Familial Adenomatous Polyposis with Atypical Clinical Morphology and Genetic Variants.

Familial adenomatous polyposis (FAP) is caused by pathogenic variants of the APC gene on the long arm of chromosome 5. An analysis showed an association between germline APC gene variants and clinical signs of FAP; however, attenuated FAP has also been reported in cases with pathogenic variants. In contrast, a phenotype of FAP with no APC germline pathogenic variant and with few signs has been reported. We herein report a 16-year-old girl in whom the presence of multiple large bowel cancers from a young age and several small bowel cancers reflected a carcinogenic tendency higher than that typical for FAP.

Real-World Data on Short-Term and Long-Term Treatment Results of Ustekinumab in Patients with Steroid-Resistant/Dependent Ulcerative Colitis.

Introduction: Ustekinumab is an IgG1 kappa monoclonal antibody directed against the common p40 subunit of interleukin-12 and interleukin-23, which activate Th1- and Th17-mediated immune responses, respectively. It has proven efficacy for the treatment of moderate to severe ulcerative colitis (UC) in the UNIFI phase III clinical trial; however, data on its efficacy in the real world are limited. In this study, we aimed to assess the real-world efficacy of ustekinumab. Methods: This observational study included 30 patients with UC who received ustekinumab from April 2020 to April 2022. We examined demographic information, disease type and activity (Mayo score, partial Mayo score [PMS]), use of biologics, concomitant use of predonisolone (PSL), 8-week ustekinumab clinical response rate, remission induction rate, 44- and 152-week remission maintenance rate, continuation rate, and 44-week steroid-free remission rate. The primary outcomes were the short- and long-term efficacy of ustekinumab. Results: Included patients (53% women; mean age: 41.2 years [16-80 years]) had an average disease duration of 86 weeks. The Mayo score (median) was 7.4 and the PMS was 5.4. Two (7%), 24 (80%), and four (13%) patients had a Mayo endoscopic subscore (MES) of MES1, MES2, and MES3, respectively. The median serum CRP was 1.0 mg/dL. Five patients had no history of biotherapy (naive), while eight and 17 had a history of one and two or more biologic agents, respectively. Eight patients were PSL-resistant and 22 were PSL-dependent. The 8-week clinical response rate was 73% and the clinical remission induction rate was 70%. The remission maintenance rates at 44 and 152 weeks were 67% and 63%, respectively. The ustekinumab retention rate was 67% (86-week mean follow-up period). Regarding biologic failure cases, the clinical response rate in the failure group with up to one biologic agent (including naive cases) was 84.6%, which was higher than the 58.0% rate in the failure group with two or more biologic agents (p = 0.06). Steroid-free remission rates at 44 and 152 weeks were 63% each. In the logistic regression analysis parameters for discontinuation of ustekinumab, only PMS remained significant after multivariate analysis (p = 0.018). Conclusion: Our study showed short-term and long-term ustekinumab effectiveness, especially with comparative low disease activity.

Serum leucine-rich alpha-2 glycoprotein in monitoring disease activity and intestinal mucosal healing for biotherapy-naïve cases with ulcerative colitis.

Background and Aim: Serum leucine-rich alpha-2 glycoprotein level has been reported to be a useful biomarker in assessing mucosal healing in patients undergoing biotherapy, where mucosal lesions caused by ulcerative colitis are difficult to assess endoscopically. However, no such reports have been reported in biotherapy-naïve cases. Methods: Sixty-eight patients with ulcerative colitis (UC) who were biotherapy-naïve at Kindai University Hospital between October 2021 and October 2022 were enrolled. We prospectively examined the correlation between leucine-rich alpha-2 glycoprotein (LRG), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and Geboes scores with clinical endoscopic activity using the Mayo endoscopic subscore (MES). Results: Mucosal healing was achieved in 39 (57%) patients. Univariate analysis revealed that the factors associated with mucosal healing were LRG (P = 0.0024), CRP (P = 0.1078), ESR (P = 0.0372), and Geboes scores (P = 0.0075). Logistic regression analysis identified LRG and Geboes scores as independent factors associated with mucosal healing assessed using MES (P = 0.0431 for LRG and P = 0.0166 for Geboes scores). Conclusion: LRG was found to be the easiest marker to monitor disease activity and mucosal inflammation in UC patients with biotherapy-naïve cases, with a performance equivalent to that of Geboes scores.

Long-Term Survival of More than 5 Years with Maintenance Therapy Using Single-Agent Pemetrexed in a Patient with Diffuse Malignant Peritoneal Mesothelioma.

A 76-year-old woman presented with lower abdominal pain and nausea and was referred to the gastroenterology department in our institution. Previous contrast-enhanced computed tomography (CE-CT) for follow-up after breast cancer surgery had indicated a soft tissue mass below the right diaphragm, which was considered a benign change. CE-CT performed at the first visit to our department revealed further thickening of the soft tissue mass with extension to the liver surface. In addition, ascites and nodules were observed in the abdominal cavity. Histopathological examination of a biopsy specimen revealed peritoneal invasion of atypical epithelioid cells with trabecular and glandular patterns. The tumor cells were positive for AE1/AE2, calretinin, WT-1, D2-40, HEG1, EMA, BAP1, and MTAP and negative for carcinoembryonic antigen, MOC-31, Ber-Ep4, ER, PgR, TTF-1, claudin 4, and desmin. A diagnosis of epithelioid mesothelioma was made. The patient received chemotherapy with cisplatin (75 mg/m2) and pemetrexed (500 mg/m2). After six courses of combined chemotherapy, pemetrexed was administered as a single agent. At the time of writing this report, she was undergoing over the 30th course of chemotherapy without any significant side effects. Diffuse malignant peritoneal mesothelioma is a rare, fatal, and progressive disease. Our patient achieved long-term survival of more than 5 years with maintenance therapy using single-agent pemetrexed.

Successful initial tofacitinib treatment for acute severe ulcerative colitis with steroid resistance: a case series.

Background: The standard therapy for acute severe ulcerative colitis (ASUC) is intravenous corticosteroids; however, 30% of ulcerative colitis (UC) patients do not recover with corticosteroids alone. Few studies have reported the efficacy and safety of tofacitinib for ASUC with steroid resistance. We report a case series of successful first-line treatment consisting of tofacitinib (20 mg/day) administered to ASUC patients with steroid resistance. Methods: Patients diagnosed with ASUC at our institution between October 2018 and February 2020 were retrospectively evaluated. They were administered a high dose of tofacitinib (20 mg) after showing no response to steroid therapy in a dose of 1-1.5 mg/kg/day. Results: Eight patients with ASUC, 4 (50%) men, median age 47.1 (range 19-65) years, were included. Four patients were newly diagnosed, and the median UC duration was 4 (range 0-20) years. Six of the 8 patients were able to avoid colectomy. One patient (patient 2) had no response; however, remission was achieved after switching from tofacitinib to infliximab. One patient (patient 6) with no response to tofacitinib underwent total colectomy. Only one patient (patient 4) experienced an adverse event, local herpes zoster, treated with acyclovir without tofacitinib discontinuation. Conclusions: Clinical remission without serious adverse events can be achieved with high probability and colectomy can be avoided by first administering high-dose tofacitinib to steroid-resistant ASUC patients. Tofacitinib may be one of the first-line treatment options for steroid-resistant ASUC.

Case Report: Regulatory T Cell-Independent Induction of Remission in a Patient With Collagenous Colitis.

Collagenous colitis (CC), a prototypical microscopic colitis, is a chronic inflammatory disorder of the colon. The diagnosis of CC depends on the pathological examination. The colonic mucosa of patients with CC is characterized by the presence of a substantially thickened collagen band (>10µm) under the surface epithelium. In addition, intraepithelial and lamina propria lymphocytes are markedly increased in patients with CC. However, the roles played by the lymphocytes accumulating in the colonic mucosa of patients with CC are poorly defined. Recent studies indicate that T cells infiltrating the colonic mucosa of patients with CC are mainly represented by CD4+ T cells, CD8+ T cells, and forkhead box P3 (FOXP3)+ regulatory T cells (Tregs). Given that activation of CD4+/CD8+ T cells and FOXP3+ Tregs usually mediates pro-inflammatory and anti-inflammatory responses, respectively, alterations in the colonic numbers of these adaptive T cells might be related to the resolution of colitis in patients with CC. We determined alterations in the composition of colonic T cells by extensive immunohistochemical (IHC) analyses in a case of CC successfully treated with budesonide and metronidazole. Colonic lamina propria immune cells mainly comprised CD3+ T cells, CD4+ T cells, CD8+ T cells, CD68+ macrophages, and FOXP3+ Tregs, but not CD20+ B cells or myeloperoxidase (MPO)+ granulocytes in the active phase. During remission, the numbers of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD68+ macrophages did not change significantly in the colonic lamina propria, whereas FOXP3+ Tregs were markedly decreased, suggesting that induction of remission was achieved in a Treg-independent manner. Thus, our study indicates that accumulation of FOXP3+ Tregs in the colonic mucosa of patients with CC might be a counter-regulatory mechanism reflecting persistent inflammation and that induction of remission might be achieved without activation of Tregs.

A case with Crohn's disease-associated spondyloarthritis exhibiting enhanced pro-inflammatory cytokine responses to Toll-like receptor ligands.

BACKGROUND: Despite the high incidence of spondyloarthritis (SpA) as an extra-intestinal manifestation of Crohn's disease (CD), the immunopathogenesis of CD-associated SpA remains largely unknown. OBJECTIVE: We tried to explore molecular mechanisms accounting for the development of CD-associated SpA in a patient successfully treated with infliximab. METHODS: Peripheral blood mononuclear cells (PBMCs) before infliximab treatment were stimulated with Toll-like receptor (TLR) ligands to measure pro-inflammatory cytokine responses. Endoscopic biopsy samples before and after infliximab treatment were subjected to quantitative polymerase chain reaction. RESULTS: PBMCs from this CD-associated SpA patient exhibited higher production of pro-inflammatory cytokines upon stimulation with TLR ligands than PBMCs from healthy controls. Induction of remission by infliximab was associated with the downregulation of pro-inflammatory cytokine responses in the small intestinal mucosa, which is continually exposed to TLR ligands. CONCLUSIONS: Excessive pro-inflammatory cytokine responses to TLR ligands might underlie the immunopathogenesis of CD-associated SpA.

Efficacy of Verbally Describing One's Own Body Movement in Motor Skill Acquisition.

The present study examined whether (a) verbally describing one's own body movement can be potentially effective for acquiring motor skills, and (b) if the effects are related to motor imagery. The participants in this study were 36 healthy young adults (21.2 ± 0.7 years), randomly assigned into two groups (describing and control). They performed a ball rotation activity, with the describing group being asked by the examiner to verbally describe their own ball rotation, while the control group was asked to read a magazine aloud. The participants' ball rotation performances were measured before the intervention, then again immediately after, five minutes after, and one day after. In addition, participants' motor imagery ability (mental chronometry) of their upper extremities was measured. The results showed that the number of successful ball rotations (motor smoothness) and the number of ball drops (motor error) significantly improved in the describing group. Moreover, improvement in motor skills had a significant correlation with motor imagery ability. This suggests that verbally describing an intervention is an effective tool for learning motor skills, and that motor imagery is a potential mechanism for such verbal descriptions.

Risk factors for local recurrence and appropriate surveillance interval after endoscopic resection.

BACKGROUND: Risk factors for local recurrence after polypectomy, endoscopic mucosal resection (EMR), and endoscopic submucosal dissection (ESD) have not been identified. Additionally, the appropriate interval for endoscopic surveillance of colorectal tumors at high-risk of local recurrence has not been established. AIM: To clarify the clinicopathological characteristics of recurrent lesions after endoscopic colorectal tumor resection and determine the appropriate interval. METHODS: Three hundred and sixty patients (1412 colorectal tumors) who underwent polypectomy, EMR, or ESD and received endoscopic surveillance subsequently for more than one year to detect local recurrence were enrolled in this study. The clinicopathological factors associated with local recurrence were determined via univariate and multivariate analyses. RESULTS: Local recurrence was observed in 31 of 360 (8.6%) patients [31 of 1412 (2.2%) lesions] after colorectal tumor resection. Piecemeal resection, tumor size of more than 2 cm, and the presence of villous components were associated with colorectal tumor recurrence after endoscopic resection. Of these three factors, the piecemeal resection procedure was identified as an independent risk factor for recurrence. Colorectal tumors resected into more than five pieces were associated with a high risk of recurrence since the average period from resection to recurrence in these cases was approximately 3 mo. The period to recurrence in cases resected into more than 5 pieces was much shorter than that in those resected into less than 4 pieces (3.8 ± 1.9 mo vs 7.9 ± 5.0 mo, P < 0.05). CONCLUSION: Local recurrence of endoscopically treated colorectal tumors depends upon the outcome of first endoscopic procedure. Piecemeal resection was the only significant risk factor associated with local recurrence after endoscopic resection.

Usefulness of Ustekinumab for Treating a Case of Myelodysplastic Syndrome-associated Inflammatory Bowel Disease.

Autoimmune diseases including inflammatory bowel disease (IBD) occur in association with myelodysplastic syndrome (MDS). MDS-associated IBD frequently demonstrates a complicated course. We herein report the first case with MDS-associated IBD that was successfully treated with ustekinumab (UST), an anti-interleukin (IL) 12/23p40 monoclonal antibody. A 63-year-old man with a 7-year history of MDS was referred for examination of diarrhea, abdominal pain and fever. A blood examination revealed a marked elevation of C-reactive protein. Colonoscopy showed multiple ulcers in the terminal ileum. He was resistant to anti-tumor necrosis factor (TNF)-α antibody and azacitidine. Subsequently, UST treatment reduced colonic IL-17 and IL-6 expression and the patient currently maintains a state of remission.

Efficacy and Safety of Chemotherapy Following Anti-PD-1 Antibody Therapy for Gastric Cancer: A Case of Sclerosing Cholangitis.

Immunotherapy targeting programmed cell death-1 (PD-1) signaling is becoming the standard of care for advanced gastric cancer. We herein report a patient with gastric adenocarcinoma with peritoneal dissemination who was treated with nab-paclitaxel and ramucirumab following nivolumab and developed sclerosing cholangitis. Endoscopic retrograde cholangiography showed irregular narrowing and widening of the entire intrahepatic biliary system. Intriguingly, the patient receiving second-line chemotherapy with nab-paclitaxel plus ramucirumab prior to being administered nivolumab, however, he had experienced progressive disease. Thereafter, the administration of fourth-line chemotherapy with nab-paclitaxel and ramucirumab following nivolumab resulted in a clinical response. Nivolumab may enhance the efficacy of the subsequent chemotherapy regimens but also induce sclerosing cholangitis.

Induction of Complete Remission by Azacitidine in a Patient with Myelodysplastic Syndrome-Associated Inflammatory Bowel Disease.

Myelodysplastic syndrome [MDS] is a clonal disorder of bone marrow [BM] cells, caused by acquired chromosomal abnormalities and gene mutations. Pro-inflammatory antigen-presenting cells [APCs] originating from BM cells bearing chromosomal abnormalities and gene mutations can cause immune-mediated disorders including inflammatory bowel disease [IBD]. Here, we report the first case with MDS-associated IBD that was successfully treated with the DNA methyltransferase inhibitor, azacitidine [AZA]. A 75-year-old man with a 5-year history of MDS was admitted for examination of diarrhoea and high fever. Blood examination revealed pancytopenia and a marked elevation of C-reactive protein. Colonoscopy revealed multiple round ulcers from the terminal ileum to the sigmoid colon. Pathological examination of the endoscopic biopsy specimens showed destruction of crypt architecture and infiltration of CD3+ T cells and CD68+ macrophages. Surprisingly, administration of AZA, which has been approved for the treatment of high-risk MDS, improved the symptoms, and the multiple round ulcers disappeared. AZA treatment markedly decreased the expressions of tumour necrosis factor-α, interleukin-12 (IL-12)/23p40 and IL-17 in colonic biopsy samples, as assessed by quantitative reverse transcription polymerase chain reaction. In contrast, AZA treatment did not change the expression of forkhead box P3, a master regulator of regulatory T cells. These data suggest that AZA treatment led to complete remission in MDS-associated IBD through suppression of pro-inflammatory cytokine responses.

Risk Factors for Postoperative Bleeding in Endoscopic Submucosal Dissection of Colorectal Tumors.

BACKGROUND: Colonoscopic removal of adenomatous polyps or early cancer prevents death from colorectal cancer. Endoscopic submucosal dissection (ESD), which enables endoscopists to perform en bloc resection of flat or depressed colorectal tumors >20 mm, has recently been introduced and become a standard procedure in Japan. Although postoperative bleeding (POB) is a major complication associated with ESD, risk factors for POB have not been fully identified. METHODS: A total of 451 patients (509 lesions) who underwent colorectal ESD were retrospectively analyzed to identify clinical parameters associated with POB. RESULTS: POB occurred in 14 patients, and 7 of them had received antithrombotic therapy before ESD. Uni- and multivariate analyses revealed that antithrombotic therapy and rectal tumor location were strongly associated with POB following colorectal ESD. The incidence of POB was higher in patients on heparin bridge therapy (HBT) for the replacement of antithrombotic therapy than in patients with no HBT. Four of 7 patients (57.1%) on antithrombotic therapy experienced POB from the rectal lesions. CONCLUSION: Antithrombotic therapy and rectal lesions result in a higher POB incidence after colorectal ESD.

Computer-Aided Diagnosis Based on Convolutional Neural Network System for Colorectal Polyp Classification: Preliminary Experience.

BACKGROUND AND AIM: Computer-aided diagnosis (CAD) is becoming a next-generation tool for the diagnosis of human disease. CAD for colon polyps has been suggested as a particularly useful tool for trainee colonoscopists, as the use of a CAD system avoids the complications associated with endoscopic resections. In addition to conventional CAD, a convolutional neural network (CNN) system utilizing artificial intelligence (AI) has been developing rapidly over the past 5 years. We attempted to generate a unique CNN-CAD system with an AI function that studied endoscopic images extracted from movies obtained with colonoscopes used in routine examinations. Here, we report our preliminary results of this novel CNN-CAD system for the diagnosis of colon polyps. METHODS: A total of 1,200 images from cases of colonoscopy performed between January 2010 and December 2016 at Kindai University Hospital were used. These images were extracted from the video of actual endoscopic examinations. Additional video images from 10 cases of unlearned processes were retrospectively assessed in a pilot study. They were simply diagnosed as either an adenomatous or nonadenomatous polyp. RESULTS: The number of images used by AI to learn to distinguish adenomatous from nonadenomatous was 1,200:600. These images were extracted from the videos of actual endoscopic examinations. The size of each image was adjusted to 256 × 256 pixels. A 10-hold cross-validation was carried out. The accuracy of the 10-hold cross-validation is 0.751, where the accuracy is the ratio of the number of correct answers over the number of all the answers produced by the CNN. The decisions by the CNN were correct in 7 of 10 cases. CONCLUSION: A CNN-CAD system using routine colonoscopy might be useful for the rapid diagnosis of colorectal polyp classification. Further prospective studies in an in vivo setting are required to confirm the effectiveness of a CNN-CAD system in routine colonoscopy.

Magnifying Narrow Band Imaging (NBI) for the Diagnosis of Localized Colorectal Lesions Using the Japan NBI Expert Team (JNET) Classification.

OBJECTIVE: The Japan NBI Expert Team (JNET) proposed a new narrow band imaging (NBI) classification system for colorectal tumors in June 2014. In this classification system, types 1, 2A, 2B, and 3 correspond to hyperplastic polyps (HPs) including sessile serrated polyps (SSPs), low-grade dysplasia (LGD), high-grade dysplasia (HGD) to shallow submucosal invasive (SM-s) carcinomas, and deep submucosal invasive (SM-d) carcinomas, respectively. METHODS: To validate this system, we performed a retrospective image evaluation study, in which 199 colorectal tumors previously assessed by NBI magnifying endoscopy were classified by 3 blinded experienced colonoscopists using the JNET system. The results were compared with the final pathological diagnoses to determine the JNET classification's accuracy. The interobserver agreement was calculated, and the intraobserver agreement was assessed after 6 months. RESULTS: The final pathological diagnoses identified 14 HPs/SSPs, 127 LGDs, 22 HGDs, 19 SM-s carcinomas, and 17 SM-d carcinomas. The respective sensitivities, specificities, positive predictive value, negative predictive value, and accuracies were as follows: Type 1, 85.7, 99.5, 92.3, 98.9, and 98.5%; Type 2A, 96.0, 81.9, 90.3, 92.1, and 90.9%; Type 2B, 75.6%, 90.5, 67.3, 93.4, and 87.4%; and Type 3, 29.4%, 100, 100, 93.8, and 94.0%. The interobserver agreement and the intraobserver agreement were moderate (κ value: 0.52) and excellent (κ value: 0.88), respectively. Lesions presenting as Type 2B during NBI comprised a range of colorectal tumors, including HGDs, SM-s, and SM-d. CONCLUSIONS: The JNET classification was useful for the diagnosis of HPs/SSPs, LGDs, and SM-d, but not SM-s lesions. For low-confidence cases, magnified chromoendoscopy is recommended to ensure correct diagnoses.

Clinical Analysis of Esophageal Stricture in Patients Treated with Intralesional Triamcinolone Injection after Endoscopic Submucosal Dissection for Superficial Esophageal Cancer.

INTRODUCTION: Endoscopic submucosal dissection (ESD) has been widely used in the resection of superficial esophageal cancers. Since its use has been extended to cases involving large esophageal tumors occupying nearly the whole or the whole circumference of the lumen, the occurrence of esophageal stricture has increased. Although endoscopic injection of triamcinolone (TA) is widely used for the prevention of postoperative stricture, a significant number of patients still develop stricture after TA injection therapy. METHODS: We performed a retrospective study to identify the clinical parameters that predispose post-ESD patients to esophageal stricture after TA injection therapy. RESULTS: A total of 207 patients who were diagnosed with superficial esophageal cancer and subsequently underwent ESD were enrolled in this study. Among these patients, 53 patients and 57 lesions bearing mucosal defects covering greater than two-thirds of the esophageal circumference after ESD were treated with TA injection therapy. The rate of esophageal stricture was found to be highest in cases involving mucosal defects that covered more than seven-eighths of the circumference. CONCLUSION: Endoscopic TA injection is not sufficient for preventing esophageal stricture in patients bearing mucosal defects covering more than seven-eighths of the esophageal circumference after ESD.

Prophylactic Suturing Closure Is Recommended after Endoscopic Treatment of Colorectal Tumors in Patients with Antiplatelet/Anticoagulant Therapy.

The prophylactic closure of mucosal defects after endoscopic resection is known to prevent postoperative bleeding in colorectal lesions. However, closure of large mucosal defects is difficult with conventional clips only, and several closure techniques have been previously described; use of an Endoloop, 8-ring loop, or loop clip and a small incision around the mucosal defect. Given that the prophylactic closure requires much cost and time, the application should be limited to high-risk cases. Medication of antithrombotics or antiplatelet agents would be one of the reasonable indications for prophylactic closure of mucosal defects after endoscopic resection of colorectal tumors.

Comparative Study of Clarithromycin- versus Metronidazole-Based Triple Therapy as First-Line Eradication for Helicobacter pylori.

INTRODUCTION: Clarithromycin (CAM)-based triple therapy comprising proton pump inhibitors and amoxicillin is administered as first-line eradication treatment against Helicobacter pylori infection. However, the eradication rate achieved with CAM-based triple therapy has decreased to <80% owing to the emergence of CAM-resistant strains. This prospective randomized study aimed to compare the efficacy of CAM-based and metronidazole (MNZ)-based triple therapy in terms of H. pylori eradication. METHODS: H. pylori-positive patients were treated with CAM-based triple therapy comprising esomeprazole and amoxicillin (EAC group) or with MNZ-based triple therapy comprising esomeprazole and amoxicillin (EAM group). RESULTS: H. pylori eradication rates achieved in the intention-to-treat (ITT) and per protocol (PP) analyses were 70.6 and 72.7%, respectively, in the EAC group. Eradication rates obtained via ITT and PP analyses were 91.7 and 94.3%, respectively, in the EAM group. In the EAC group, eradication rates were significantly lower in patients harboring CAM-resistant strains than in those harboring CAM-sensitive strains. In contrast, eradication rates were comparable between patients harboring CAM-resistant strains and those harboring CAM-sensitive strains in the EAM group. CONCLUSION: MNZ-based triple therapy consisting of esomeprazole and amoxicillin is superior to CAM-based triple therapy containing esomeprazole and amoxicillin as first-line eradication treatment against H. pylori.

Unique Characteristics Associated with Sustained Liver Damage in Chronic Hepatitis C Patients Treated with Direct Acting Antivirals.

BACKGROUND AND AIMS: Direct-acting antivirals (DAAs) dramatically improve the sustained virological response (SVR) of chronic hepatitis C (CHC) patients. However, continuous liver damage after SVR may be a risk of hepatocellular carcinoma (HCC). We clarified pretreatment characteristics related to sustained liver damage after SVR. METHODS: A total of 286 CHC patients were treated with an interferon-free DAA regimen. Among them, 250 patients achieved SVR for 12 weeks after the end of treatment (SVR12); these individuals were classified based on α-fetoprotein (AFP) and alanine transaminase (ALT) levels posttreatment. Baseline characteristics significantly associated with AFP >5 ng/mL and ALT level ≥20 IU/L after SVR were clarified using multivariate analyses. RESULTS: Among the pretreatment factors examined, serum AFP values and the presence of fatty liver (FL) were significantly associated with abnormal AFP (p < 0.0001) and ALT levels 12 weeks after SVR12 (SVR24; p = 0.0109). For 126 patients who showed an increase in baseline AFP level, FL, fibrosis-4 (FIB-4) index, and albumin levels before treatment were related to abnormal AFP at SVR24 (p = 0.0005, 0.0232, and 0.0400 for FL, FIB-4 index, and albumin, respectively). Similarly, for 150 patients with abnormal baseline ALT levels, FL was associated with an ALT level ≥ 30 IU/L after SVR (p = 0.0430). CONCLUSIONS: High FIB-4 index, low albumin level, and FL before DAA treatment were associated with a risk of sustained liver damage with AFP and ALT elevation after SVR; patients with these factors should be carefully monitored for emergence of HCC.

Hepatocellular Carcinoma after Achievement of Sustained Viral Response with Daclatasvir and Asunaprevir in Patients with Chronic Hepatitis C Virus Infection.

BACKGROUND: Interferon-based antiviral therapies against hepatitis C virus (HCV) infection have been shown to reduce the incidence of hepatocellular carcinoma (HCC) in patients with sustained viral response (SVR). Recently, direct-acting antivirals (DAAs) have been proven to be much more effective in achieving SVR than interferon-based therapies. However, whether DAAs can efficiently prevent the occurrence of HCC after SVR remains controversial. To clarify this issue, we analyzed the clinical features of patients in whom HCC developed after achievement of SVR with DAAs for chronic HCV infection. SUMMARY: Among patients who achieved SVR with daclatasvir and asunaprevir (n = 100), HCC developed in 17 patients (HCC group; n = 17) and did not develop in 83 patients (non-HCC group; n = 83) during a mean observation period of 15 months. A multivariate Cox proportional hazards analysis identified past history of HCC and male sex as significant risk factors for the emergence of HCC after DAAs. Sixteen cases with HCC after DAAs were in the very early or early stage (16/17, 94.1%), and one case was in the advanced stage (1/17, 5.9%) with portal venous tumor thrombus. Radiofrequency ablation and/or transarterial chemoembolization were performed in most cases as curative therapy (16/17, 94.1%). Key Messages: SVR by DAAs did not completely prevent the occurrence of HCC. However, even if HCC did develop after SVR, curative anticancer therapy was applicable in most cases.