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Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract. The prognosis depends on the primary site, and small intestinal GISTs have a worse prognosis than gastric GISTs. Molecularly targeted drugs to inhibit tyrosine kinase activity of KIT were used for unresectable or recurrent GISTs. However, secondary resistance to the drugs is often acquired, and treatments based on other mechanisms are needed. Previously, we reported that cell adhesion molecule 1 (CADM1) was highly expressed in most of small intestinal GISTs but not in most of gastric GISTs. In the present study, we examined whether the antibody-drug conjugate (ADC) with anti-CADM1 antibody and monomethyl auristatin E (anti-CAD-ADC) shows anti-tumor effect on CADM1-expressing human GIST cells. The ADC adhibited in this study was previously used for CADM1-expressing human mesothelioma cells and showed anti-tumor effect for them in vitro. GIST-T1 cell line of gastric origin which scarcely expresses CADM1 and GIST-T1 cells transfected with CADM1 cDNA (GIST-T1-CAD cells) which highly expresses CADM1 and represents small intestinal GIST were used. In vitro, anti-CAD-ADC showed remarkable cytotoxic activity on GIST-T1-CAD cells, but control ADC did not. Both anti-CAD-ADC and control ADC did not show anti-tumor effect on original GIST-T1 cells. When GIST-T1-CAD cells were subcutaneously injected to the nude mice, intravenous administration of anti-CAD-ADC showed inhibitory effect for tumor enlargement. Tumor of GIST-T1 cells grew even after anti-CAD-ADC injection. When GIST-T1-CAD cells were injected into peritoneal cavity of the SCID mice, intraperitoneal administration of anti-CAD-ADC showed reduction of the peritoneal tumor. On the other hand, peritoneal tumor grew after control ADC administration. Tissue and organ damage due to administration of anti-CAD-ADC was not apparent by macroscopic and histological examinations in mice. These results indicate that anti-CAD-ADC could have apparent anti-tumor effect on CADM1-expressing human GIST cells both in in vitro and in vivo mouse models.

AbstractYKL-40 is implicated in inflammation and tissue repair, but no reports have investigated its involvement in myositis in polymyositis (PM) and dermatomyositis (DM). Therefore, we aimed to investigate the relationship between YKL-40 and PM/DM. We retrospectively enrolled 35 patients diagnosed with PM/DM along with 26 healthy controls (HCs). Both PM and DM were diagnosed according to Bohan and Peter’s criteria. Serum YKL-40 levels were measured, age-corrected to YKL-40 percentile values, and compared to HCs. Patients with myositis without interstitial lung disease were also enrolled and compared to HCs. Immunofluorescence staining was performed to identify YKL-40-positive inflammatory cells in muscle biopsy samples from two patients each with PM and DM. Age-corrected serum YKL-40 levels were significantly higher in patients with PM/DM compared to HCs with and without lung disease; however, these levels decreased significantly after treatment. Immunohistochemical analysis showed infiltration of YKL-40-positive inflammatory cells into the intramuscular sheath and perimuscular membrane. Immunofluorescence staining showed CD68 expression in YKL-40-positive inflammatory cells, suggesting that these cells were macrophages. To the best of our knowledge, this is the first study to demonstrate that YKL-40-positive macrophages are present in PM and DM, indicating that YKL-40 may be involved in PM/DM.

Abstract Background Familial gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the digestive tract caused by germline gain-of-function mutations in the KIT gene or platelet-derived growth factor receptor alpha gene (PDGFRA). These mutations cause not only multiple GISTs but also diffuse hyperplasia of interstitial cells of Cajal (ICCs), which is related to esophageal motility disorder. Case presentation A 53-year-old man was referred to our hospital because of anemia and dysphagia. Fifteen years earlier, he had undergone a laparoscopic partial gastrectomy for multiple gastric GISTs with a germline mutation in exon 17 of the KIT gene. An upper gastrointestinal endoscopy revealed that the patient had multiple gastric GISTs and a large esophageal diverticulum directly above the esophagogastric junction. The largest gastric tumor was 7 cm, with a delle that might cause bleeding. Because the patient presented with dysphagia, we performed video-assisted thoracic esophagectomy and laparoscopic-assisted proximal gastrectomy simultaneously. The patient had survived without metastasis for 4 years after surgery and dysphagia had improved. Conclusions This is the first report of successful laparoscopic–thoracoscopic surgery for a patient with familial gastric GISTs accompanied with a large esophageal diverticulum.

We report a 58-year-old male with a histopathologically proven grade 2 (G2) pancreatic neuroendocrine neoplasm and multiple abdominal node metastases by use of a laparoscopic pancreatic body and tail resection procedure, plus abdominal lymph node dissection. A primary pancreatic tail neuroendocrine tumor sized 20 × 25 mm was detected by contrast-enhanced computed tomography, somatostatin receptor scintigraphy (SRS), and fluorodeoxyglucose positron emission tomography (FDG-PET) examinations and pathologically diagnosed as a pancreatic neuroendocrine tumor (PNET, G2) based on positive immunostaining for somatostatin receptor (SSTR) type 2. Of three metastatic histopathological lymph nodes, two measured 18 × 21 and 10 × 12 mm, respectively, with whole strong SSTR immunostaining showing moderate uptake in SRS findings, whereas the other node, sized 8 × 10 mm, had strong SSTR immunostaining only in a small 6 × 6-mm-sized portion and showed no uptake in SRS findings, likely because of the limited spatial resolution of scintigraphy. On the other hand, only the largest node (18 × 21 mm) was visualized by FDG-PET. SRS may be useful for metastatic lymph node diagnosis based on SSTR immunostaining, though a disadvantage is the spatial resolution limitation.

Objectives: Despite the prognostic impacts of preoperative fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examination, fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography–based prognosis prediction has not been used clinically because of the disparity in data between institutions. By applying an image-based harmonized approach, we evaluated the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters in clinical stage I non–small cell lung cancer. Methods: We retrospectively examined 495 patients with clinical stage I non–small cell lung cancer who underwent fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examinations before pulmonary resection between 2013 and 2014 at 4 institutions. Three different harmonization techniques were applied, and an image-based harmonization, which showed the best-fit results, was used in the further analyses to evaluate the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. Results: Cutoff values of image-based harmonized fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters, maximum standardized uptake, metabolic tumor volume, and total lesion glycolysis were determined using receiver operating characteristic curves that distinguish pathologic high invasiveness of tumors. Among these parameters, only the maximum standardized uptake was an independent prognostic factor in recurrence-free and overall survivals in univariate and multivariate analyses. High image-based maximum standardized uptake value was associated with squamous histology or lung adenocarcinomas with higher pathologic grades. In subgroup analyses defined by ground-glass opacity status and histology or by clinical stages, the prognostic impact of image-based maximum standardized uptake value was always the highest compared with other fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. Conclusions: The image-based fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography harmonization was the best fit, and the image-based maximum standardized uptake was the most important prognostic marker in all patients and in subgroups defined by ground-glass opacity status and histology in surgically resected clinical stage I non–small cell lung cancers.

Abstract Background Colorectal carcinoma with enteroblastic differentiation is a rare subtype of colorectal carcinomas expressing at least one characteristic immunohistochemical marker among α-fetoprotein, glypican-3, and spalt-like transcription factor 4. On the other hand, colorectal carcinoma with neuroendocrine differentiation is also a unique subtype of colorectal carcinomas showing expression of at least one distinctive marker among chromogranin A, synaptophysin, and CD56. Case presentation We experienced an extremely rare case of rectal carcinoma with dual differentiation toward enteroblastic and neuroendocrine features in a 53-year-old male patient with long-standing ulcerative colitis (UC). Most of the tumor cells were positive for enteroblastic differentiation markers and approximately a half of them for neuroendocrine differentiation markers. Some tumor cells showed only enteroblastic differentiation, and some did only neuroendocrine feature, but some showed both enteroblastic and neuroendocrine differentiation. Conclusion Colorectal carcinoma with dual differentiation toward enteroblastic and neuroendocrine features has not been reported yet. Neoplastic transformation from pluripotent stem cells in dysplastic epithelium of long-standing UC patients may be associated with such dual differentiation features.

The intestinal lumen is rich in gut microbial metabolites that serve as signaling molecules for gut immune cells. G-protein-coupled receptors (GPCRs) sense metabolites and can act as key mediators that translate gut luminal signals into host immune responses. However, the impacts of gut microbe-GPCR interactions on human physiology have not been fully elucidated. Here, we show that GPR31, which is activated by the gut bacterial metabolite pyruvate, is specifically expressed on type 1 conventional dendritic cells (cDC1s) in the lamina propria of the human intestine. Using human induced pluripotent stem cell-derived cDC1s and a monolayer human gut organoid coculture system, we show that cDC1s extend their dendrites toward pyruvate on the luminal side, forming transepithelial dendrites (TED). Accordingly, GPR31 activation via pyruvate enhances the fundamental function of cDC1 by allowing efficient uptake of gut luminal antigens, such as dietary compounds and bacterial particles through TED formation. Our results highlight the role of GPCRs in tuning the human gut immune system according to local metabolic cues. [ABSTRACT FROM AUTHOR]

Abstract Background Most gastrointestinal stromal tumors (GIST) harbor a mutation in KIT or platelet‐derived growth factor receptor alfa (PDGFRA). Although genotyping is a useful predictive marker of tyrosine kinase inhibitors, whether it can predict prognosis remains controversial. Methods Data on 402 patients with GIST who underwent macroscopically complete surgery and received no neoadjuvant/adjuvant therapy were selected from a prospective GIST database at the three, participating hospitals. The types and locations of KIT and PDGFRA mutations were analyzed by direct sequencing of the amplified genes. The association between the genotypic characteristics and prognosis was then examined. Results Tumor genotypes were analyzed in 398 of 402 (99%) patients, and 120 mutation patterns were identified. KIT mutations had broad malignancy potential which differed according to the type of mutation. Deletion and deletion‐insertion type mutations were associated with worse RFS while duplication and substitution type mutations were associated with favorable RFS KIT deletion/deletion‐insertion, including codons 557 and 558, were especially associated with worse RFS on multivariate analysis both of all the patients and those with KIT mutations. Conclusions Specific GIST genotypes were significantly associated with a risk of recurrence. Genotype analysis may be useful for predicting the prognosis and determining the indications for adjuvant imatinib in patients with GIST.

Abstract A 64‐year‐old man with angioimmunoblastic T‐cell lymphoma (AITL) subsequently developed diffuse large B‐cell lymphoma (DLBCL) and myelodysplastic syndrome (MDS). Genomic profiling of AITL, DLBCL, and MDS samples revealed that the tumor cells from all samples shared common mutations in TET2 and DNMT3A. In addition, the IDH2 mutation was observed in AITL, and TP53 mutation was observed in DLBCL and MDS. These findings illustrate the clonal relationship between AITL and DLBCL in addition to AITL and MDS, with the latter being increasingly reported. The present findings strongly support the theory of multistep and multilineage tumorigenesis from a common founder clone.

Inflammatory myofibroblastic tumor (IMT) of the urinary bladder is a rare soft tissue tumor characterized by spindle cell proliferation with inflammatory cell infiltration. We present a case of bladder IMT occurring in a 6-year-old boy. Pretreatment CT images depicted a polypoid and broad-based mass measuring 18 mm in the superior to the front wall of the bladder, and the mass showed isodensity on precontrast image and ring enhancement of the mass after the intravenous administration of contrast material. Pelvic MRI demonstrated the 18 × 17 × 16 mm broad-based mass, suggesting submucosal tumor in the dome of the bladder. The mass showed low-to-moderate signal intensity on T1-weighted images and slight high signal intensity on T2-weighted images and restricted diffusion with low signal intensity on ADC map and abnormal high signal intensity on DWI. Transurethral resection of the bladder tumor and partial cystectomy were undertaken, and the pathology revealed IMT of the bladder. We suggest its inclusion in the differential diagnosis of cases of a polypoid and broad-based mass on the superior wall or the front wall of the bladder with ring enhancement on contrast-enhanced CT and MRI.

Abstract Background Synovial sarcomas are a rare type of high-grade sarcomas with unknown cell origin. They arise predominantly in the soft tissues but rarely in the stomach. We recently encountered a rare case of minute gastric synovial sarcoma. Case presentation A 61-year-old Japanese woman was pointed out edematous erosion at the body of the stomach. Biopsy specimen showed dense proliferation of spindle-shaped tumor cells mixed with smooth muscle fibers of the muscularis mucosae. Although the definite histological diagnosis was undetermined, the patient underwent laparoscopic wedge resection of the stomach. Histological examination of the resected sample revealed that the maximum diameter of the tumor was only 6 mm and that dense proliferation of rather uniform spindle tumor cells were observed mainly in the submucosa. Immunohistochemistry showed that they were positive for pan-keratin, CD99 and TLE1. SS18-SSX fusion-specific antibody gave diffuse positive staining to the tumor cells, and analysis using mRNA extracted from paraffin sections revealed that the tumor had SS18-SSX1 fusion gene. Thus, it was diagnosed as gastric synovial sarcoma, monophasic fibrous type. Conclusions Primary synovial sarcoma of the stomach is rare and only 47 cases have been reported in the English literature to date. The maximum diameter of the lesion of our case was 6 mm which is the smallest among them.

Abstract Background Ectopic pancreas is basically a benign disease and is not always necessary to be removed. However, all types of neoplasms occurring in the normal pancreas such as ductal adenocarcinomas and intraductal papillary mucinous neoplasms (IPMNs) may develop even within ectopic pancreas. We recently encountered an extremely rare case of ectopic pancreas in the gastric antrum associated with IPMN possessing a GNAS mutation. Case presentation A 71-year-old Japanese woman complained of epigastric pain. Computed tomography and upper gastrointestinal endoscopy showed an intramural cystic mass in the antrum of the stomach. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy did not give a definitive diagnosis, and the patient underwent resection of the lesion. Histology of the resected specimen showed that the gastric intramural lesion was ectopic pancreas. Moreover, the lesion contained dilated duct components with tubulo-villous epithelial proliferation consistent with pancreatic IPMN. Since the covering epithelial cells had highly atypical nuclei, the lesion was diagnosed as IPMN with high grade dysplasia. Immunohistochemistry showed that the IPMN component showed to be MUC2-, MUC5AC-, and CDX2-positive but MUC1- and MUC6-negative. Mutational analyses using genomic DNA revealed that the IPMN component had a mutation of GNAS at exon 8 (Arg201Cys). Conclusion We finally diagnosed this case as gastric ectopic pancreas accompanied by intestinal type IPMN with high grade dysplasia possessing GNAS mutation. Although there were 17 cases of ectopic pancreas with IPMN including 6 cases of gastric ones reported in the English literature, this is the first case of ectopic pancreas with IPMN which was proved to have GNAS mutation. Intimate preoperative examinations including imaging analyses and EUS-FNA biopsy/cytology are recommended to decide whether the lesion has to be resected or not even if they are not effective for getting the right diagnosis.

Ductal adenocarcinoma is a variant of prostatic adenocarcinoma, originating from the epithelial lining of the primary and secondary ducts of the prostate. We report a 63-year-old male with prostatic ductal adenocarcinoma, presenting as urinary retention and a prostate-specific antigen (PSA) level of 11.71 ng/mL and biopsy-proven prostate cancer (Gleason score 3 + 3). MRI showed 2 hemorrhagic, multilocular cysts projecting into the bladder side from the prostatic inner gland and between the prostate and the right seminal vesicle. The prostate inner gland showed high signal intensity on the T2-weighted image and included tiny hyperintense spots on the fat-suppression T1-weighted image. In the part of the border of the hemorrhagic, multilocular cyst, a solid portion showing slight low intensity on T1-weigthed imaging and markedly restricted diffusion was observed, suggesting prostate cancer. He underwent total prostatectomy, and ductal adenocarcinoma (Gleason score 4 + 4) in the prostate inner gland and multilocular cysts was pathologically diagnosed. After the operation, his PSA level gradually increased, and MRI 8 months after the operation showed a vesical multilocular cyst, suggesting local recurrence. After he underwent radiation therapy and hormonal therapy, PSA level decreased, and no re-recurrence was observed during 8 years. We suggest its inclusion in the differential diagnosis of cases of prostatic ductal adenocarcinoma’s multiloculated cystic formation around the prostate and the bladder.

Abstract Background Cap polyposis (CP) is extremely rare in Japan, and there is no established cure. We report a case in which CP was improved by surgical treatment. Case presentation A 48-year-old man was investigated at a local hospital because of diarrhea and bloody stools in 2018. The patient was treated with metronidazole for suspected amoebic dysentery, but his symptoms did not improve. Subsequent close examination revealed possible CP, but treatment with 5-aminosalicylic acid and a steroid enema had no effect. The patient was then referred to our hospital. The bloody stools, diarrhea, and abdominal pain worsened despite medical treatment, so laparoscopic-assisted total proctocolectomy and ileal J-pouch anal anastomosis with ileostomy were performed. CP has no known cause or established treatment, but Helicobacter pylori (HP) infection has been reported in many CP cases in Japan, and HP eradication is often successful. This patient was HP-negative and did not improve with antimicrobial treatment, but the symptoms improved after surgery. Conclusions Even after surgery, CP recurrence reportedly occurs within a short period in many cases. However, our patient has had no signs of CP recurrence during 1 year of follow-up.

Primary angiosarcomas of the kidney are very rare but highly aggressive tumors showing poor prognosis. We present a case of primary renal angiosarcoma occurring in a 60-year-old man with left flank pain. CT images depicted a huge exophytic mass (14 cm in diameter) in the left kidney, exhibiting central extensive hemorrhage or necrosis without contrast enhancement. The mass showed centripetal peripheral nodular enhancement on dynamic contrast-enhanced CT images. We suggest its inclusion in the differential diagnosis of cases of hemorrhagic renal tumors with prominent vasculature.

Abstract Pathological changes after third-generation drug-eluting stent implantation remain unclear. We compared the tissue responses of coronary arteries after the implantation of third-generation abluminal biodegradable-polymer everolimus-eluting stent (3rd EES) and second-generation durable-polymer EES (2nd EES) using autopsy specimens and an atherosclerotic porcine model. We compared the histology of stented coronary arteries obtained by autopsy performed 1–10 months after 3rd EES (n (number of cases) = 4, stent-implanted period of 3–7 months) and 2nd EES (n (number of cases) = 9, stent-implanted period of 1–10 months) implantations. The ratio of covered stent struts was higher with 3rd EESs than with 2nd EESs (3rd; 0.824 ± 0.032 vs. 2nd; 0.736 ± 0.022, p = 0.035). Low-density lipoprotein receptor knockout minipigs were stented with 3rd or 2nd EES in the coronary arteries and the stented regions were investigated. The fibrin deposition around the 2nd EES was more prominent. Additionally, higher density of smooth muscle cells was confirmed after the 3rd EES implantation. Pathological examination after the 3rd EES demonstrated a combination of less fibrin deposition and more rapid acquisition of well-developed neointima as compared to the 2nd EES at autopsy and the atherosclerotic porcine model.

Abstract Background Gastrointestinal stromal tumors (GISTs) generally form well-defined mass lesions. However, some cases of the flatly distributed and muscularis propria-replacing GISTs have been reported so far. We experienced an additional case of planar-type GIST of the sigmoid colon accompanied by a diverticulum with perforation. Case presentation A 68-year-old Japanese male with sudden onset of abdominal pain was clinically diagnosed with gastrointestinal perforation, and an emergency abdominal operation was performed. A diverticulum with rupture was found in the sigmoid colon, but no apparent tumor was observed. Histological examination revealed bland spindle cells flatly proliferating and diffusely replacing the muscularis propria at the diverticular structure. The spindle cells were positive for KIT, DOG1, and CD34. Mutational analysis of the c-kit gene revealed that the lesion had a heterozygous deletion of 2 amino acids at codons 557 and 558 of exon 11. The mutation was not observed in the normal mucosa of the surrounding tissue. Conclusion We diagnosed this case as an unusual planar-type GIST. Some similar cases have been reported in the sigmoid colon and other sites. We discuss the mechanism of development of the planar-type GISTs associated with the diverticulum.

Background & Aims: Ral guanosine triphosphatase–activating protein α2 (RalGAPα2) is the major catalytic subunit of the negative regulators of the small guanosine triphosphatase Ral, a member of the Ras subfamily. Ral regulates tumorigenesis and invasion/metastasis of some cancers; however, the role of Ral in colitis-associated cancer (CAC) has not been investigated. We aimed to elucidate the role of Ral in the mechanism of CAC. Methods: We used wild-type (WT) mice and RalGAPα2 knockout (KO) mice that showed Ral activation, and bone marrow chimeric mice were generated as follows: WT to WT, WT to RalGAPα2 KO, RalGAPα2 KO to WT, and RalGAPα2 KO to RalGAPα2 KO mice. CAC was induced in these mice by intraperitoneal injection of azoxymethane followed by dextran sulfate sodium intake. Intestinal epithelial cells were isolated from colon tissues, and we performed complementary DNA microarray analysis. Cytokine expression in normal colon tissues and CAC was analyzed by quantitative polymerase chain reaction. Results: Bone marrow chimeric mice showed that immune cell function between WT mice and RalGAPα2 KO mice was not significantly different in the CAC mechanism. RalGAPα2 KO mice had a significantly larger tumor number and size and a significantly higher proportion of tumors invading the submucosa than WT mice. Higher expression levels of matrix metalloproteinase-9 and matrix metalloproteinase-13 were observed in RalGAPα2 KO mice than in WT mice. The expression levels of interleukin 1β, NLRP3, apoptosis associated speck-like protein containing a CARD, and caspase-1 were apparently increased in the tumors of RalGAPα2 KO mice compared with WT mice. NLRP3 inhibitor reduced the number of invasive tumors. Conclusions: Ral activation participates in the mechanism of CAC development via NLRP3 inflammasome activation. Keywords: Ral, Ral-GTPase Activating Protein (RalGAP), Colitis-Associated Cancer, NLRP3 Inflammasome

Although cardiac dysfunction after chimeric antigen receptor (CAR) T-cell therapy has been increasingly reported, the underlying dynamics and pathogenesis are not well documented. Herein, we describe the clinical presentation and treatment for two patients who developed severe acute heart failure after CAR T-cell therapy. Both cases shared several common characteristics, including the bone marrow involvement at the time of CAR T-cell therapy and early onset of cytokine release syndrome (CRS) with fever developing on the day of CAR T-cell infusion. Patients with early onset and/or severe CRS should be carefully monitored for the possibility of heart failure.

Metastasis of hepatocellular carcinoma (HCC) in the pouch of Douglas is relatively rare. A 65-year-old man with liver cirrhosis was admitted for detailed examination of a pelvic tumor. He had a previous history of ruptured HCC, and received emergent hemostasis with transcatheter arterial embolization followed by curative ablation. His blood tests showed an increase in des-gamma-carboxy prothrombin (DCP). Contrast-enhanced computed tomography (CE-CT) revealed a heterogeneously enhanced large pelvic tumor, but no additional tumorous lesions were detected in other organs, including the lungs, liver and abdominal lymph nodes. The colonoscopy showed compression by an extra-luminal/submucosal tumor, and computed tomography-guided percutaneous needle biopsy revealed that the pelvic tumor was metastasis of HCC. Because of the poor liver function, the solitary pelvic tumor was treated with three-dimensional conformal radiation therapy (3D-CRT). The tumor size and the DCP value were markedly decreased after radiation therapy. Nine months later, occasional mild bloody stool due to radiation proctitis was observed; however, no serious side effects occurred. Our case suggests that radiation therapy may be a therapeutic option for a solitary metastatic lesion of HCC in the pouch of Douglas.

We present a 76-year-old Japanese male who had a history of removal of a gastric gastrointestinal stromal tumor (GIST) 6 years ago. Although asymptomatic and having no evidence of recurrence, follow-up endoscopy revealed a small, white depressed lesion of approximately 1 cm with converging mucosal folds in the greater curvature of the fundus, which was suspicious of depressed-type early gastric cancer (GC) by conventional endoscopy. However, no evidence of GC except a “white globe appearance”-like area was identified by magnifying endoscopy with blue laser imaging. The biopsy specimens showed a proliferation of anaplastic lymphoma kinase (ALK)-positive spindle cells in the gastric mucosa, and ALK-rearrangement was detected by fluorescent in situ hybridization. Furthermore, clathrin heavy chain (CLTC)-ALK fusion was seen by genetic analysis, thus the lesion was preoperatively diagnosed as gastric inflammatory myofibroblastic tumor (IMT). For the curative intent, a laparoscopic endoscopic cooperative surgery (LECS) was performed. On the specimens resected by LECS, ALK-positive cells were sporadically distributed in the gastric mucosa and submucosa in the depressed area. In addition, two sporadic GISTs originating from the muscularis propria were found under the gastric IMT. Although there have been many reported cases of gastric IMTs, almost all those cases showed huge elevated tumors. Thus, this lesion is an extremely rare IMT case presenting a superficial depressed-type appearance, like 0-IIc type early GC. Keywords: Stomach, Superficial depressed-type, IMT, CLTC-ALK fusion

We experienced a 70-year-old female with brain and liver tumors. She underwent surgical operations for rectal cancer 8 year ago and lung cancer 16 years ago. Surgical removal of a brain tumor and a liver biopsy were performed. The brain tumor consisted of an adenocarcinoma with a solid signet-ring cell pattern. Under the possibility of metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer in the brain and liver, immunohistochemistries (IHCs) for ALK were performed, returning positive results. Thus, metastasis of ALK-rearranged lung adenocarcinoma in the brain and liver had been confirmed. The patient was administered alectinib, which was well tolerated and has been in partial response for about one year and a half. By the genetic analyses for EML4-ALK variants, both the previous lung cancer and metastatic brain tumor were shown to harbor the same EML4-ALK variant 3 fusion. We thus concluded that ALK-rearranged lung adenocarcinoma has recurred as liver and brain metastases 16 years after curative surgery.

Inflammatory pseudotumor (IPT) of the liver is a rare benign disease. IPTs generally develop as solitary nodules, and cases with multiple lesions are uncommon. We herein report a case of multiple IPTs of the liver that spontaneously regressed. A 70-year-old woman with a 10-year history of primary biliary cholangitis and rheumatoid arthritis visited our hospital to receive a periodic medical examination. Abdominal ultrasonography revealed multiple hypoechoic lesions, with a maximum size of 33 mm, in the liver. Contrast-enhanced computed tomography revealed low-attenuation areas in the liver with mild peripheral enhancement at the arterial and portal phases. We first suspected metastatic liver tumors, but fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and contrast-enhanced ultrasonography suggested the tumors to be inconsistent with malignant nodules. A percutaneous biopsy showed shedding of liver cells and abundant fibrosis with infiltration of inflammatory cells. Given these findings, we diagnosed the multiple tumors as IPTs. After careful observation for two months, the tumors almost vanished spontaneously. Physicians should avoid a hasty diagnosis of multiple tumors based solely on a few clinical findings, and a careful assessment with various imaging modalities should be conducted.

We report two cases of WWTR1-CAMTA1 fusion-positive epithelioid hemangioendotheliomas (EHEs) with extremely different clinical behaviors. The first case was a 52-year-old Japanese woman with a complaint of an enlarging right axillary mass. Surgical specimen showed that the epithelioid tumors within the vein had the pathological feature of a cord-like pattern with myxoid or hyaline matrix and the intracytoplasmic lumen with erythrocytes and the immunophenotype of endothelial cells. The final pathological diagnosis was classic EHE. An RT-PCR analysis showed positivity of WWTR1-CAMTA1 fusion. The patient has now been free of disease for 7 years after surgery. The second case was a 70-year-old Japanese male with a complaint of severe pain of his left thigh. The radiographic findings showed ectopic calcification near the left femur. Surgical specimen showed clusters of malignant epithelioid cells with necrosis and obvious mitoses in soft tissue. They were also shown to be of endothelial origin by immunohistochemistry (IHC). The pathological diagnosis was malignant EHE or epithelioid angiosarcoma with ectopic ossification. An RT-PCR analysis showed the tumor had WWTR1-CAMTA1 fusion. Thus, the final pathological diagnosis was malignant EHE. Unfortunately, he died 7 months after surgery due to pleural dissemination. Although fusion gene is thought to define one spectrum of specific tumors, our two cases of EHEs with WWTR1-CAMTA1 fusion showed extremely different outcomes, one is rather benign and the other fatal. Retrospective study showed that both tumors were positive for nuclear CAMTA1 by IHC. Fusion-genes define a unique spectrum of tumors, but even in the tumors within the same spectrum defined by a specific fusion-gene, there are heterogeneities of malignant potentials. Therefore, factors other than fusion-genes may contribute to prognoses. Keywords: Epithelioid hemangioendothelioma, WWTR1-CAMTA1 fusion, CAMTA1 immunohistochemistry, Ossification

We experienced a 58-year-old Japanese female complaining of bleedings at defecation for about one year. Endoscopy revealed an Ip submucosal tumor (SMT) at the rectum. Continuous bleedings at defecation and no evidence malignancy in a biopsy specimen led to a polypectomy. The specimen showed SMT with erosion, while the macroscopic cross-section implied a lipomatous mesenchymal tumor. Under the probable diagnosis of liposarcoma, especially myxoid liposarcoma, fusion-gene analyses were performed. The detection of type 1 FUS-DDIT3 fusion gene led to a definite diagnosis of rectal myxoid liposarcoma. For further treatment, a super low anterior resection was performed, revealing neither residual tumors nor lymph node metastases. The patient is now alive and free of disease for 5 years. To our knowledge of the literature, this is the first case of a rectal myxoid liposarcoma. Keywords: Rectum, Myxoid liposarcoma, Submucosal tumor

A 76-year-old female presented with cognitive impairment and multiple brain infarcts and died of massive subcortical cerebral hemorrhage. A premortem clinical diagnosis was not possible. She did not show apparent microbleeds on brain images during her lifetime. An autopsy revealed vasculitis at various stages with amyloid β deposition and granulomatous reaction in cortical and leptomeningeal arteries, although almost vasculitic processes were in the healing stage, suggestive of the inactive stage of the disease process. Affected vessels were strictly limited to the brain. The final pathological diagnosis of the autopsy was amyloid β-related angiitis. Genotype analyses of ApoE revealed ApoE ε3/ε3 genotype, low risk for Alzheimer's disease. On retrospective examination, the titer of anti-amyloid β autoantibody in cerebrospinal fluid was rather high in our case, but the exact clinical significance remains unknown. Since microbleeds on brain images are diagnostic findings in patients with cerebral amyloid angiopathy-associated conditions, it is very difficult to make an accurate diagnosis of amyloid β-related angiitis without typical microbleeds or open brain biopsy like our case. Keywords: Amyloid β-related angiitis, Cerebral amyloid angiopathy, ApoE, Subcortical cerebral hemorrhage, Primary central nervous system vasculitis

Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue malignant neoplasm with a deceptively benign histological appearance and a potential for late recurrence and metastasis. LGFMS cases with significant ossification are extremely rare. To our knowledge, only three cases of LGFMS with bone formation which is detected as apparent calcification by radiological examinations and proven by histopathology have been reported. Here, we report the fourth such case. A 39-year-old female presented with a 10-year history of a painless tumor in her right buttock. Computed tomography images showed multiple foci of intratumoral calcification. A needle biopsy specimen of the tumor revealed a spindle cell neoplasm with hyalinizing/collagenous stroma and ossification. The tumor cells were immunohistochemically positive for MUC4 and the molecular analysis of the tumor detected FUS-CREB3L2 fusion. Pathological diagnosis of LGFMS was made. Total resection of the tumor with wide margins was performed, and histology of the resected sample showed multiple foci of intratumoral ossification.

Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft tissue neoplasm with a deceptively benign histological appearance. Only several LGFMS cases originating from the gastrointestinal tract have been reported, but all of them are from the small intestine or colon. Here, we describe a case of gastric LGFMS that was proven to have a characteristic FUS-CREB3L1 fusion gene. A 54-year-old Japanese female complained of epigastralgia. Abdominal computed tomography revealed a solid mass probably originating from the lessercurvature of the gastric body and protruding outside the gastric wall. Under the clinical diagnosis of suspicious gastrointestinal stromal tumor of the stomach, gastric wedge resection including the tumor was done. The macroscopic finding showed a mass approximately 8.0cm in maximal diameter with white-tan cut surface, arising from the gastric wall. Histological examination revealed a mesenchymal tumor consisting of blunt spindle cells with occasional collagen rosettes and inflammatory cells. Tumor was immunohistochemically positive for MUC4 and the molecular analysis using formalin-fixed paraffin embedded tissue detected FUS-CREB3L1 fusion which is a minor fusion gene type in LGFMS. Thus, the pathological diagnosis of gastric LGFMS was confirmed. To the best of our knowledge, the present case is the first one of LGFMS arising from the stomach in the English literature. Keywords: Low-grade fibromyxoid sarcoma, FUS-CREB3L1 fusion, Stomach

We report a 65-year-old male with histopathologically proven prostate cancer and multiple pelvic node metastases using a robotic-assisted radical prostatectomy procedure plus extended pelvic lymph node dissection. Positron emission tomography (PET) scan findings demonstrated a moderate accumulation of 11C-choline in a metastatic left obturator node sized 8 × 8 mm, though only a faint uptake of fluorodeoxyglucose (FDG) was noted. 11C-choline PET/computed tomography (CT) may be useful for the diagnosis of a tiny metastatic lymph node not demonstrated by CT, magnetic resonance imaging, or FDG-PET/CT and to determine the need for an extended pelvic lymph node dissection.

We experienced a diagnostically challenging case of Carney complex (CNC). A 24-year-old woman had a past history of surgical removal of multiple cutaneous tumors in the childhood. She was followed as a patient of neurofibromatosis type 1 (NF1) and referred to our hospital for further treatment after she grew up to adulthood. At our hospital, several cutaneous tumors were excised, and the pathological diagnosis was myxoma arising from not deep soft tissue but cutis (so-called cutaneous myxoma). Despite previous clinical diagnosis of NF1, because of the probability of CNC, detailed systemic examination was undertaken including radiological and endocrinological tests. Imaging techniques showed multiple lumps in both breasts, a mass in left atrium and nodular lesions in adrenal glands. Serum ACTH level was markedly suppressed. Surgically resected specimens revealed breast myxomas, cardiac myxoma and primary pigmented nodular adrenocortical disease (PPNAD). These findings met the diagnostic criteria for CNC. Genetic analysis revealed known non-sense mutation of PRKAR1A c.124C>T (p.R42X) (ClinVar ID 41382). Her 50-year-old mother was also shown to have cardiac myxomas, radiological finding of breast myxomatosis and the same PRKAR1A mutation as her daughter. In the present case, the accurate diagnosis of CNC was difficult not only because CNC is a rare disease but also because skin pigmentation was not obvious. Since cardiac myxoma might result in poor or fatal outcome, early and accurate diagnosis of CNC and subsequent systemic investigation including heart are important. Although pediatric cutaneous myxomas are rare, multiple cutaneous myxomas might suggest the possibility of CNC. In such cases, systemic investigation should be done for the accurate diagnosis. Keywords: Carney complex, Cutaneous myxoma, PPNAD, PRKAR1A mutation

We experienced a case of meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) with symptomatic intratumoral hemorrhage in a 67-year-old Japanese woman. Her chief complaints were sudden onset of motor aphasia and right hemiparesis. Brain computed tomography showed the hemorrhagic mass adjacent to the superior sagittal sinus. The mass was resected and pathological examination of the specimen revealed a tumor that is rich in vessels and accompanied with intratumoral hemorrhage. Short spindle tumor cells were proliferating with myxoid stroma. Tumor cells appeared to be arranged around the vessels and sometimes attached to the vessel wall directly. Although hyalinization of the vessel wall was observed, neither patternless pattern nor staghorn vessels were seen. Immunohistochemistry revealed that the tumor cells were positive for both CD34 and nuclear STAT6. Moreover, gene analyses revealed unique NAB2-STAT6 fusion. Immunohistochemical findings and fusion-gene analyses enabled us to make the definite diagnosis of meningeal myxoid SFT/HPC. The present case showed the three unique features such as clinically symptomatic intratumoral hemorrhage at the onset, rare variant of myxoid SFT/HPC, and unique NAB2-STAT6 fusion. Keyword: Meninx, Myxoid solitary fibrous tumor/hemangiopericytoma, Cerebral hemorrhage, NAB2-STAT6 fusion

We experienced a case of malignant orbital tumor in a 72-year-old Japanese man. He noticed protrusion of his left eye, and received resection of the left orbital tumor. The tumor contained several different components such as high-grade invasive ductal carcinoma, low-grade/minimally invasive adenocarcinoma and pleomorphic adenoma. Pathological diagnosis of high-grade invasive ductal carcinoma ex pleomorphic adenoma of the left lacrimal gland was made. He had undergone surgical removal of the left lacrimal gland tumor at the other hospital 19 years before, and the surgical specimen revealed that most part of the tumor was pleomorphic adenoma but low-grade/minimally invasive adenocarcinoma was included as a minor component (low-grade/minimally invasive adenocarcinoma ex pleomorphic adenoma). Thus, we could observe the natural course of low-grade/minimally invasive adenocarcinoma ex pleomorphic adenoma which transformed into high-grade invasive ductal carcinoma ex pleomorphic adenoma. Lacrimal gland ductal carcinoma is an extremely rare tumor, and only 25 cases have been reported before in English literature. Moreover, our case is the 5th case of lacrimal gland ductal carcinoma ex pleomorphic adenoma. Keywords: Lacrimal gland, Carcinoma ex pleomorphic adenoma, Androgen receptor, HER2

Ovarian Sertoli cell tumors (SCTs) are rare sex cord tumors (Oliva et al., 2005). The standard treatment for high-grade SCTs is surgery followed by platinum-based chemotherapy. Although platinum-based chemotherapy is also an option for recurrent SCTs (Sigismondi et al., 2012), there is no established chemotherapy regimen for platinum-resistant recurrent SCTs. The effectiveness of pazopanib in treating epithelial ovarian cancer has recently been reported (du Bois et al., 2014; Pignata et al., 2015). In the case described herein, pazopanib was used to treat the platinum-resistant recurrence of a high-grade Sertoli cell tumor, and the response was evaluated by 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET)-computed tomography (CT). Written informed consent to reporting the case was obtained from the patient.

Endometriosis is an estrogen-dependent disease with symptoms of dysmenorrhea, chronic pain, and infertility that affects 6–10% of women of reproductive age. Medical or surgical therapy, such as administration of an anti-gonadotropin or ovarian cystectomy, provide effective pain relief. However, neither therapy can be used for patients wishing to become pregnant. Despite the high morbidity, the pathogenesis of endometriosis has not been well-elucidated. Several inflammatory cytokines are reported to participate in the onset of endometriosis. Here, we examined the role of interleukin (IL)-1/IL-33 signaling in the development of endometriosis using a mouse model of endometriosis. Endometriotic lesion volume was significantly reduced in Il33−/− and Il1r1−/− mice, and almost completely suppressed in Myd88−/− mice. Mice intraperitoneally administered with an antibody against IL-1 receptor 1 (IL-1R1) or IL-33 developed limited endometriotic lesions. Oral administration of an inhibitor against IL-1R-associated kinase 4 (IRAK4), a downstream signal molecule of MyD88, also suppressed lesion formation. Furthermore, even after the development of cystic lesions the IRAK4 inhibitor prevented the enlargement of lesions. These treatments all significantly reduced cellular proliferation, shown by decreased Ki-67 expression. These results reveal that IL-1/IL-1R1, IL-33/IL-33R and associated downstream signaling molecules are involved in the pathogenesis of endometriosis, and may provide novel therapeutic targets for endometriosis.

We report a 20-year-old male with a past history of diarrhea and discharge of a strobila of a broad tapeworm from his anus 3 months ago. He again noticed passing a tapeworm strobila and he visited our hospital with the tapeworm sample. The macroscopic appearance and the pathological features strongly suggested Diphyllobothriasis. Soon after the first visit to our hospital, a capsule endoscopy was performed with the result of no evidence of strobilae or scoleces. Praziquantel at 20 mg/kg was orally administered once. Before drug administration, egg-like structures were present in the stool. They disappeared soon after drug administration. In human Diphyllobothriasis, Dibothriocephalus nihonkaiensis (D. nihonkaiensis) infection and Dibothriocephalus latus (D. latus) infection are common. These two species are morphologically similar but genetically distinct. Accordingly, polymerase chain reaction (PCR) using genomic DNA of the tapeworm infecting our case was performed for amplifying mitochondrial cytochrome c oxidase subunit 1 (cox1) gene. The amplified DNA fragment by PCR of our case was phylogenetically compared with other mitochondrial cox1 gene sequences of D. nihonkaiensis, D. latus, D. dendriticus, Taenia saginata, Taenia solium and Spirometra erinaceieuropaei. As a result, the tapeworm of our case was most likely within the spectrum of D. nihonkaiensis. Although human diphyllobothriasis is not a life-threatening disease for human beings, it has become a re-emerging problem even in the most developed countries with the increasing popularity of eating raw fish. The knowledge of how to cook or freeze raw fish before eating can reduce the risk of infection. However, without general awareness of human parasite infection, food-borne infections will continue to be a public health problem. Keywords: Tapeworm, Dibothriocephalus nihonkaiensis, Dibothriocephalus latus, Mitochondrial cytochrome c oxidase subunit 1 gene, Praziquantel

Although sessile serrated adenoma/polyps (SSA/Ps) may arise through a pathway different from the traditional adenoma–carcinoma sequence, details of SSA/P tumorigenesis still remain unclear. Fusobacterium nucleatum (Fn) is frequently detected in colorectal cancer (CRC) tissues and may play a pivotal role in colorectal carcinogenesis. Here, we investigated the relationship between Fn and the β-catenin/REG Iα axis in SSA/Ps and their involvement in the proliferation of these lesions. Fn was detected in SSA/Ps by fluorescence in situ hybridization using a Fn-targeted probe, and expression of β-catenin, REG Iα and Ki67 was examined using immunohistochemistry. Sixteen of 30 SSA/P lesions (53.3%) were positive for Fn. Eighteen SSA/P lesions (60%) showed β-catenin immunoreactivity in the tumor cell nuclei. A significant majority of Fn-positive lesions showed nuclear expression of β-catenin (87.5%) and higher REG Iα scores and Ki67 labeling indices relative to Fn-negative lesions. The SSA/P lesions expressing β-catenin in nuclei had significantly higher REG Iα scores and Ki67 labeling indices than those expressing β-catenin on cytomembranes. The REG Iα score was positively correlated with the Ki67 labeling index in SSA/P lesions. The treatment with Wnt agonist SKL2001 promoted nuclear β-catenin translocation and enhanced REG Ia expression in Caco2 cells. Fn may play a role in the proliferation of SSA/P lesions through promotion of β-catenin nuclear translocation and REG Iα expression.

We studied a 17-year-old Japanese male with huge mass arising from the left third rib. The mass compressed the left lung and adhered to the pericardium, but the patient had no distant metastasis. He had a high level of plasma pro-gastrin-releasing peptide (proGRP). Histopathological examination of the bone biopsy specimen revealed small round cell tumor which was immunohistochemically positive for CD99 and vimentin. Gene analyses demonstrated EWSR1-FLI1 fusion, confirming the pathological diagnosis of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET). Several cycles of chemotherapy resulted in clinical good partial response, and plasma proGRP level at that time was normalized. Thereafter residual tumor was resected. Histopathological examination of the resected specimen showed no viable tumor cells, verifying the pathological complete response. High level of plasma proGRP before the chemotherapy and its normalization after the successful chemotherapy strongly suggest that ES/PNET in the present case was a proGRP producing tumor.