retrospectively reviewed. Obviously detectable lesions were not included in the main analysis when determining the target lesion. White light imaging (WLI)/LCI images of 508 endoscopically obscure malignant lesions were included in the final analysis and evaluated by three non-expert and three expert endoscopists using visibility scores for detection and extent. RESULTS: The detection visibility scores using LCI were significantly higher than those using WLI regardless of lesion characteristics including location, size, histological type, depth of invasion, and Helicobacter pylori status. The detection score improved in 46.4% cases and deteriorated in 4.9% when the modality changed from WLI to LCI. A mixed-effects multivariate logistic regression analysis showed that use of LCI (odds ratio [OR] 2.57), elevated type (OR 1.92), invasion to submucosa (OR 2.18) were significantly associated with improved visibility of EGC. CONCLUSIONS: Linked color imaging significantly improves visibility of EGC regardless of differences in lesion morphology, histology, location, depth of invasion, and H. pylori status compared to conventional WLI.

Development of a Non-invasive Diagnostic Method for Esophageal Squamous Cell Carcinoma by Gas Chromatographic Analysis of Exhaled Breath.

Objectives: Since esophageal carcinoma progresses asymptomatically, for many patients the disease is already advanced at the time of diagnosis. The main methods that are currently used to diagnose esophageal carcinoma are upper gastrointestinal radiographic contrast examinations and upper gastrointestinal endoscopy, but early discovery of this disease remains difficult. There is a need to develop a diagnostic method using biomarkers that is non-invasive while both highly sensitive and specific. Materials and Methods: Exhaled breath was collected from 17 patients with esophageal squamous cell carcinoma (ESCC), as well as 9 control subjects without history of any cancer. For each fasting subject, 1L of exhaled breath was collected in a gas sampling bag. Volatile organic compounds (VOCs) were then extracted from each sample using Solid phase micro-extraction (SPME) fibers and analyzed by gas chromatography-mass spectrometry (GC-MS). Results: Levels of acetonitrile, acetic acid, acetone, and 2-butanone in exhaled breath were significantly higher in the patient group than in the control group (p = 0.0037, 0.0024, 0.0024 and 0.0037, respectively). ROC curves were drawn for these 4 VOCs, and the results for the area-under-the-curve (AUC) indicated that ESCC patients can be identified with a high probability of 0.93. Conclusion: We found distinctive VOCs in exhaled breath of ESCC patients. These VOCs have a potential as new clinical biomarkers for ESCC. The measurement of VOCs in exhaled breath may be a useful, non-invasive method for diagnosis of ESCC.

Cutaneous metastasis emerging during chemotherapy and progressing during immunotherapy for urothelial carcinoma.

INTRODUCTION: Cutaneous metastasis of urothelial carcinoma is uncommon. We experienced a case of cutaneous metastasis that emerged during chemotherapy and progressed rapidly during immunotherapy for bladder tumor with lymph node metastasis. CASE PRESENTATION: A 77-year-old female patient received chemotherapy using gemcitabine and cisplatin for bladder urothelial carcinoma with para-aortic and pelvic lymph node metastases (clinical stage T2N1M1). After eight courses of chemotherapy, skin rash appeared in the lower abdomen with leg edema caused by multiple lymphadenopathy. Skin biopsy revealed cutaneous metastasis of urothelial carcinoma. The cutaneous tumor progressed rapidly and the patient died 5 weeks after the start of second-line pembrolizumab treatment. CONCLUSION: A patient with cutaneous metastasis of urothelial carcinoma that emerged during chemotherapy had poor prognosis and lack of efficacy of an immune checkpoint inhibitor.

Follow-up after Direct-acting Antiviral Treatment for Chronic Hepatitis C Virus Infection: Most Patients Are Followed Appropriately.

Objective Chronic hepatitis C virus (HCV) infection carries a residual risk of hepatocarcinogenesis even after viral elimination, so appropriate follow-up is necessary. The present study investigated the current hospital visits and hepatocarcinogenesis status of patients who received daclatasvir plus asunaprevir treatment (DCV+ASV) to determine whether or not appropriate follow-up was being performed. Methods We retrospectively analyzed hepatocarcinogenesis, the overall survival, and the length of hospital visits in 442 patients who applied for the medical expense subsidy system for viral hepatitis and received DCV+ASV treatment in Gunma Prefecture between October 2014 and December 2015. This also included 61 patients who had a history of hepatocellular carcinoma (HCC). Results Among 442 patients, 388 achieved a sustained viral response (SVR) by DCV+ASV therapy (87.8%), and 95.9% achieved an SVR if additional treatment was included. HCC was found in 75 cases (17.0%). A history of HCC, the FIB-4 index and the treatment effect SVR were determined to be factors affecting the incidence of HCC. Regarding the follow-up rate, 89.9% of patients continued to regularly visit the hospital after 5 years of treatment. However, patients ≤60 years old had significantly lower persistence rates than older patients. The persistence rate of hospital visits to the same institution was 67.7% over a 5-year period, which was significantly better in small and medium-sized institutions than in large, specialized institutions (71.7% vs. 63.9%, p=0.039). Conclusion Patients with direct-acting antiviral treatment generally received adequate follow-up, but younger patients had a slightly higher rate of follow-up interruption and were considered to need support.

Lenvatinib for Hepatocellular Carcinoma Patients with Nonviral Infection Who Were Unlikely to Respond to Immunotherapy: A Retrospective, Comparative Study.

AIM: Atezolizumab plus bevacizumab (atezo + bev) shows a good overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients. However, the OS of patients with nonviral infection is quite worse than that in those with viral infection. The present study investigated the efficacy and safety of lenvatinib in patients with nonviral infection, who were unlikely to obtain benefit from atezo + bev. METHODS: We conducted a multicenter retrospective study that included 139 advanced HCC patients treated with lenvatinib between March 2018 and September 2020. RESULTS: The median age was 72 years, and 116 patients (83.5%) were male. Based on the etiology of liver disease, 84 (60.4%) and 55 patients (39.6%) were assigned to the viral infection and nonviral infection groups, respectively. The significant extents in patient characteristics were not observed in both groups. The objective response rate per mRECIST and progression-free survival (PFS) did not differ significantly between the viral infection and nonviral infection groups (36.0 vs. 33.0%, p = 0.85; and 7.6 vs. 7.5 months, p = 0.94, respectively). The 1-year survival rates were 68.7% (95% confidence interval [CI] 57.7-79.7%) in the viral infection group and 59.5% (95% CI 45.2-73.8%) in the nonviral infection group. The viral infection group was not a significant factor associated with the PFS or OS in a multivariate analysis. CONCLUSIONS: Lenvatinib shows no significant difference in response between patients with and without viral infection. Treatment strategies based on the etiology of liver disease may lead to good clinical outcome.

Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives as novel selective Axl inhibitors.

Axl and Mer are members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases. Previously, we reported that enzyme-mediated inhibition of Mer by an Axl/Mer dual inhibitor led to retinal toxicity in mice, whereas selective Axl inhibition by compound 1 did not. On the other hand, compound 1 showed low membrane permeability. Here, we designed and synthesized a novel series of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives and evaluated their Axl and Mer inhibitory activities, leading to identification of ER-001259851-000 as a potent and selective Axl inhibitor with drug-likeness and a promising pharmacokinetic profile in mice.

Appropriate Color Enhancement Settings for Blue Laser Imaging Facilitates the Diagnosis of Early Gastric Cancer with High Color Contrast.

PURPOSE: Screening image-enhanced endoscopy for gastrointestinal malignant lesions has progressed. However, the influence of the color enhancement settings for the laser endoscopic system on the visibility of lesions with higher color contrast than their surrounding mucosa has not been established. MATERIALS AND METHODS: Forty early gastric cancers were retrospectively evaluated using color enhancement settings C1 and C2 for laser endoscopic systems with blue laser imaging (BLI), BLI-bright, and linked color imaging (LCI). The visibilities of the malignant lesions in the stomach with the C1 and C2 color enhancements were scored by expert and non-expert endoscopists and compared, and the color differences between the malignant lesions and the surrounding mucosa were assessed. RESULTS: Early gastric cancers mainly appeared orange-red on LCI and brown on BLI-bright or BLI. The surrounding mucosae were purple on LCI regardless of the color enhancement but brown or pale green with C1 enhancement and dark green with C2 enhancement on BLI-bright or BLI. The mean visibility scores for BLI-bright, BLI, and LCI with C2 enhancement were significantly higher than those with C1 enhancement. The superiority of the C2 enhancement was not demonstrated in the assessments by non-experts, but it was significant for experts using all modes. The C2 color enhancement produced a significantly greater color difference between the malignant lesions and the surrounding mucosa, especially with the use of BLI-bright (P=0.033) and BLI (P<0.001). C2 enhancement tended to be superior regardless of the morphological type, Helicobacter pylori status, or the extension of intestinal metaplasia around the cancer. CONCLUSIONS: Appropriate color enhancement settings improve the visibility of malignant lesions in the stomach and color contrast between the malignant lesions and the surrounding mucosa.

Discovery of a potent and selective Axl inhibitor in preclinical model.

Axl and Mer are a members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases, which, when activated, can promote tumor cell survival, proliferation, migration, invasion, angiogenesis, and tumor-host interactions. Chronic inhibition of Mer leads to retinal toxicity in mice. Therefore, successful development of an Axl targeting agent requires ensuring that it is safe for prolonged treatment. Here, to clarify whether enzyme inhibition of Mer by a small molecule leads to retinal toxicity in mice, we designed and synthesized Axl/Mer inhibitors and Axl-selective inhibitors. We identified an Axl/Mer dual inhibitor 28a, which showed retinal toxicity at a dose of 100 mg/kg in mice. Subsequent derivatization of a pyridine derivative led to the discovery of a pyrimidine derivative, 33g, which selectively inhibited the activity of Axl over Mer without retinal toxicity at a dose of 100 mg/kg in mice. Additionally, the compound displayed in vivo anti-tumor effects without influencing body weight in a Ba/F3-Axl isogenic subcutaneous model.

Therapeutic efficacy of lenvatinib as third-line treatment after regorafenib for unresectable hepatocellular carcinoma progression.

AIM: Multiple molecular agents have been developed for treating unresectable hepatocellular carcinoma. This study aimed to elucidate the clinical efficacy of sequential treatment with lenvatinib after regorafenib failure. METHODS: From June 2017 to October 2020, 63 patients with Child-Pugh A and treated with regorafenib followed by sorafenib were enrolled (median age 71 years, 52 men, Barcelona Clinic Liver Cancer B:C = 23:40). They were divided into two groups, those treated with lenvatinib after regorafenib treatment (R-L group, n = 47) and those who did not receive lenvatinib after regorafenib (non-R-L group, n = 16). Prognostic factors were retrospectively analyzed after adjustment with inverse probability weighting. RESULTS: Serum albumin level at the start of regorafenib and reasons for discontinuation of regorafenib were significantly different between the R-L and non-R-L groups, whereas the albumin-bilirubin score, Child-Pugh class, and tumor burden were not. Progression-free survival was also not significantly different (median 4.1 vs. 3.8 months, p = 0.586). As for overall survival, the R-L group showed better prognosis after introducing regorafenib and after introducing sorafenib, following inverse probability weighting adjustment (MST 19.7 vs. 10.3 months, 33.8 vs. 15.3 months, p < 0.001 and p = 0.022, respectively). Modified albumin-bilirubin grade 2b (score >-2.27) at the start of regorafenib (HR 2.074, p = 0.041) and the presence of lenvatinib treatment after regorafenib failure (HR 0.355, p = 0.004) were found to be significant prognostic factors in Cox proportional hazards multivariate analysis, after inverse probability weighting adjustment. CONCLUSION: These results show that lenvatinib is a good sequential treatment option after progression under regorafenib therapy in unresectable hepatocellular carcinoma patients with better hepatic reserve function.

Duodenal sessile serrated adenoma/polyp with characteristic endoscopic and pathologic features.

Sessile serrated adenomas/polyps (SSA/Ps), recently called sessile serrated lesions, have a neoplastic pathway in the large intestine and are treated as lesions with malignant potential. There are a few reports of traditional serrated adenomas in the duodenum but no reports of duodenal SSA/Ps. A 66-year-old man underwent screening upper gastrointestinal endoscopy and was found to have a white elevated lesion in the second portion of the duodenum. Magnifying blue laser imaging showed various sized villous-like structures with dilated crypt openings in the white surface mucosa, similar to a SSA/P. Based on these images, a duodenal adenoma was suspected at the time of endoscopic resection. Pathological findings of the resected specimen showed a saw-tooth structure corresponding to basal crypt dilatation and branching with mucus and positive immunostaining for MUC6 and MUC2, similar to a colonic SSA/P. MUC5AC did not stain the glandular crypt cells. KRAS mutation was detected. Immunohistochemical expression of Annexin A10 was clearly identified in the lesion. Although not all of molecular biological features were satisfied, these findings were similar to a colonic SSA/P which has malignant potential. This is the first report of a duodenal SSA/P which should be considered when evaluating elevated duodenal lesions.