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A 70-year-old woman was diagnosed with intramucosal rectal cancer and advanced sigmoid colon cancer at the same time. First, the intramucosal rectal cancer was curatively resected by endoscopic submucosal dissection, and surgery was subsequently performed for sigmoid colon cancer. After 20 months, a follow-up colonoscopy revealed a tumor growth at the ulcer scar of the endoscopic submucosal dissection. Histological findings and KRAS mutation analysis suggested implantation of sigmoid colon cancer to the post-endoscopic submucosal dissection site of intramucosal rectal cancer.

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The emergence of hepatitis C virus (HCV) with resistance-associated substitution (RAS), produced by mutations in the HCV genome, is a major problem in direct acting antivirals (DAA) treatment. This study aimed to clarify the mutational spectrum in HCV-RNA and the substitution pattern for the emergence of RASs in patients with chronic HCV infection. HCV-RNA from two HCV replicon cell lines and the serum HCV-RNA of four non-liver transplant and four post-liver transplant patients with unsuccessful DAA treatment were analyzed using high-accuracy single-molecule real-time long-read sequencing. Transition substitutions, especially A>G and U>C, occurred prominently under DAAs in both non-transplant and post-transplant patients, with a mutational bias identical to that occurring in HCV replicon cell lines during 10-year culturing. These mutational biases were reproduced in natural courses after DAA treatment. RASs emerged via both transition and transversion substitutions. NS3-D168 and NS5A-L31 RASs resulted from transversion mutations, while NS5A-Y93 RASs was caused by transition substitutions. The fidelity of the RNA-dependent RNA polymerase, HCV-NS5B, produces mutational bias in the HCV genome, characterized by dominant transition mutations, notably A>G and U>C substitutions. However, RASs are acquired by both transition and transversion substitutions, and the RASs-positive HCV clones are selected and proliferated under DAA treatment pressure.

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A 60-year-old woman presented with a protruding tumor at the anterior wall of the middle gastric body, and she was positive for anti-parietal cells antibodies with elevated serum gastrin level. Final diagnosis was a mixed neuroendocrine-non-neuroendocrine neoplasm consisting of adenocarcinoma (tub1) and neuroendocrine tumor G2 with autoimmune gastritis.

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Ulcerative colitis (UC) is a chronic relapsing inflammatory disorder of the colon. Patients with UC have an increased risk of developing colorectal cancer. However, appendix adenocarcinoma associated with UC is extremely rare.

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While direct-acting antivirals (DAAs) for hepatitis C virus (HCV) have dramatically progressed, patients still suffer from treatment failures. For the radical eradication of HCV, a deeper understanding of multiple resistance-associated substitutions (RASs) at the single-clone level is essential. To understand HCV quasispecies and their dynamics during DAA treatment, we applied single-molecule real-time (SMRT) deep sequencing on sera from 12 patients with genotype-1b HCV infections with DAA treatment failures, both pre- and post-treatment. We identified >3.2 kbp sequences between NS3 and NS5A genes of 187,539 clones in total, classifying into haplotype codes based on the linkage of seven RAS loci. The number of haplotype codes during the treatment, per sample, significantly decreased from 14.67 ± 9.12 to 6.58 ± 7.1, while the number of nonsynonymous codons on the seven RAS loci, per clone, significantly increased from 1.50 ± 0.92 to 3.64 ± 0.75. In five cases, the minority multi-drug resistant haplotypes at pre-treatment were identical to the major haplotypes at relapse. Moreover, various structural variations (SVs) were detected and their dynamics analysed. These results suggest that SMRT deep sequencing is useful for detecting minority haplotypes and SVs, and to evaluate the dynamics of viral genomes at the single-clone level.

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Lenvatinib was recently approved as a novel first-line molecular targeted agent (MTA) for treating hepatocellular carcinoma (HCC). The importance of relative dose intensity (RDI) has been shown in the treatment of various types of cancers. However, RDI may not accurately reflect the treatment intensity of lenvatinib, as it is the first oral MTA where the dose is based on the patient's weight. We aimed to evaluate the utility of 2M-DBR (the delivered dose intensity/body surface area ratio at 60 days) by comparing the relationship between 2M-DBR, 2M-RDI (RDI at 60 days), and the therapeutic response. The therapeutic response to lenvatinib was evaluated in 45 patients who underwent computed tomography 8-12 weeks after treatment initiation. We also investigated the clinical factors associated with high 2M-DBR. The area under the receiver operating characteristic of 2M-DBR that predicts the response to lenvatinib was higher than that of 2M-RDI (0.8004 vs. 0.7778). Patients with high 2M-DBR achieved significantly better objective responses and disease control rates than those with low 2M-DBR (p < 0.0001 and 0.0008). Patients with high 2M-DBR experienced significantly longer progression-free survival (PFS) than those with low 2M-DBR (p = 0.0001), while there was no significant correlation between 2M-RDI levels and PFS (p = 0.2198). Patients who achieved higher levels of 2M-DBR had a significantly better modified ALBI grade (p = 0.0437), better CONUT score (p = 0.0222), and higher BTR (p = 0.0281). Multivariate analysis revealed that high 2M-DBR was the only significant factor associated with longer PFS. In conclusion, 2M-DBR could be an important factor that reflects treatment intensity and useful for predicting the response to lenvatinib against HCC, instead of 2M-RDI.

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AIM: Recent advances in next-generation sequencing (NGS) technologies allow for evaluation of genetic alterations in various cancer-related genes in daily clinical practice. Archival formalin-fixed paraffin-embedded (FFPE) tumor tissue is often used for NGS-based clinical sequencing assays; however, the success rate of NGS assays using archival FFPE tumor tissue is reported to be lower than that using fresh tumor tissue. We aimed to evaluate the feasibility and safety of ultrasound (US)-guided liver tumor biopsy for NGS-based multiplex gene assays. METHODS: We compared the success rate of NGS assays between archival FFPE tumor tissues and US-guided liver tumor biopsy tissues, and summarized the treatment progress of the patients. RESULTS: Next-generation sequencing assays using US-guided liver biopsy samples were successful in all patients (22/22), whereas the success rate with archival FFPE tumor tissue was 84.8% (151/178, P < 0.05). At least one potentially actionable genetic alteration was identified from the US-guided liver biopsy samples in 20 of 22 patients. Among the 18 patients with actionable genetic alterations targetable with drugs approved by the US Food and Drug Administration, eight initiated mutation-driven targeted therapies. Of these eight patients, four achieved partial response or stable disease for at least 4 months, and three were not assessable for response due to short exposure. There were no biopsy-related complications requiring additional treatment. CONCLUSION: Our findings suggest that US-guided liver tumor biopsy is a useful and safe method for obtaining high-quality samples for NGS-based clinical sequencing. In cases with metastatic liver tumors, US-guided biopsy should be considered to provide accurate and optimal sequencing results for patients.

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A 36-year-old woman was admitted to our hospital due to swelling and redness of the left lateral malleolus and dorsum of the left foot with severe pain, with a flare-up of ulcerative colitis (UC). A pathologic examination by skin biopsy led to a diagnosis of pyoderma gangrenosum (PG). She was treated with the intravenous administration of prednisolone (60 mg/day), and granulocyte and monocyte adsorption apheresis (GMA) was performed twice-a-week for 5 weeks. This treatment dramatically improved both the skin and colonic mucosal lesions. These results suggest that a combination of GMA and corticosteroids might be recommendable to induce the remission of serious PG complicated with UC.

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We experienced a case of primary intestinal follicular lymphoma and premature atherosclerosis in a diabetic patient with familial partial lipodystrophy (FPL) that was detected when the patient was evaluated for laparoscopic sleeve gastrectomy (LSG). As FPL is generally considered to be rare, FPL is often underdiagnosed, especially in obese patients. Therefore, the prevalence of FPL is higher than previous estimates. Our case illustrates that clinicians should perform screening for atherosclerosis and malignancy at the preoperative evaluation and may need to perform metabolic surgery earlier to prevent the development of excess truncal fat, complicated diabetes and atherosclerosis in patients with FPL.

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A 59-year-old man treated with 5-fluorouracil and cisplatin for advanced oesophageal cancer presented abnormal behaviour and subsequently developed impairment of cognitive function, dysphagia and dysarthria on the fifth day of the treatment. Although brain computed tomography revealed no abnormal findings, brain magnetic resonance imaging using diffusion-weighted imaging clearly revealed the presence of a high signal intensity in the deep white matter of the bilateral cerebral hemispheres, including the corpus callosum symmetrically. A diagnosis of acute leukoencephalopathy was reached based on these findings. His clinical symptoms normalized four days after the discontinuation of the chemotherapy. Improvement in magnetic resonance imaging findings was delayed compared with that of clinical symptoms; however, the high signal intensity detected in the deep white matter had disappeared completely five months after the onset of symptoms. Early detection of drug-induced leukoencephalopathy is important as the clinical symptoms can be reversed by early discontinuation of the causative drug. Diffusion-weighted magnetic resonance imaging is a useful modality for the early detection and definitive diagnosis of this characteristic encephalopathy.

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A 75-year-old woman who had been given a diagnosis of a giant liver cyst occupying the right hepatic lobe was admitted to our hospital complaining of abdominal pain. CT examination revealed the size of cyst was smaller than before and the level of CRP was elevated, suggesting the development of peritonitis due to rupture of the cyst. As Candida albicans was detected from both ascites and the cyst, we treated her with continuous percutaneous transhepatic drainage and antimycotic agents. The cyst markedly diminished, and she became free of infection and peritonitis, suggesting drainage was exceedingly effective.

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BACKGROUND/AIMS: Although chromosomal abnormalities in bone marrow (BM) cells, such as trisomy 8, are risk factors for the development of inflammatory bowel diseases (IBD) as well as myelodysplastic syndrome (MDS), the mechanisms of how these cytogenetic abnormalities cause intestinal inflammation are poorly understood. METHODS AND RESULTS: A 55-year-old man with a 3-month history of watery diarrhea, fever and abdominal pain was admitted. Blood examinations revealed pancytopenia. Pathological analysis and endoscopic images of the entire colon led to the diagnosis of IBD of unclassified type. BM examination showed that the pancytopenia was due to MDS and that his BM cells had dual chromosomal abnormalities: 47, XY, +1, der(1;7)(q10;p10), +8. Immunological studies using peripheral blood monocytes from this patient revealed that the dual chromosomal abnormalities of BM cells led to the development of colitogenic monocytes producing a large amount of pro-inflammatory cytokines and showing resistance to apoptosis upon stimulation with microbial antigens. CONCLUSION: An abnormal karyotype of BM cells is not only responsible for the development of MDS, but also for IBD in this case.

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INTRODUCTION: Ws/Ws rats have a small deletion of the c-kit gene and are deficient in both mucosal-type mast cells and connective tissue-type mast cells. AIM: To investigate the role of pancreatic mast cells in the development of experimental closed duodenal loop (CDL)-induced pancreatitis using Ws/Ws rats. METHODOLOGY: Pancreatitis was induced by the CDL technique for 5 and 12 hours, and the subsequent ascites volume, wet pancreatic weight, pancreatic myeloperoxidase activities, and serum amylase levels were evaluated. The pancreatic tissue damage was also evaluated histologically. RESULTS: The CDL technique induced equally severe ascites, pancreatic edema and hyperemia, and hyperamylasemia in the Ws/Ws versus the control (+/+) rats. The microscopic mucosal damage score was also equivalent in the Ws/Ws and control (+/+) rats, and there were no significant differences in mucosal myeloperoxidase activity between the Ws/Ws and control (+/+) rats. CONCLUSION: These results indicate that mast cells may not be crucial for the development of CDL-induced pancreatitis.

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