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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.

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.

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

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.

The N-terminal amino acid sequence of TA02 (molecular weight 35.0 kDa, isoelectric point 5.29), which is associated with primary lung adenocarcinoma, was determined and a fragment peptide was used to generate mouse monoclonal antibodies (mAbs) against TA02. The amino acid sequence suggested that TA02 might be homologous with napsin A, a new type of aspartic proteinase. In this context, we confirmed the expression of napsin A in primary lung adenocarcinoma using reverse-transcription polymerare chain reaction (RT-PCR) and showed that the TA02 mAbs reacted with glutathione-S-transferase (GST)-napsin A fusion protein. We concluded that TA02 is the same molecule as napsin A, and showed immunohistochemically that it is distributed mainly in type II pneumocytes, alveolar macrophages, renal tubules and exocrine glands and ducts in the pancreas. In particular, type II pneumocytes and alveolar macrophages showed high expression of TA02 among human normal tissues. In primary lung adenocarcinoma, 47 out of 58 (81.0%) primary lesions were positive. All well-differentiated adenocarcinomas except those of goblet cell type showed high expression of TA02. In addition, two out of seven (28.6%) large cell carcinomas showed low expression of TA02. The other histopathological types of primary lung cancer did not express TA02 at all. A few cases of renal cell cancer, pancreatic cancer, breast cancer, thyroid cancer, colon cancer and ovarian cancer showed low expression, but the staining patterns were completely different from that of primary lung adenocarcinoma, which showed a granular staining pattern. Our novel mAbs should be valuable for immunochemical detection of TA02/napsin A.