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Background Metastatic neuroendocrine carcinoma has an extremely poor prognosis, and no effective second-line treatment is available. Herein, we describe a case of multiple metastases after primary resection of esophageal neuroendocrine carcinoma successfully treated with nivolumab plus radiotherapy in a short time. Case presentation A man in his 70s presented to our hospital after an abnormality was detected on an upper gastrointestinal series. Upper gastrointestinal endoscopy revealed a type 2 tumor spanning the endothelial cell junction to the abdominal esophagus. Histopathological examination of the biopsy confirmed a diagnosis of esophageal neuroendocrine carcinoma. The patient had no distant metastases. Thoracoscopic esophagectomy with three-field lymph node dissection was performed. Histopathological examination confirmed a diagnosis of esophageal neuroendocrine carcinoma with features of adenoid cystic-like carcinoma and squamoid pattern (pT2 [MP], INF a, ly1, v1 [EVG], pIM0, pDM0, pRM0, pN1 [1/28], M0; Stage II), which was positive for synaptophysin. The postoperative course was good, with no complications. The patient was treated with 100 mg of irinotecan and 100 mg of cisplatin, administered every 4 weeks, as postoperative adjuvant chemotherapy. Grade 3 loss of appetite was observed, and adjuvant chemotherapy was discontinued after four cycles of first-line treatment. A positron emission tomography–computed tomography scan 3 years after surgery showed abnormal uptake in the subaortic, left hilar, and left axillary lymph nodes, and in a mass in the right lung apex. The patient was diagnosed with metastatic esophageal neuroendocrine carcinoma postoperatively. First-line treatment could not be repeated due to toxicity from the initial treatment. Nivolumab (240 mg every 2 weeks) was administered as second-line treatment, and radiotherapy was started (56 Gy delivered in 28 fractions to the local [subaortic and hilar] lymph nodes). After 10 cycles of nivolumab in combination with radiotherapy (56 Gy), a positron emission tomography–computed tomography scan showed disappearance of all lesions. A complete response was achieved. Maintenance therapy (240 mg of nivolumab) was continued. No recurrence has been observed for 42 months. Conclusions We experienced a case in which nivolumab in combination with radiotherapy was effective for metastatic esophageal neuroendocrine carcinoma after primary resection.

Coronavirus disease (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 virus, was reported in Wuhan of China in December 2019. The world is still in a state of pandemic owing to COVID-19. COVID-19 vaccines help our bodies develop immunity against the virus that causes COVID-19 without having to get the illness. Herein, we describe a rare case of a critical disorder, hemophagocytic lymphohistiocytosis (HLH), in a patient with nephritic sclerosis associated with hypertension, following mRNA COVID-19 vaccination. HLH is a life-threatening hyperinflammatory syndrome caused by aberrantly activated macrophages and cytotoxic T cells that may rapidly progress to terminal multiple organ failure.An 85-year-old Japanese woman with chronic renal failure and hypertension was included in this study. Routine laboratory investigations provided the following results: white blood cell (WBC) count, 4.6 × 109/L; hemoglobin (Hb), 8.1 g/dL; platelet count, 27 × 109/L; blood urea nitrogen 48.9 mg/dL, and serum creatinine 3.95 mg/dL. The patient developed malaise, vomiting, and persistent high fever (up to 39.7°C) on the 12th day after receiving the second dose of the vaccine. Initial evaluation revealed neutropenia. The total WBC count was 0.40 × 109/L (Neutrophils 0, Lymphocytes 240/μ, blast 0%); Hb 9.0 g/dL, platelet count 27 × 109/L; and, C Reactive Protein 9.64 mg/dL.Further tests showed hyperferritinemia (serum ferritin 2284.4 μg/L). Bone marrow examination revealed haemophagocytosis. A provisional diagnosis of HLH associated with the Comirnaty® vaccination was made based on the HLH-2004 diagnostic criteria.The patient was treated with granulocyte colony-stimulating factor and 500 mg methylprednisolone.A significant improvement was observed in the patient's condition; the abnormal laboratory results resolved gradually, and the patient was discharged.This case serves to create awareness among clinicians that HLH is a rare complication of COVID-19 vaccination and should be considered, especially in patients with a history of chronic renal failure and hypertension.

Poorly differentiated adenocarcinoma of colorectal carcinoma (CRC) is a rare condition with poor prognosis. Here, we describe the case of a 69-year-old man who underwent laparoscopic low anterior resection and was pathologically diagnosed with stage IIIA CRC. At 10 months post-operation, he developed fever and loss of appetite. Laboratory examination revealed fibrin degradation products > 120.0 µg/dL and D-dimer > 60.0 µg/dL. Bone marrow (BM) examination showed malignant epithelioid infiltrate with CK20 and CDX2 expression, leading to a diagnosis of disseminated carcinomatosis of bone marrow, which is rare in CRC and indicates widespread disease is throughout the body. Furthermore, immunohistochemistry indicated the predominant expression of receptor activator of nuclear factor κB ligand (RANKL) in CRC and BM tissues. Thus, RANKL expression, which is known to indicate metastatic behavior of cancer cells, in CRC may play a critical role in promoting osteoclast formation, which has been associated with the pathogenesis of BM lesions.

Introduction We report a case of sustained complete response in unfavorable cancer of unknown primary site (CUP) successfully treated with chemotherapy combining pembrolizumab, pemetrexed and platinum. Case presentation A 66-year-old man was presented with weight loss and cough for 3 months. Contrast-enhanced computed tomography (CT) confirmed a mass in the superior anterior mediastinum and multiple enlarged mediastinal and axillary lymph nodes. Positron emission tomography-CT (PET-CT) showed abnormal uptake in the corresponding lesions. Histopathological analysis of the left axillary nodule revealed poorly differentiated adenocarcinoma. Immunohistochemistry showed the tumor cells were positive for cytokeratin 7 and thyroid transcription factor-1 and negative for cytokeratin 20. Thus, the patient was diagnosed as poorly differentiated adenocarcinoma of unknown primary, and treated as non-small-cell lung cancer. Additional genetic testing revealed the patient was negative for EGFR, ALK fluorescence in situ hybridization, ROS1, BRAF, and PD-L1 22C3 IHC with Tumor Proportion Score (TPS) was less than 1%. The patient received six cycles of pembrolizumab, platinum, and pemetrexed intravenously. Cisplatin was switched to carboplatin because of cisplatin nephrotoxicity in one course. PET-CT after six cycles showed all lesions disappeared; complete response was considered to have been achieved. Maintenance therapy of pembrolizumab and pemetrexed has been continued for 6 months after the induction therapies to prevent progressive disease. Complete response has been maintained. Discussion Chemotherapy with pembrolizumab, platinum and pemetrexed could be valuable for treating unfavorable CUP. Conclusion Chemotherapy with pembrolizumab, platinum, and pemetrexed helped achieved sustained complete response in a patient with unfavorable CUP., Highlights • The prognosis of patients with unfavorable CUP remains poor. • Pembrolizumab's addition to standard chemotherapy resulted in significantly longer overall survival for patients with NSCLC. • Chemotherapy with pembrolizumab, platinum, and pemetrexed helped achieved sustained complete response in a patient with unfavorable CUP.

Cronkhite-Canada syndrome (CCS) is a rare disease characterized by diffuse gastrointestinal polyposis with chronic diarrhea and ectodermal change, but its etiology is unknown. We present a case at the age of 26 years complaining of epigastralgia and weight loss. Endoscopic examination revealed extensive diffuse polypoid lesions of the stomach and the terminal ileum, all of which showed hyperplastic polyps pathologically. There were no polypoid lesions in his colon. He has no family history of diffuse gastrointestinal polyposis. Diffuse gastrointestinal hyperplastic polyposis without any hereditary association led us to suspect this case as CCS although he did not show chronic diarrhea and any ectodermal symptoms such as onychodystrophy, alopecia, and hyperpigmentation. After initiation of a corticosteroid therapy, his epigastralgia disappeared and he gained appetite and weight, accompanied by normalization of serum albumin levels. Endoscopic examination 1 year after initiation of corticosteroid therapy revealed a decrease in the number of gastric polyposis and those inflammations. This rare young case may suggest that early therapeutic intervention with corticosteroids could improve the prognosis of CCS, preventing not only malnutrition but also appearance of several ectodermal symptoms.

Background: The AMATERASU randomized trial of vitamin D3 supplementation (2,000 IU/day; UMIN000001977) showed the potential benefit of vitamin D in a subgroup of patients with digestive tract cancer. By conducting post hoc analyses of this trial, we further explored whether subgroups stratified by expression levels of p53, vitamin D receptor (VDR), and Ki-67 modify the effect of vitamin D supplementation. Methods: The primary outcome was relapse-free survival (RFS). On IHC using pathologic specimens, the degree of p53 protein expression parallel with TP53 missense mutations was classified as p53 positive (>10%) and p53 negative (≤10%). In addition, VDR and Ki-67 expression levels were divided into quartiles. Results: The p53 status of 372 patients' pathologic specimens was evaluated. In a subgroup of patients with p53-positive cancer (n = 226), 5-year RFS was 79% in the vitamin D group, which was significantly higher than the 57% in the placebo group (HR, 0.52; 95% confidence interval, 0.31–0.88; P = 0.02). In the subgroup of patients with p53-negative cancer, 5-year RFS in the vitamin D group versus placebo group was 72% versus 84% (not significantly different), respectively. Effect modification by p53 positivity was significant (Pinteraction = 0.02). However, no significant effect modification by either VDR or Ki-67 was observed. Conclusions: These results generate a hypothesis that vitamin D supplementation may improve RFS in patients with p53-positive digestive tract cancer. Impact: The results are still preliminary, but potentially important, because TP53 is the most frequently mutated gene across cancers at all sites.

The aim was to examine whether vitamin D supplementation (2000 IU/day) reduces the risk of relapse in a subgroup of patients with digestive tract cancer, showing a sufficient immune response in tumor stroma by conducting secondary subgroup analyses of the AMATERASU randomized, double-blind, placebo-controlled trial (UMIN000001977). A total of 372 patients were divided into two subgroups stratified by the median density of immune cells infiltrating in tumor stroma into higher and lower halves. In the higher-half subgroup of CD56+ cells, the relapse ratio was significantly lower in the vitamin D group (7.4%) than in the placebo group (20.5%) (subdistribution hazard ratio (SHR), 0.35, 95% confidence interval (CI), 0.15–0.82), but it was equivalent (25.2% vs. 22.7%) in the lower-half subgroup of CD56+ cells (SHR, 1.21, 95% CI, 0.68–2.19) with a significant interaction (Pinteraction = 0.02). Although there were no significant differences, the risk of relapse was lower in the vitamin D group than in the placebo group in the higher half of CD45RO+ memory T cells (8.9% vs. 19.2%), and of CD8+ cytotoxic T cells (11.3% vs. 22.5%). In patients with digestive tract cancer, vitamin D supplementation was hypothesized to reduce the risk of relapse in the subgroup of patients who already have an adequate infiltration of immune cells in their tumor stroma.

IgG4-related disease (IgG4-RD) is a chronic inflammatory disease of unknown etiology that causes mass-forming lesion consisting of lymphoplasmacytic infiltrates, fibrosis and sclerosis especially in exocrine tissues. Although chronic paranasal sinusitis is known to be a nasal manifestation of IgG4-RD, little is known whether chronic rhinitis accompanies IgG4-RD. Here we report a case with hypertrophic rhinitis without sinusitis histologically compatible with IgG4-RD. An 80-year-old male complained bilateral nasal obstruction with occasional oral breathing and watery rhinorrhea for several years. Nasal endoscopic examination showed a pale and swollen anterior part of bilateral inferior turbinate leading to almost complete blockade of common meatus. Levels of serum total IgE and IgG4 were normal, and serum specific IgE to major inhaled antigens was negative. Due to resistance to conservative treatments, we performed an endoscopic mucosal resection of bilateral anterior part of inferior turbinate. The pathological findings met the diagnostic criteria for IgG4-RD. Additional examinations did not find lesion suspicious of IgG4-RD in other organs. After surgery, symptoms and objective nasal passage were improved with the use of intranasal corticosteroid. In case of hypertrophic rhinitis with severe swelling especially in the anterior part of the inferior turbinate, IgG4-related rhinitis should be suspected.

Although an excellent photoacoustic (PA) ultrasound method has been reported for the evaluation of lymph node melanoma metastasis in animal experiments, it remains to be evaluated in clinical trials. Recently, we performed PA ultrasound assessment using light-emitting diodes to detect metastatic melanoma in the lymph nodes of specimens prepared for microscopic examination. The PA effect was not obvious in amelanotic melanoma, but was seen in melanotic melanoma by PA imaging (PAI) and histopathological correlation in cases of primary melanotic melanoma accompanied by metastatic lymph nodes, including the coexistence of amelanotic melanoma and melanotic melanoma. Clinical workup should be performed with not only PAI but also conventional ultrasonography in cases with metastasis related to amelanotic transformation, which would likely be missed by PAI alone.

Primary gastrointestinal lymphoma is relatively rare and typically treated by chemotherapy. In some cases, surgery for obstruction in the proximal small intestine is challenging and has a high risk for anastomotic leakage. An 80-year-old woman presented to our hospital with vomiting and abdominal distension. Enteroscopy showed a type 2 circumferential tumor in the proximal jejunum 6 cm on the anal side from Treitz ligament. Biopsy showed solid and diffuse proliferation of large atypical cells with round and irregular nuclei. On immunohistochemistry, these cells were positive for CD20, CD79a, and CD138. Diffuse large B-cell lymphoma (DLBCL) was diagnosed and classified as Ann Arbor stage IIE and Lugano classification stage II 2 and scored 1 point on the International Prognostic Index (i.e., low risk). Given the risk of anastomotic leakage due to lesions and residual obstructive enteritis, surgery was not performed. The patient received double percutaneous transesophageal gastrotubing (dPTEG) to facilitate decompression and enteral nutrition. Enteral nutrition and chemotherapy were initiated immediately after dPTEG insertion. After one course of rituximab plus cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (R–CHOP), the tumor showed a partial response, and the obstruction was improved. Oral ingestion was started, and the dPTEG tube was removed. After six courses of R–CHOP, enhanced CT, positron emission tomography-CT, and serum interleukin-2 levels indicated complete treatment response. During treatment, gastrointestinal perforation did not occur, oral intake was good, and careful follow-up will be continued. dPTEG for obstructive small intestinal DLBCL could help avoid high-risk surgery, and a complete response to chemotherapy was achieved., Highlights • ・Surgery for obstruction in the proximal small intestine is challenging and has a high risk for anastomotic leakage. • ・Double percutaneous transesophageal gastrotubing is a novel treatment that can achieve both intestinal decompression and enteral nutrition. • ・Performing dPTEG for obstructive small intestinal DLBCL precluded the use of high-risk surgery and facilitated a complete response to chemotherapy.

Isao Okazaki,1,* Shinsuke Shibata,2,3,* Wataru Ando,4,* Takayo Yanagawa,5,6 Hiroaki Yokomori,7 Akira Sonoda,8 Norihiko Suzuki,9 Eigoro Yamanouchi,10 Shinya Okada,11 Shinichi Kamikura,11 Kazuaki Hachimura,11 Takashi Takaki,12 Katsuya Otori,4 Yutaka Suzuki,9 Hideyuki Okano,2 Yutaka Inagaki5,6 1Department of Internal Medicine, International University of Health and Welfare (IUHW) Hospital, Nasu-Shiobara City, Tochigi Prefecture, Japan; 2Department of Physiology, Keio University School of Medicine, Shinjuku-Ku, Tokyo, Japan; 3Electron Microscope Laboratory, Keio University School of Medicine, Shinjuku-Ku, Tokyo, Japan; 4Department of Clinical Pharmacy, Kitasato University School of Pharmacy, Minato-Ku, Tokyo, Japan; 5Center for Matrix Biology and Medicine, Tokai University Graduate School of Medicine, Isehara City, Kanagawa Prefecture, Japan; 6Department of Innovative Medical Science, Tokai University School of Medicine, Isehara City, Kanagawa Prefecture, Japan; 7Department of Internal Medicine, Kitasato University Medical Center, Kitamoto City, Saitama Prefecture, Japan; 8Collaborative Research Resources, Core Instrumentation Facility, Keio University School of Medicine, Shinjuku-Ku, Tokyo, Japan; 9Department of Surgery; 10Deparment of Radiology; 11Department of Pathology, IUHW Hospital, Nasu-Shiobara City, Tochigi Prefecture, Japan; 12Division of Electron Microscopy, Showa University School of Medicine, Shinagawa-Ku, Tokyo, Japan*These authors contributed equally to this workCorrespondence: Isao OkazakiHigashi Nippon International University, Iwaki City, Fukushima Prefecture, JapanTel +81-246-35-0001Fax +81-246-25-9188Email okazakiisao@hotmail.co.jpBackground/Aims: Matrix metalloproteinase-1 (MMP-1) is a key enzyme in collagen metabolism and tissue remodeling. We previously reported that MMP-1 expression in monocytes and other types of cells in the liver is associated with disease progression in patients with nonalcoholic steatohepatitis (NASH). To further implicate MMP-1 up-regulation in NASH pathogenesis, we examined dynamic and sequential MMP-1 expression in peripheral blood monocytes and cells in steatotic liver, and attempted to elucidate the mechanism of MMP-1 induction.Methods: Twenty-nine NASH patients and 26 non-NASH subjects were recruited in the study. Their peripheral blood mononuclear cells were isolated and analyzed by fluorescence-activated cell sorting, and liver specimens were subjected to confocal laser-scanning and immunoelectron microscopic examinations. Peripheral blood monocytic lineage cells were co-cultured with steatotic hepatocytes obtained from biopsy specimens to examine MMP-1 induction.Results: Infiltrating monocytes were the earliest to acquire an MMP-1-expressing phenotype among all investigated cell types in early-stage NASH liver. On the other hand, circulating monocytes did not express significant levels of MMP-1 mRNA or protein before infiltrating steatotic liver. Co-culture with steatotic hepatocytes induced MMP-1 expression in otherwise MMP-1-negative peripheral blood monocytic lineage cells. As disease progressed, MMP-1 was sequentially expressed by other types of cells in NASH liver. Notably, clusters of OV-6- or CK19-positive hepatic progenitor cells with a morphological feature of ductular reaction showed strong MMP-1 staining in advanced-stage NASH.Conclusion: MMP-1 up-regulation in infiltrating monocytic lineage cells represents an initial event in early-stage NASH and, together with the subsequent expression in other types of cells, modulates pathophysiological aspects of NASH.Keywords: matrix metalloproteinase-1, nonalcoholic steatohepatitis, monocytic progenitor cells, hepatic progenitor cells, liver fibrosis

Varicella-zoster virus (VZV) encephalitis in the absence of vasculopathy may rarely occur in association with herpes zoster. We herein report the case of a 67-year-old woman with non-Hodgkin's lymphoma undergoing chemotherapy who presented with an acute alteration in consciousness. Magnetic resonance imaging of the brain revealed multiple and nonspecific lesions of hyperintensity with mild edema in the cortex and subcortex. She was treated with intravenous acyclovir. However, two days after admission, the patient died and was diagnosed with VZV encephalitis. This case highlights the risk of VZV reactivation with severe neurological complications in patients undergoing immunosuppressive therapy.

We held a multidisciplinary discussion (MDD) about a 61‐year‐old woman who had an interstitial lung disease (ILD) without extrathoracic lesions that met the classification criteria for interstitial pneumonia with autoimmune features (IPAF) and the proposed diagnostic criteria for immunoglobulin G4 (IgG4)‐related respiratory disease (IgG4‐RRD). Clinically, the marked progression of lung‐limited diffuse lesions was consistent with IPAF. Serum IgG4 and rheumatoid factor levels simultaneously increased and did not contribute to a diagnosis. Pathologically, the significant hyperplasia of lymphoid follicles was consistent with rheumatoid arthritis (RA)‐associated ILD. Pulmonary venous occlusions by intimal fibrosis and intimal thickening were not important because these occlusions are found in IgG4‐related lung disease (IgG4‐RLD) and also in IPAF or ILDs related to connective tissue diseases (CTDs). Radiologically, fibrosing shadows that remained in the lung periphery after treatment were compatible with RA‐associated chronic ILD. We concluded that the present case was IPAF that met the proposed diagnostic criteria for IgG4‐RRD., We held a multidisciplinary discussion on a case of interstitial lung disease without extrathoracic lesions that met the classification criteria for interstitial pneumonia with autoimmune features (IPAF) and the proposed diagnostic criteria for immunoglobulin G4 (IgG4)‐related respiratory disease (IgG4‐RRD). We concluded that the present case was IPAF that met the proposed diagnostic criteria for IgG4‐RRD.

Fundamental understanding of the state of catalyst inks and fabrication process is important to fabricate well-established catalyst layers of proton exchange membrane fuel cells (PEMFCs). The catalyst ink is a slurry which contains platinum-supported carbon and ionomer in a solvent. The state of the catalyst ink affects dynamics of materials during the fabrication process of the catalyst layer(1), and then the resultant structure(2). Additionally, the state of the catalyst ink can have time dependence, which means the procedure of particle agglomeration and sedimentation inside the slurry. Therefore, quantitative evaluation of the catalyst ink is required. In this study, a rheological measurement was conducted to characterize catalyst inks used to fabricate PEMFC catalyst layers. The rheological measurement can apply to opaque and high viscosity slurries like catalyst inks. Ionomer dispersion, pseudo-catalyst ink and catalyst ink with various ionomer content were measured to clarify the relationship between the rheological behavior and the types and amount of particles and interparticle interactions in the slurry. The rheological measurement was conducted by using a rheometer with a cone and plate system. Shear rate range was 200 to 3000 /s. The measurement temperature was 25°C. Downward measurement (from upper to lower shear rate) following the upward measurement was conducted. Ionomer dispersion (DE2020, Sigma-Aldrich), carbon black (Ketjenblack, Lion)–ionomer dispersion (pseudo-catalyst ink), and platinum-supported carbon (Pt/C, TEC10E50E, Tanaka Kikinzoku Kogyo)–ionomer dispersion (catalyst ink) were prepared. The volume fraction of carbon to the solvent (45wt.% 1-propanol aqueous solution) was 2% and ionomer to carbon ratio (I/C) was a parameter from 0.3 to 2.0. The viscosities of the slurries as a function of the shear rate are shown in Figure 1. The three types of the slurries showed quite different rheological properties with each other. The ionomer dispersions are Newtonian fluid in all I/C conditions from 0.3 to 2.0 (Fig. 1 (a)). On the other hand, pseudo-catalyst ink (Fig. 1 (b)) and catalyst ink (Fig. 1 (c)) were non-Newtonian fluid when I/C was low. The pseudo-catalyst ink showed a transition from non-Newtonian to Newtonian as I/C increased from 0.3 to 0.5. The ink also showed the transition from Newtonian to non-Newtonian as I/C increased from 1.0 to 2.0. The catalyst ink slightly showed non-Newtonian properties even in I/C 0.5 and 1.0. Additionally, the catalyst ink with I/C 0.3 and 0.5 showed relatively large hysteresis between the upward and downward measurements. The rheological property of the slurries can be the results of the state difference of the particles in the slurries such as the particle agglomeration and/or ionomer adsorption. The measurements of particle size distribution by dynamic light scattering and zeta potential were applied to the slurries (The results are not shown here). The comprehensive discussion to understand the state of the catalyst ink will be presented. Acknowledgments This work was supported by JSPS KAKENHI Grant Number 16K18028. References T. Suzuki, M. Kobayashi, H. Tanaka, M. Hayase and S. Tsushima, ECS Trans., 69, 465 (2015). W. K. Epting, J. Gelb and S. Litster, Adv. Funct. Mater., 22, 555 (2012). Figure 1

Highlights • Preoperative diagnosis of gastric cancer invasion is not always sufficiently accurate. • We encountered a patient with the gastric cancer of which the pre-operative diagnosis of the invasion was indeterminable. • Diagnostic ESD was performed. • Pathohistological diagnosis revealed that the resection was curative and met the expanded criteria for ESD, so gastrectomy was not required., Introduction Preoperative diagnosis of gastric cancer invasion is not always sufficiently accurate. Diagnostic endoscopic submucosal dissection (ESD) can be performed for the purpose of accurate decision making and to avoid partial treatment vs aggressive over-treatment. We present a patient with the gastric cancer with indeterminate pre-operative diagnosis for depth of the invasion. Case presentation A 70-year-old man presented at our hospital because both anti-Helicobacter pylori (Hp) IGG antibody and serum pepsinogen (PG) levels were classified as positive. Upper gastrointestinal endoscopy was performed, and a large (3.5 cm) pedunculated polyp-shaped gastric cancer with prolapse into the duodenal bulb was found. [fluorine-18]-fluorodeoxy-glucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) imaging showed high 18F-FDG uptake, suggesting the possibility of advanced gastric cancer. Since the pre-operative diagnosis of the cancer invasion was indeterminable, diagnostic ESD was performed. The pathohistological diagnosis was early gastric cancer (33 × 35 × 20 mm, well differentiated tubular adenocarcinoma [tub1], pT1a[M], ly[––], v[––], UL[––], pHM0, pVM0) according to the Japanese classification of gastric carcinoma. Discussion and conclusion It was reported that ESD for early gastric cancers that met the expanded criteria was acceptable and should be the standard treatment instead of gastrectomy. The expanded criteria included cancer confined to the mucosa (cT1a), a single primary intestinal-type gastric adenocarcinoma, an ulcer-negative lesion of any size. We reported a case of pedunculated gastric cancer with prolapse into the duodenal bulb that could be treated by ESD. The present case is a good example of diagnostic ESD being used to minimize the damage of gastric cancer treatment.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease associated with eosinophilic infiltration of the esophageal mucosa mostly due to exposure to allergens. However, the causes and pathogenesis of EoE are not fully understood. We encountered a case of EoE that was triggered by sublingual immunotherapy (SLIT) for cedar pollen allergy. A 40-year-old man who was treated with Japanese cedar pollen tablet SLIT for cedar pollen allergy developed heartburn 3 weeks after the initiation of the treatment. He took vonoprazan for the heartburn, but the heartburn did not improve. Then, esophagogastroduodenoscopy was performed; it revealed longitudinal furrows and white spots on the esophageal mucosa, decreased vascular permeability, and erosions. Consequently, the patient was diagnosed with EoE. Heartburn and chest discomfort disappeared 1 week after the discontinuation of Japanese cedar pollen tablet SLIT, and the patient tested positive for drug allergy to Japanese cedar pollen tablet SLIT. In this study, we found that if heartburn persists during SLIT for cedar pollen allergy, and does not improve on administration of vonoprazan or proton pump inhibitors, EoE should be suspected. In addition, the occurrence of EoE due to drug allergy is indicated.

Background The present study describes the retrospective feasibility study of ICG fluorescence SN mapping in back-table for early gastric cancer using PINPOINT®. Method SN mapping were performed as following; the day before surgery, 0.5 ml ICG was injected endoscopically in four quadrants of the submucosa surrounding the gastric cancer using an endoscopic puncture. Intraoperatively, the gastrocolic ligament was divided to visualize all possible directions of lymphatic flow from the stomach. PINPOINT® (NOVADAQ, Canada) was used to illuminate regional lymph nodes from the serosal side. Positive staining was confirmed by at least 3 surgeons and an endoscopist during surgery (Figure 1). Lymph node dissection and gastrectomy were performed according to the criteria of gastric cancer treatment guidelines of JGCA. Result All 6 patients had gastrectomy with laparoscopic approach. ICG positive lymphatic flow and lymph nodes were able to be observed in all the patients. Final pathological diagnosis was all StageI and curative resection. All the patients had ICG positive lymphatic area in left gastric artery (LGA) area. Two patients with tumor located in L area had ICG positive flow to right gastroepipoloic artery (RGEA) area. The mean of ICG positive lymph nodes was 8.6. One patient had a metastatic lymph node in station No.4, which was positive for ICG. Conclusion Our method made identification of ICG positive lymph nodes easy in SN mapping in back-table under room light. Although further accumulation and analysis are necessary, we may be able to apply this method for intraoperative SN mapping of laparoscopic gastric cancer surgey., Highlights • ICG fluorescence SN mapping for early gastric cancer using PINPOINT® is described. • ICG positive nodes were able to be observed in all the patients. • The mean of ICG positive lymph nodes was 8.6. • One patient had a metastatic lymph node in SN. • PINPOINT® make identification of SNs easy and simple for gastric cancer surgey.

We identified a case of lymphadenopathy of metastatic papillary thyroid carcinoma (PTC) with CD20 expression, which was also expressed by the primary tumor. CD20 expression was identified using immunohistochemistry (IHC) in metastatic PTC biopsy samples from a 58-year-old woman. CD20 expression was initially determined using a CD20-recognizing L26 clone. To validate this phenomenon, we performed IHC with another antibody that recognizes the N-terminus of CD20 and fluorescent double staining using anti-TTF-1 and anti-CD20 antibodies. Taken together, we concluded metastatic PTC expressed CD20. We also examined 21 additional PTC cases and found four more cases that were CD20 positive. Therefore, five of the 22 (23%) cases were positive for CD20. In the positive cases, four cases were classical papillary thyroid carcinoma and one case was a follicular variant of papillary thyroid carcinoma. CD20 is an important target for molecularly targeted therapy for a subset of B-cell lymphomas. Complement-dependent and antibody-dependent cellular cytotoxicities are important effector mechanisms of anti-CD20 therapy. Here, for the first time, we report PTC with expression of CD20. Our findings provide a rationale for treating CD20-positive PTC patients with anti-CD20 therapy.

Good syndrome is a rare condition in which thymoma is associated with hypogammaglobulinemia; it is characterized by repeated respiratory or systemic infections caused by bacteria, viruses, and fungi, as well as with various autoimmune disorders such as pure red cell aplasia. A 65-year-old woman was admitted to our hospital with ptosis and abdominal muscle weakness. Based on the presence of anti-acetylcholine receptor (Ach-R) antibodies, she was diagnosed with myasthenia gravis (MG). At that time, invasive thymoma of Masaoka stage IVa was also detected. Regression of thymoma and clinical remission of MG was achieved by chemotherapy followed by high-dose corticosteroid. However, several months later, the patient started developing repeated bacterial respiratory tract infections, cytomegalovirus infections, and esophageal and systemic candidiasis. Laboratory tests revealed a marked decrease of serum gamma-globulin levels (IgG 586 mg/dl, IgA 32 mg/dl, IgM 29 mg/dl) and severe reduction in the B cells ratio, as well as a decrease in the CD4+CD25+T cell to CD4+CD25-T cell ratio indicative of deregulation of CD4+T cell activation. These results suggested that the patient impaired humoral and cell-mediated immune responses. We continued the treatment with antibiotics and regular immunoglobulin supplementation through intravenous injections. Although autoimmune disorders are often observed in Good syndrome, the association with MG is quite rare. The case report is followed by the review of literature.

The AMATERASU randomized trial of vitamin D3 supplementation (2,000 IU/day; UMIN000001977) showed the potential benefit of vitamin D in a subgroup of patients with digestive tract cancer. By conductingThe primary outcome was relapse-free survival (RFS). On IHC using pathologic specimens, the degree of p53 protein expression parallel withThe p53 status of 372 patients' pathologic specimens was evaluated. In a subgroup of patients with p53-positive cancer (These results generate a hypothesis that vitamin D supplementation may improve RFS in patients with p53-positive digestive tract cancer.The results are still preliminary, but potentially important, because

IMPORTANCE: Randomized clinical trials of vitamin D supplementation for secondary prevention in patients with cancer are needed, given positive results of observational studies. OBJECTIVE: To determine whether postoperative vitamin D(3) supplementation can improve survival of patients with digestive tract cancers overall and in subgroups stratified by 25-hydroxyvitamin D (25[OH]D) levels. DESIGN, SETTING, AND PARTICIPANTS: The AMATERASU trial, a randomized, double-blind, placebo-controlled trial conducted at a single university hospital in Japan. Enrollment began in January 2010 and follow-up was completed in February 2018. Patients aged 30 to 90 years with cancers of the digestive tract from the esophagus to the rectum, stages I to III, were recruited. Of 439 eligible patients, 15 declined and 7 were excluded after operation. INTERVENTIONS: Patients were randomized to receive oral supplemental capsules of vitamin D (2000 IU/d; n = 251) or placebo (n = 166) from the first postoperative outpatient visit to until the end of the trial. MAIN OUTCOMES AND MEASURES: The primary outcome was relapse-free survival time to relapse or death. The secondary outcome was overall survival time to death due to any cause. Subgroups analyzed had baseline serum 25(OH)D levels of 0 to less than 20 ng/mL, 20 to 40 ng/mL, and greater than 40 ng/mL; because of small sample size for the highest-baseline-level group, interactions were tested only between the low- and middle-baseline-level groups. RESULTS: All 417 randomized patients (mean age, 66 years; male, 66%; esophageal cancer, 10%; gastric cancer, 42%; colorectal cancer, 48%) were included in the analyses. There was 99.8% follow-up over a median 3.5 (interquartile range, 2.3-5.3) years, with maximal follow-up of 7.6 years. Relapse or death occurred in 50 patients (20%) randomized to vitamin D and 43 patients (26%) randomized to placebo. Death occurred in 37 (15%) in the vitamin D group and 25 (15%) in the placebo group. The 5-year relapse-free survival was 77% with vitamin D vs 69% with placebo (hazard ratio [HR] for relapse or death, 0.76; 95% CI, 0.50-1.14; P = .18). The 5-year overall survival in the vitamin D vs placebo groups was 82% vs 81% (HR for death, 0.95; 95% CI, 0.57-1.57; P = .83). In the subgroup of patients with baseline serum 25(OH)D levels between 20 and 40 ng/mL, the 5-year relapse-free survival was 85% with vitamin D vs 71% with placebo (HR for relapse or death, 0.46; 95% CI, 0.24-0.86; P = .02; P = .04 for interaction). Fractures occurred in 3 patients (1.3%) in the vitamin D group and 5 (3.4%) in the placebo group. Urinary stones occurred in 2 patients (0.9%) in the vitamin D group and 0 in the placebo group. CONCLUSIONS AND RELEVANCE: Among patients with digestive tract cancer, vitamin D supplementation, compared with placebo, did not result in significant improvement in relapse-free survival at 5 years. TRIAL REGISTRATION: UMIN Identifier: UMIN000001977

Background: One quarter of global adults by overeating and reduced physical activity cause nonalcoholic fatty liver, and progress to nonalcoholic steatohepatitis (NASH), in which 10% of cases lead to liver cirrhosis and/or hepatocellular carcinoma. Adequate therapeutic option is urgent. We previously reported that matrix metalloproteinase-1 (MMP-1) expression in monocytes (MCs) and other types of cells in NASH livers is associated with disease progression. To test the hypothesis that bone marrow-derived monocytes (BMMCs) secrete exosomes with MMP-1 before their infiltration into steatosis liver, we examined MMP-1 mRNA and protein expression in circulating BMMCs. Methods: Twenty-nine NASH patients and 26 non-NASH patients were recruited in this study. Confocal laser scanning microscopic (CLSM) and immune-electron microscopic examinations (IEM), and fluorescence-activated cell sorting of CD34+ BMMCs were performed. Peripheral CD45+CD14+CD34+ cells were co-cultured with steatosis hepatocytes (HCs) isolated from NASH liver. Findings: IEM revealed that MCs were the earliest to acquire an MMP-1-expressing phenotype amongst all investigated cell types. CLSM showed that MMP-1 expression in Kupffer cells, hepatic stellate cells, progenitor cells, HCs, and endothelial cells were observed in subsequent to MCs. In advanced stage of NASH, OV-6- or CK19-positive hepatic progenitor cells around lethal HCs showed strong staining for MMP-1. These results suggested that MMP-1 expressed in progenitor cells may contribute to regeneration of injured liver, while MMP-1 up-regulation in hepatic stellate cells caused their activation leading to fibrosis. Unlike our initial hypothesis, circulating BMMCs did not express significant amounts of MMP-1 mRNA or protein before their infiltration into steatosis liver. By contrast, co-culture with steatosis HCs induced MMP-1 expression in otherwise MMP-1-negative CD34+ BMMCs. This phenotypic change in MMP-1 expression was the most pronounced in CD45+CD14+CD34+ cells. Interpretation: The results of the present study implicated MMP-1 expression by the monocyte progenitor cell population after their migration into steatosis liver in NASH pathogenesis. Funding Statement: This work is supported by grant no. IUHW 2016-24 and -25 from Mr. Takeshi Mori and Mrs. Eiko Mori to Dr. Okazaki. Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: The study protocol was approved by the Ethics Committee of IUHW (13-B-136, February 22, 2016; 13-B-205, November 24, 2016; 13-B-229, April 27, 2017). All patients provided written formal informed consent for participation in this study.

Ionomer distribution in catalyst layers (CLs) of polymer electrolyte fuel cells has garnered much attention because it affects proton and gas transfer. In this study, a novel visualization method of the overall through-plane ionomer and platinum-supported carbon (Pt/C) distributions in the CLs using two-stage ion-beam processing is proposed. The first stage is the formation of a flat and smooth cross-section using a broad ion beam. The second stage is the selective removal of the materials in the CL by a focused-ion beam. Scanning ion microscopic images were obtained after the first and second stages. The ionomer and Pt/C distributions were then obtained by image processing. CLs were prepared with the ionomer-to-carbon (I/C) ratio varied from 0.5 to 3.0. The effect of the dispersion process on the structure of the CL was also studied. With increasing I/C ratio, a thin ionomer layer was formed at the interface with the polymer electrolyte membrane. This behavior is attributed to deposition of ionomer during solvent evaporation. Ionomer thickness, agglomerate size of Pt/C, and pore size were evaluated. The agglomerate size of Pt/C was found to be affected by both I/C ratio and the dispersion process.

Conclusion: The volume of fat tissue loss after vocal fold augmentation can be decreased when augmentation is performed with addition of basic fibroblast growth factor (b-FGF). Objectives: The effectiveness of augmentation is easily decreased due to absorption. Canine experiments have confirmed that the decreased effectiveness caused by absorption after augmentation can be reduced by administering low-concentration b-FGF. Clinical application was trialed after acquiring approval from the institutional clinical review committee. Method: Autologous fat tissue with b-FGF was injected into the vocal folds in cases of unilateral vocal cord paralysis. This study compared fat tissue survival after injection by assessing images from computed tomography (CT). Results: Assessments using CT revealed that the decrease in volume of injected fat tissue was smaller in cases treated using b-FGF than in cases using the conventional method. No severe complications were encountered using this method.

We identified a case of lymphadenopathy of metastatic papillary thyroid carcinoma (PTC) with CD20 expression, which was also expressed by the primary tumor. CD20 expression was identified using immunohistochemistry (IHC) in metastatic PTC biopsy samples from a 58-year-old woman. CD20 expression was initially determined using a CD20-recognizing L26 clone. To validate this phenomenon, we performed IHC with another antibody that recognizes the N-terminus of CD20 and fluorescent double staining using anti-TTF-1 and anti-CD20 antibodies. Taken together, we concluded metastatic PTC expressed CD20. We also examined 21 additional PTC cases and found four more cases that were CD20 positive. Therefore, five of the 22 (23%) cases were positive for CD20. In the positive cases, four cases were classical papillary thyroid carcinoma and one case was a follicular variant of papillary thyroid carcinoma. CD20 is an important target for molecularly targeted therapy for a subset of B-cell lymphomas. Complement-dependent and antibody-dependent cellular cytotoxicities are important effector mechanisms of anti-CD20 therapy. Here, for the first time, we report PTC with expression of CD20. Our findings provide a rationale for treating CD20-positive PTC patients with anti-CD20 therapy.

We report a rare preschool case of Ramsay Hunt syndrome with delayed herpes zoster oticus presentation over a week following facial paralysis. A 5-year-old girl found by her guardians to have right facial palsy had neither herpetic eruptions nor the eighth cranial nerve disorders on the first visit. She was therefore diagnosed with severe Bell’s palsy (6/40 points) and administered steroid—10 mg/kg of hydrocortisone—alone intravenously for 7 days. On the evening of the last infusion day, she reported right earache and was found to have auricular swelling, after which and the diagnosis was changed to Ramsay Hunt syndrome. Intravenous administration of acyclovir with the same dose of steroid was given, but electroneuronography (ENoG) was 0% on the last infusion day. Following this assessment, transmastoid decompression surgery was conducted on day 16. Her facial movement recovered up to 34/40 3 months postoperatively. Serologically, anti-VZV IgG was significantly elevated. Viral facial nerve paralysis origin is believed to be by far rarer than pediatric idiopathic facial palsy, so steroid alone is usually administered. Those insufficiently immune to VZV, however, risk early viral reactivation, if acyclovir was given for chicken pox or subjects were affected by varicella before becoming 1 year old. Our case underscores the need to use concomitant antiviral agents with the steroid. Acyclovir should be considered especially in those with suspected low VZV immunity.

Regarding the process of uveitis development, many past studies have used the experimental autoimmune uveoretinitis (EAU) and other animal models to observe histologically the infiltration of inflammatory cells and the process of lesion progression. However, no detailed study of the process of clearance of infiltrated inflammatory cells from the eye has been reported. The purpose of this study was to investigate the process of clearance of polymorphonuclear leukocytes (PMNs) using an experimental hypopyon model. PMNs obtained from ascites of SD rat were injected into the anterior chamber of SD rats. The process of PMNs clearance was evaluated by serial photography and 3D optical coherence tomography (3D-OCT), and histological changes were observed simultaneously. The hypopyon heights regressed from 1.04±0.06 mm at 1h (day 0) to 0.45±0.07 mm at day 1, and 0 mm at day 3 after PMNs injection. When the hypopyon heights at the three time points were compared, significant differences were found between groups (P0.05). The hypopyon volumes also decreased from 1.46±0.07 mm(3) at 1h to 1.16±0.09 mm(3) at 2h, and 0.83±0.04 mm(3) at 3h after PMN injection. When the hypopyon volumes at the three time points were compared, significant differences were found between groups (P0.05). Light micrographs of inferior segment of the eyeball revealed dense PMNs in the chamber angle at 1h after PMNs injection and many PMNs in the iris stroma and vessels, as well as at the episcleral and subconjunctival tissues around limbus at 3h and day 1 after PMNs injection. Light micrographs of superior segment of the eyeball at 3h after injection revealed PMNs in the episcleral and subconjunctival vessels. Electron micrographs of inferior segment of the eyeball at 3h after PMNs injection revealed dense PMNs with slightly condensed nuclei in the anterior chamber, as well as in the iris stroma and vessels. In conclusion, in the experimental hypopyon model, PMNs injected into the anterior chamber were cleared from the eye mainly through the iris stroma and vessels, as well as the episcleral and subconjunctival tissues around limbus.

[Introduction] It has been reported that satisfactory surgical treatment is difficult to accomplish on cases with post-operative vocal fold scarring where flexibility has decreased. In the present study, the primary goal was to attain voice improvement for a professional singer, who had undergone laryngeal micro-surgery repeatedly. We removed scar tissue and performed autologous fat augmentation thereby successfully improving the wave motion of mucosa during phonation. The result of our study on the changes of acoustical analyses are reported. [The Case and the Course] The patient was a 60-year-old female folk singer. She had a history of smoking and had undergone laryngeal micro-surgery for polypoid degeneration of the vocal folds several times in the past. Mucosal depression was noted on left vocal fold. Using a stroboscope, mucosal wave motion was determined to be partially lacking on the left, and a deficiency of glottal closure was seen. In order to repair the vocal fold defect, autologous fat augmentation was performed. After the operation, her daily conversation voice had improved; however, no improvement of her singing voice was noted and mucosal defect remained. The patient was a professional singer and had a strong desire for her voice to be improved further. Subsequently, using laryngeal microscope, we tried to remove the intra-mucosal scar tissue and to inject fat tissue. Post-operatively, mucosal defect had diminished almost completely and wave motion during phonation had improved.[Summary] The results of the study suggest that the removal of scar tissue and fat augmentation seem to be effective surgical treatments for vocal fold scarring.