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Background Late recurrence of gastric cancer of over 10 years post-gastrectomy is extremely rare, and the mechanism of late recurrence is unclear. We report a case of para-aortic lymph node metastasis that recurred 12 years postoperatively. Case presentation A 44-year-old woman who was pathologically diagnosed with moderately to poorly differentiated adenocarcinoma with T2N2M0 Stage IIIA according to the Japanese Classification of Gastric Carcinoma (the 13th Edition) underwent laparoscopic distal gastrectomy with D1 + lymph node dissection. She received adjuvant chemotherapy with tegafur-uracil (400 mg/day) for 2 years. At postoperative year (POY) 5, a swollen lymph node was detected in the No.16b1lat lymph node station. However, positron emission tomography (PET) revealed normal uptake, and tumor markers were within normal limits; hence, the possibility of metastasis was judged to be low, and the patient was placed under observation. At POY 12, computerized tomography revealed an enlargement of the No.16b1lat lymph node station, and PET revealed abnormal uptake. Endoscopic ultrasound-guided fine-needle aspiration revealed a moderately differentiated adenocarcinoma. Hence, a diagnosis of recurrence of gastric cancer was made. She underwent para-aortic nodal dissection (PAND) of No.16b1lat & int stations. Immunochemical staining was similarly consistent with recurrence of gastric cancer. Meanwhile, CD44 variant 9 (CD44v9), a cancer stem cell marker for gastric adenocarcinoma, was attenuated in the recurrent lesions compared with the primary lesions. Postoperatively, she received chemotherapy with tegafur-gimeracil-oteracil (80 mg/day) for 1 year. At POY 4 after PAND, the patient remained well with no evidence of recurrence and distant metastasis. Conclusions The degree of staining for CD44v9 in the recurrent lesions may be related to the timing of recurrence. Hence, it is important to continue to investigate the role of the expression of CD44v9 in gastric cancer and to clarify the details.

Micronodular thymic neoplasm with lymphoid stroma (MNT), a subtype of thymic tumor, is histopathologically characterized by micronodular thymic epithelial cell nests with lymphoid stroma. Despite the distinct histopathology of MNT, its pathogenesis remains unclear.In this study, we aimed to examine a thymic tumor harboring thymic epithelial and lymphoid cells in a nonobese diabetic/severe combined immunodeficiency mouse.The excised tumor cells were cultured in vitro and comprised epithelial tumor cells and lymphoid cells. During a three-dimensional cell culture, the epithelial tumor cells formed micronodular cell nests surrounded by lymphoid stroma. Notably, the lymphoid cells underwent apoptosis when they were separated from the epithelial tumor cells. Cutaneous transplantation of the cultured epithelial cells with splenocytes from BALB/c mice led to tumor formation, and these cells demonstrated a histopathology similar to that of human MNT in a nonobese diabetic/severe combined immunodeficiency mouse.Given its overlapping features with human MNT, the transplanted tumor could serve as an experimental model of this disease.

Cancer-associated antigens are not only a good marker for monitoring cancer progression but are also useful for molecular target therapy. In this study, we aimed to generate a monoclonal antibody that preferentially reacts with colorectal cancer cells relative to noncancerous gland cells. We prepared antigens composed of HT-29 colorectal cancer cell lysates that were adsorbed by antibodies to sodium butyrate-induced enterocytically differentiated HT-29 cells. Subsequently, we generated a monoclonal antibody, designated 12G5A, which reacted with HT-29 colon cancer cells, but not with sodium butyrate-induced differentiated HT-29 cells. Immunohistochemical staining revealed 12G5A immunoreactivity in all 73 colon cancer tissue specimens examined at various degrees, but little or no immunoreactivity in noncancerous gland cells. Notably, high 12G5A immunoreactivity, which was determined as more than 50% of colon cancer cells intensively stained with 12G5A antibody, exhibited significantly higher association with a poor overall survival rate of patients with colorectal cancer (P = 0.0196) and unfavorable progression-free survival rate of patients with colorectal cancer (P = 0.0418). Matrix-assisted laser desorption ionization time-of-flight mass spectrometry, si-RNA silencing analysis, enzymatic deglycosylation, and tunicamycin treatment revealed that 12G5A recognized the glycosylated epitope on annexin A2 protein. Our findings indicate that 12G5A identified a cancer-associated glycosylation epitope on annexin A2, whose expression was related to unfavorable colorectal cancer behavior. KEY MESSAGE: • 12G5A monoclonal antibody recognized a colorectal cancer-associated epitope. • 12G5A antibody recognized the N-linked glycosylation epitope on annexin A2. • 12G5A immunoreactivity was related to unfavorable colorectal cancer behavior.

Patients with advanced gastric cancer, especially diffuse-type gastric cancer, which is often accompanied by stromal fibrosis, commonly exhibit a poor prognosis. This study was designed to unravel the potential roles of C1q/TNF-related protein 6 (CTRP6) in the fibrotic cancer microenvironment of diffuse-type gastric adenocarcinoma. A total of 49 diffuse-type gastric cancer samples were evaluated in this study, and 23 of these samples exhibited focal CTRP6 immunoreactivity. CTRP6 immunoreactivity was found to be correlated with favorable survival outcomes, in terms of both overall and relapse-free survival rates, but this trend did not reach significance (P = 0.15). By contrast, CTRP6 immunoreactivity was significantly correlated with relapse-free survival rates in patients with diffuse-type gastric cancer at a distal site (P = 0.028). Notably, most gastric cancer cells at the cancer invasive front were CTRP6 negative, especially in areas of robust fibrosis. Double immunohistochemical staining demonstrated an inverse expression profile for CTRP6 and the activated fibroblast marker alpha smooth muscle actin (α-sma) in stromal and gastric cancer cells at the cancer invasion front. The addition of recombinant CTRP6 protein attenuated the TGF-β-induced α-sma expression in cultured human fibroblasts but did not alter the proliferation rate or Matrigel-invasion activity of the cultured gastric cancer cells. In addition, CTRP6 did not affect the viability of normal human gastric epithelial cells. This study suggests that CTRP6 may have potential application in combating stromal fibrosis in diffuse-type gastric cancers.

This study was designed to unravel the pathobiological role of impaired ARID1A expression in gastric carcinogenesis. We examined ARID1A expression immunohistochemically in 98 gastric cancer tissue specimens with regard to the clinicopathological features. Based on the proportion and intensity of ARID1A immunoreactivity at the cancer invasion front, we subdivided the specimens into low- and high-expression ARID1A groups. Notably, low ARID1A expression was significantly correlated with overall survival of the patients. Subsequently, we determined the molecular signature that distinguished ARID1A low/poor prognosis from ARID1A high/good prognosis gastric cancers. A comprehensive gene profiling analysis followed by immunoblotting revealed that a mitochondrial apoptosis mediator, Harakiri, was less expressed in ARID1A low/poor prognosis than ARID1A high/good prognosis gastric cancers. siRNA-mediated ARID1A downregulation significantly reduced expression of the Harakiri molecule in cultured gastric cancer cells. Interestingly, downregulation of ARID1A conferred resistance to apoptosis induced by the mitochondrial metabolism inhibitor, devimistat. In contrast, enforced Harakiri expression restored sensitivity to devimistat-induced apoptosis in ARID1A downregulated gastric cancer cells. The present findings indicate that impaired ARID1A expression might lead to gastric carcinogenesis, putatively through gaining resistance to the Harakiri-mediated apoptosis pathway.

Objectives JAG2 is one of Notch ligands, which recently appear to exert various carcinogenesis. In the present study, we aimed to unveil the relation of JAG2 expression and clinicopathological features in oral squamous cell carcinoma (OSCC). Materials and Methods We examined JAG2 expression in OSCC plus adjacent nontumorous epithelia in eight patients. Ninety‐one OSCC tissue specimens were immunohistochemically stained with specific antibodies to JAG2. The immunoreactivities of JAG2 were correlated with clinicopathological factors, including the prognosis of patients. Chi‐square test, Kaplan–Meier survival, and Cox proportional hazard analysis were used to determine the statistical value of JAG2 expression in OSCC. Results JAG2 mRNA expression was much expressed in OSCC tissues compared with adjacent tissue specimens in five of eight patients. JAG2 immunoreactivity was found at invasion front in 31 of 91 OSCC. JAG2 immunoreactivity was significantly associated with age, less than 50 years old of patients (P = .048). Kaplan–Meier analysis demonstrated that the patients with JAG2 immunoreactvty have a short overall survival. With the Cox proportional hazard regression mode, the independent factors predictive of poor overall survival included JAG2 immunoreactivity (P < .05). Conclusions The present findings suggest that JAG2 overexpression, especially at the cancer invasion front, has potential prognostic value.

BackgroundGastric carcinosarcoma is most frequently diagnosed at an advanced stage when the tumor is generally large with invasion into other organs, lymph node metastasis, and distant metastasis. Standard chemotherapy has not been established, and surgery is the only curative treatment. Here, we present a case of postoperative recurrence of gastric carcinosarcoma under long-term tumor control with pazopanib.Case presentationA 77-year-old man was referred to our hospital because of nausea and vomiting. Computed tomography and upper gastrointestinal endoscopy revealed a type 1 tumor arising from the gastric antrum and extending into the duodenal bulb. He underwent distal gastrectomy (D2) with Roux-en-Y reconstruction. Histopathologically, the tumor had mixed adenocarcinoma and sarcoma components. According to the tumor–node–metastasis classification, the diagnosis was primary gastric carcinosarcoma pT1bN1M0 stage IB. Liver metastasis was detected 2 months after surgery; multiple lung metastases were detected 17 month after surgery. A genomic profiling test was performed using liver specimens as the patient became refractory to chemotherapy commonly used for gastric cancer, and the test revealedFGFR2amplification along withTP53R209*,AKT3N127D,NOTCH1A2036T, andPOLD1M161I. The patient was treated with pazopanib (800 mg/daily), and the tumor growth was controlled for 11 months.ConclusionsWe report a case of postoperative recurrence of gastric carcinosarcoma under long-term tumor control with pazopanib. This case suggested that pazopanib may be effective in treating gastric carcinosarcoma.

Oxidative stress serves an important role in carcinogenesis. The present study investigated the clinical significance of oxidative stress as a prognostic factor for diffuse large B-cell lymphoma (DLBCL). The participants comprised 55 consecutive patients with DLBCL. A commercially available derivatives of reactive oxygen metabolites (d-ROMs) test kit was used to assess oxidant levels. Similarly, a commercially available biological antioxidant potential (BAP) test was used to assess antioxidant levels. The antioxidative/oxidative stress ratio was calculated as d-ROMs/BAP. The median serum concentration of d-ROMs was 425 µM. The levels of d-ROMs were significantly higher in patients with DLBCL than in healthy volunteers (P

Approximately 24 cases of cytokeratin-positive interstitial reticulum cell tumors have been reported in English literature. In this paper, we report a case of cytokeratin-positive interstitial reticulum cell tumor that was localized in the parafollicular region of the axillary lymph node and was an incidental finding in a patient with breast cancer. A 50 year-old woman underwent a mastectomy and lymph node dissection following a preoperative diagnosis of bilateral breast cancer. Histopathological examination revealed that the patient had non-invasive and invasive ductal carcinoma in the right and left mammary glands. Although we could not detect breast cancer metastasis in the lymph nodes, one of eight right axillary lymph nodes harbored an 11 × 8 mm discohesive sheet of large polygonal epithelioid tumor cells in the parafollicular area. Tumor cells were immunoreactive for AE1/AE3, CAM5.2, CK18 and l-caldesmon and negative for CD1a, CD21, CD23, CD31, CD68, and S‑100 protein markers. Based on these findings, the lesion was diagnosed as a cytokeratin-positive interstitial reticulum cell tumor of the lymph node. Notably, this early-stage cytokeratin-positive interstitial reticulum cell tumor demonstrated focal nuclear YAP/TAZ proto-oncogene products, which were recently identified as critical for differentiation, maturation, and function of fibroblastic reticular cells. To the best of our knowledge, this is the first report to describe nuclear YAP/TAZ immunoreactivity in cytokeratin-positive interstitial reticulum cell tumors.

C1q/tumor necrosis factor-related protein-6 (CTRP6), also known as CTRP6 is identified adiponectin paralog. Although recent studies have revealed that adiponectin has an inhibitory role in carcinogenesis, the role of CTRP6 in carcinogenesis remains unclear. In this study, we found that eukaryotic recombinant CTRP6 protein bound to the cell surface membrane of cultured oral squamous cell carcinoma cells by immunofluorescence staining. Screening of CTRP6 binding protein in expression library followed by co-immunoprecipitation assay revealed that CTRP6 bound to the precursor of laminin receptor. CTRP6 disturbed the binding of laminin to the laminin receptor. Interestingly, the eukaryotic recombinant CTRP6 protein significantly suppressed the proliferation and Matrigel invasion activity of oral squamous cell carcinoma SAS cells in a dose-dependent manner. Moreover, administration of CTRP6 significantly attenuated the growth of SAS cells in xenoplant mice model. Laminin and laminin receptor are known to be overexpressed and promote the tumor growth in OSCC. Combined together, the present findings suggest that CTRP6 could repress progression of oral squamous cell carcinoma cells, putatively through disrupting the laminin-laminin receptor axis.

Background:Low-density lipoprotein receptor-related protein 1B(LRP1B) is thought to have a pleiotropic biological function. Notably, intracellular domain of LRP1B is released and transported to nucleus in a γ-secretase dependent fashion; however, pathological property, which is driven by nuclear transport of intracellular domain of LRP1B is largely unclear. In this study, we aimed to unravel the pathological significance of nuclear localization of intracellular domain of LRP1B in mammary gland carcinogenesis. Aims: We examine the clinical significance of LRP1B for breast cancer and we clarify mechanism of nuclear localization of LRP1B in invasive ductal carcinoma. Methods: Immunohistochemical staining using newly generated antibodies to intracellular domain of LRP1B was used to determine LRP1B expression in 92 invasive ductal carcinomas of the breast. The clinicopathological significance including prognosis value was statistically analyzed. Doxycycline dependent nuclear expression of intracellular domain of LAP1B was established in cultured breast cancer cells. Subsequently, a series of in vitro experiments were performed to explore the role of nuclear localized intracellular domain of LRP1B in cultured breast cancer cells. Comprehensive microarray-based analysis followed by quantitative RT-PCR and chromatin immunoprecipitation assay was performed to know the altered molecular signature induced by nuclear localized intracellular domain of LRP1B. Results: Non-tumorous mammary duct epithelial cells did not exhibit LRP1B staining, whereas different degrees of LRP1B immunoreactivity were observed in 75 of 92 invasive ductal carcinoma of the breast. LRP1B immunoreactivity was found in surface membrane and cytoplasm of 60 of 92(65.2%) invasive ductal carcinoma cells, whereas it was detected in nucleus of 15 of 92(16.3%)cancer cells. Interestingly, nuclear LRP1B immunoreactivity was significantly associated with poor prognosis of the patients, especially with luminal A type breast cancers. Notably, nuclear localized intracellular domain of LRP1B significantly related to status of nodal metastasis in luminal A type breast cancers. Enforced nuclear expression significantly increased Matrigel invasion activity in MCF-7 luminal A breast cancer cells without affecting cell growth. Notably, nuclear expression of intracellular domain of LRP1B decreased transcription of LRP1B. Comprehensive microarray-based analysis demonstrated that nuclear expression of intracellular domain of LRP1B significantly increased the expression of long non-coding RNA nuclear paraspeckle assembly transcript1(NEAT1), which facilitates breast cancer invasion with poor survival. Conclusions: Present findings indicated that nuclear localized intracellular domain of LTP1B promoted breast cancer progression with a poor prognostic value, possible through NEAT1 pathway. Nuclear transport of intracellular domain of LRP1B could be a therapeutic target for breast cancer patients. Citation Format: Asano Y, Futamura M, Takeuchi T, Yoshida K. Nuclear localization of intracellular domain of LDL receptor-related protein 1B predicts poor outcome in breast cancer; putative relation to NEAT1 mediated mammary gland carcinogenesis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-04.

Overexpression of Cleft Lip and Palate Transmembrane 1-Like (Clptm1L) confers cancer cell survival through the endoplasmic reticulum (ER) stress survival signaling pathway, while TMEM207 impairs the tumor suppressor function of WW domain containing oxidoreductase (WWOX), which sensitizes cancer cells to ER stress-induced apoptosis. In the present study, we examined whether these two ER stress-related proteins, Clptm1L and TMEM207, could be prognostic markers in oral squamous cell carcinoma (OSCC). Immunohistochemical staining using specific antibodies to Clptm1L or TMEM207 revealed that 31 of 89 tissue specimens exhibited concomitant expression of Clptm1L and TMEM207 at the cancer invasion front. A Kaplan–Meier plot of the patient survival curve followed by a log-rank test revealed that the coexpression of Clptm1L and TMEM207 was significantly associated with poor outcome in patients with OSCC (P = 0.00252). Coexpression of Clptm1L and TMEM207 was closely related to lymph node metastasis (P=0.000574). Both univariate and multivariate analyses demonstrated that coexpression of Clptm1L and TMEM207 predicted the poor prognosis of the patients with OSCC. The present study indicated that the double positive Clptm1L and TMEM207 immunoreactivity was closely related to lymph node metastasis with prognostic value in patients with OSCC.

Objective Preoperative chemotherapy (PC) for colorectal liver metastasis (CRLM) is widely used to improve prognosis, but its clinical benefit has not been fully established. This study aimed to assess the effectiveness of PC for synchronous CRLM and the correlation between the histologic response to PC and survival. Summary of Background Data We enrolled 69 patients who underwent initial hepatectomy for synchronous CRLM between 2004 and 2018 at Gifu University Hospital. Methods We retrospectively analyzed the clinicopathologic factors and outcomes of 69 patients who underwent hepatectomy after receiving PC (PC group: n = 43) or who underwent upfront hepatectomy (non-PC group: n = 26). In the PC group, the patients were divided into the Grade 1 (n = 27) and Grade 2/3 (n = 16) groups according to their histologic responses to PC. Results The median survival and 5-year overall survival (OS) rates were 80.9 months and 61.5%, respectively, in the PC group and 71.7 months and 61.5%, respectively, in the non-PC group (P = 0.867). Regarding recurrence-free survival (RFS) and remnant liver-RFS, there were no significant differences between the 2 groups (P = 0.087 and 0.291). However, in a subgroup analysis, the median 5-year OS, RFS, and remnant liver-RFS were significantly longer in the Grade 2/3 than Grade 1 group (P = 0.008, P = 0.002, and P < 0.001, respectively). Conclusions Some patients benefit from PC, and the histologic response to PC had prognostic significance for patients with synchronous CRLM.

Clear cell sarcoma (CCS) affects the deep soft tissues in young adults and is known to have high rates of metastasis, including lymphatic metastasis. In our previous study an xenoplant model of CCS was established, which exhibited local tumor growth, lymphatic metastasis, and distant metastasis in SCID-Beige mice. In the current study, the role of NK cells during metastasis in the same xenoplant murine model was investigated. Injection of murine or human NK cells significantly suppressed the metastasis of HS-MM CCS cells in SCID-Beige mice. Notably, reverse transcription-quantitative PCR analysis demonstrated that injection of NK cells did not alter the mRNA expression levels of ERSR1-ATF1, which is specifically transcribed in CCS, in the buffy coat of circulating blood cells of HS-MM-xenoplanted SCID-Beige mice. BALB/c nude mice xenoplanted with HS-MM cells exhibited local growth without evident metastasis, whereas inoculation with the anti-asialo-GM1 antibody, which has previously been found to abolish NK-cell activity, resulted in metastasis of HS-MM cells in BALB/c nude mice. The injection of the anti-CD96 antibody, which increases the cytotoxicity of NK cells, significantly suppressed the metastasis of HS-MM cells in SCID-Beige mice. These results indicated that NK cells impaired the metastatic tumor microenvironments in the present mice xenoplant model.

Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracyclin with less cardiotoxicity than doxorubicin (DOX). We previously reported the efficacy and safety of R-THP-COP consisting of rituximab (R), THP, cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL) for diffuse large B cell lymphoma (DLBCL) in phase 2 studies. Here, we prospectively compared the efficacy and safety of the R-THP-COP and standard R-CHOP regimen (consisting of R, CPA, DOX, VCR, and PSL) in a noninferiority phase 3 trial. This prospective, randomized phase 3 study included patients younger than 70 years of age with previously untreated DLBCL. The regimen consisted of R (day 1), DOX, or THP (day 3), CPA (day 3), VCR (day 3), and PSL for 5 days every 3 weeks for 6 to 8 cycles. Between July 5, 2006 and June 11, 2013, 81 patients were randomly assigned to the treatment groups (R-CHOP group, 40 patients; R-THP-COP group, 41 patients). R-THP-COP was noninferior to R-CHOP, as assessed by the primary endpoint of complete response rate (85% vs 85% respectively). With a median follow-up of 75.2 months, the 5-year overall survival was 87% in the R-CHOP group and 82% in the R-THP-COP group (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.31-2.49; P = .82). The 5-year progression-free survival was 74% in the R-CHOP group and 79% in the R-THP-COP group (HR: 1.37, 95% CI: 0.56-3.55; P = .49). No grade 3 cardiac side effects were observed in either group. No serious late adverse reactions were observed in either group, with the exception of therapy-related acute myeloid leukemia in the R-THP-COP group. These data indicate that R-THP-COP is noninferior to R-CHOP with regard to clinical response, and has an acceptable safety profile. Thus, this regimen may be an alternative therapy to R-CHOP.

Synovial sarcoma is an aggressive sarcoma with specific reciprocal chromosomal translocation of SS18 (also known as SYT) and SSX genes. In the present study, we aimed to detect the SS18-SSX fusion gene product in routinely processed pathologic synovial sarcoma tissue section. Monoclonal antibodies to peptide QRPYGYDQ-IMPKKPA, which covered the fusion region of SS18-SSX, were newly established and subsequently characterized by enzyme-linked immunosorbent assay, Western-immunoblotting, and immunohistochemical staining. A monoclonal antibody designated BG35, reacted with boundary region of SS18-SSX chimera protein in a specific manner, when C-terminal or neighboring region of QRPYGYDQ-IMPKKPA is structurally exposed. Immunoreactivity of BG35 was localized in nucleus of synovial sarcoma cells, but not in other sarcoma cells, examined. Interestingly, synovial sarcoma cells with epithelial differentiation exhibited much strong BG35 immunoreactivity than synovial sarcoma cells with sarcomatous differentiation. BG35 may be useful for evaluating molecular kinetics of SSX-SS18 gene product in situ.

This study aimed to investigate the relationship between loss of AT-rich interactive domain-containing protein 1A (ARID1A) expression and the prognosis of patients with oral squamous cell carcinoma (OSCC). Seventy-five OSCC tissue specimens were immunohistochemically stained with a specific antibody to ARID1A. The immunoreactivity of ARID1A was then correlated with clinicopathological factors, including the prognosis of the patients. Non-tumorous oral squamous cells exhibited nuclear ARID1A staining, whereas the invasive OSCC cells showed different degrees of loss of ARID1A immunoreactivity. Little-to-no ARID1A immunoreactivity was found at the cancer invasion front in 20 of the 75 OSCC tissue specimens, with significant association with unfavorable patient outcomes. Notably, downregulation of ARID1A immunoreactivity was also related to lymphovascular involvement and poor outcome in patients with T1 and T2 OSCC without lymph node metastasis. The results suggest that loss of ARID1A expression at the cancer invasion front might be related to tumor progression in many OSCCs.

Esophageal cancer rarely grows as an intramural tumor with an intact surface epithelium. A previous report described submucosal tumor-like esophageal cancer that had an overlapping morphological phenotype similar to that of a cutaneous sweat gland tumor. Here, we encountered another case of submucosal esophageal cancer mimicking skin adnexal carcinoma. A man in his early 60s who presented with difficulty in swallowing was admitted to our hospital. He had a 30 × 30 mm submucosal tumor in the abdominal esophagus and underwent partial esophagogastrectomy. Histopathological examination revealed that the tumor was composed of cord-like squamoid cell nests that was partially accompanied by gland structure in the inner layer, as found in cutaneous squamoid ductal eccrine carcinoma. The tumor exhibited CK7 immunoreactivity as did the neighboring dilated ducts of the esophageal gland. We describe a unique submucosal tumor-like esophageal cancer that had overlapping morphological features with squamoid ductal eccrine carcinoma and putatively originated in the esophageal submucosal gland ducts.

The WW domain‐containing oxidoreductase (WWOX) functions as a tumour suppressor in oral carcinogenesis. As aberrant TMEM207 expression may lead to tumour progression by hampering the tumour suppressor function of WWOX in various cancers, we explored the expression and pathobiological properties of TMEM207, focusing on the WWOX‐mediated regulation of the HIF‐1α pathway in oral squamous cell carcinoma (OSCC). TMEM207 immunoreactivity was detected in 40 of 90 OSCC samples but not in neighbouring non‐tumorous epithelial tissues. Moreover, TMEM207 expression was significantly correlated with lymph node metastasis and poor prognosis. An in situ proximal ligation assay demonstrated the colocalization of TMEM207 and WWOX in invasive OSCC cells, especially glycogen‐rich ones. Enforced expression of TMEM207 abrogated the binding of WWOX to HIF‐1α, increased HIF‐1α and GLUT‐1 expression, even under normoxic conditions, and promoted tumour growth in a xenoplant assay using SAS tongue squamous cancer cells. In contrast, TMEM207 knockdown decreased GLUT‐1 expression in two OSCC cell lines. As a whole, our findings indicate that the aberrant expression of TMEM207 contributes to tumour progression in OSCC, possibly via promoting aerobic glycolysis.

GP88 (progranulin; PGRN) is a secreted 88kDa glycosylated protein, with important functions, including inflammation and tumorigenesis. We assessed the significance of GP88 expression in survival outcomes of patients with malignant lymphoma (ML).Serum samples from 254 previously untreated ML patients were examined to measure GP88 concentrations using a sandwich human GP88 ELISA kit. Immunohistochemical analyses were performed to examine GP88 tumor tissue expression.The median serum GP88 concentration of ML patients was 91.3ng/ml, and was significantly higher than that of the control group (median, 57.7ng/ml) (p0.0001). Association between GP88 serum concentrations and overall survival (OS) was examined in patients with diffuse large B cell lymphoma (DLBCL) who had been stratified based on their serum GP88 concentrations. Kaplan Meier survival analysis showed that patients with serum GP88 concentrations of ≤116 and116ng/ml, had 5-y OS rates of 70% and 50%, respectively (p=0.02). The immunohistochemical analyses of GP88 tumor expression revealed that DLBCL patients had lymphoma cells that were positive for GP88.High serum GP88 concentrations are associated with poor prognosis in patients with DLBCL.

Transmembrane protein 207 (TMEM207) is characterized as an important molecule for invasiveness of gastric signet-ring cell carcinoma cells. To clarify the pathobiological effects of TMEM207, we generated 13 transgenic mouse strains, designated C57BL/6-transgenic (Tg) (ITF-TMEM207), where the mouse Tmem207 is ectopically expressed under the proximal promoter of the murine intestinal trefoil factor gene. A C57BL/6-Tg (ITF-TMEM207) mouse strain unexpectedly exhibited a high incidence of spontaneous kidney cysts with histopathological features resembling human polycystic kidney disease, which were found in approximately all mice within 1 year. TMEM207 immunoreactivity was found in noncystic kidney tubules and in renal cysts of the transgenic mice. The ITF-TMEM207 construct was inserted into Mitf at chromosome 6. Cystic kidney was not observed in other C57BL/6-Tg (ITF-TMEM207) transgenic mouse strains. Although several genetically manipulated animal models exist, this mouse strain harboring a genetic mutation in Mitf and overexpression of Tmem207 protein was not reported as a model of polycystic kidney disease until now. This study demonstrates that the C57BL/6-Tg (ITF-TMEM207) mouse may be a suitable model for understanding human polycystic kidney disease.

Although intrabiliary metastasis of carcinoma in the liver is unusual, intraductal and/or intraepithelial spread of cancer cells along intrahepatic bile ducts is now well recognized as hepatic metastasis. However, several clinical and laboratory findings, including images, lead us to differentially diagnose from primary intrahepatic cholangiocarcinoma. We report here on a case of colonic adenocarcinoma that metastasized to the liver with spread along with the intrahepatic bile duct of S5/6 area. The patient was a 51-year-old man and clinically diagnosed liver metastasis of sigmoid colon cancer (tub2, pMP, ly1, v0, n0), which was diagnosed and treated by sigmoidectomy 7 years ago. The right hepatic lobectomy was performed in March 2016 and histopathological examination revealed that moderately differentiated adenocarcinoma proliferated along the epithelium of intrahepatic bile ducts. Immunohistochemistry (IHC) showed that cancer cells in the intrahepatic bile ducts were positive for CK20, CDX2, CK17 and CK19, but negative for CK7, MUC-5AC, MUC-2 and CA19-9. The findings were almost the same as those of the sigmoid colon cancer removed in July 2009. We finally diagnosed the liver tumor as intrahepatic biliary metastasis of sigmoid colon cancer. Patients with liver metastasis of cancer are hard to be detected biliary invasion and spread on diagnostic image examination. Knowledge of distinctive morphological and IHC features can help to accurately diagnose this rare intrahepatic biliary metastasis of colonic cancer in routine pathological diagnostic procedures.

Recent studies unraveled that AT-rich interactive domain-containing protein 1A (ARID1A), a subunit of the mammary SWI/SNF chromatin remodeling complex, acts as a tumor suppressor in various cancers. In this study, we first evaluated ARID1A expression by immunohistochemistry in invasive breast cancer tissue specimens and assessed the correlation with the prognosis of patients with breast cancer. Non-tumorous mammary duct epithelial cells exhibited strong nuclear ARID1A staining, whereas different degrees of loss in ARID1A immunoreactivity were observed in many invasive breast cancer cells. We scored ARID1A immunoreactivity based on the sum of the percentage score in invasive cancer cells (on a scale of 0 to 5) and the intensity score (on a scale of 0 to 3), for a possible total score of 0 to 8. Interestingly, partial loss of ARID1A expression, score 2 to 3, was significantly correlated with poor disease free survival of the patients. Subsequently, we performed siRNA-mediated ARID1A knockdown in cultured breast cancer cells followed by comprehensive gene profiling and quantitative RT-PCR. Interestingly, many genes were downregulated by partial loss of ARID1A, whereas RAB11FIP1 gene expression was significantly upregulated by partial loss of ARID1A expression in breast cancer cells. In contrast, a more than 50% reduction in ARID1A mRNA decreased RAB11FIP1gene expression. Immunoblotting also demonstrated that partial downregulation of ARID1A mRNA at approximately 20% reduction significantly increased the expression of RAB11FIP1 protein in MCF-7 cells, whereas, over 50% reduction of ARID1A mRNA resulted in reduction of RAB11FIP1 protein in cultured breast cancer cells. Recent studies reveal that RAB11FIP1 overexpression leads to breast cancer progression. Altogether, the present findings indicated that partial loss of ARID1A expression is linked to unfavorable outcome for patients with breast cancer, possibly due to increased RAB11FIP1 expression.

Transmembrane protein 207 (TMEM207) is an important molecule involved in invasiveness of gastric signet ring cell carcinoma. To understand the pathobiological effects of TMEM207, we generated thirteen transgenic mouse lines, designated C57BL/6-Tg (ITF-TMEM207), where mouse TMEM207 is expressed heterotrophically, regulated by the proximal promoter of the murine intestinal trefoil factor (ITF) gene (also known as Tff3). A C57BL/6-Tg (ITF-TMEM207) mouse line unexpectedly exhibited a high incidence of a spontaneous condition resembling myeloproliferative disease-like phenotype. Increased numbers of CD117+ cells and appearance of dysplastic myeloid cells in bone marrow were observed. These histopathological features suggested human myeloproliferative disease or its precursor manifestations, and were found in almost all mice within 1 year. TMEM207 immunoreactivity was identified in megakaryocytes and erythroblasts of the transgenic mice. The ITF-TMEM207 construct was inserted into Atg4b on murine chromosome 1. Myeloproliferative disease was not observed in other C57BL/6-Tg (ITF-TMEM207) transgenic mouse lines. However, although several other genetically manipulated animal models of myeloproliferative disease and Atg4b knockout mice exist, this mouse line harboring a mutated Atg4b gene, and with overexpression of TMEM207 protein, has not been reported as a model of myeloproliferative disease to date. The present study demonstrated that the C57BL/6-Tg (ITF-TMEM207) mouse may be a valuable model for improved understanding of human myeloproliferative disease., Summary: We generated a mouse model similar to human myeloproliferative disease-like phenotype. Mutations in Atg4b and overexpression of TMEM207 may lead to myeloproliferative disease in the present model.