Helicobacter pylori Reinfection Diagnosed by Endoscopic and Histologic Recurrence in a Patient with Gastric Mucosa-Associated Lymphoid Tissue Lymphoma.

Helicobacter pylori infection is a major cause of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Successful H. pylori eradication can induce a complete remission (CR); however, it takes a long time. In this case, the recurrence of gastric MALT lymphoma was observed by endoscopic and histologic findings during a 11-year follow-up and due to H. pylori reinfection twice. After the first successful eradication and achieving histologic CR, the patient was starting to work at a nursing home for older adults, where she frequently came in contact with their vomitus or feces. In the examinations 2 years later after the first successful eradication, endoscopic and histologic findings have demonstrated deterioration. Similar findings were continuously observed in the examinations 3 months later, and H. pylori reinfection was confirmed by the rapid urease test. After the second successful eradication, endoscopic and histologic CR of gastric MALT lymphoma was achieved. However, endoscopic and histologic findings have shown deterioration again 1 year later after the histologic CR and at 3.5 years later after the second successful eradication. H. pylori reinfection was confirmed by the repeated urea breath test, and the patient had received the third eradication treatment; and the patient had achieved successful eradication. In addition, proper hygiene practices were advised to avoid H. pylori reinfection. H. pylori reinfection is very rare in adults after successful eradication in developed countries. After successful eradication and proper hygiene practice, endoscopic and histologic CR has been maintained for 2 years up to the present.

The potential diagnostic significance of crypt differentiation in gastric dysplasia.

AIMS: This study investigated the relationship between the differentiation of tumour cells into crypts, which is determined by cell differentiation into Paneth and neuroendocrine cells, and tumour infiltration in gastric dysplasia. METHODS AND RESULTS: The lesions were endoscopically biopsied low-grade dysplasia (LGD), endoscopically resected high-grade dysplasia (HGD) or cancer with submucosal invasion. LGD (n = 32) displayed crypt differentiation across the entire width of the tumour in all cases. Crypt differentiation was identified as a characteristic of tumours with low biological malignancy. HGD (n = 40) included tumours with a mixture of areas with and without crypt differentiation (n = 25) and tumours with crypt differentiation throughout the entire width (n = 15). Of the cancers with submucosal invasion (n = 30), the morphological progression of the HGD area with crypt differentiation, the HGD area without crypt differentiation and invasive cancer without crypt differentiation was confirmed for 23 samples. In two lesions, invasive cancer without crypt differentiation developed from HGD without crypt differentiation throughout the tumour width. In five samples, well-differentiated tubular adenocarcinoma with crypt differentiation developed from HGD with crypt differentiation and invaded with lamina propria-like stroma. CONCLUSIONS: Loss of crypt differentiation could be an objective indicator of infiltration in the progression of HGD to invasive cancer. The invasive potential of dysplasia depends upon the presence or absence of crypt differentiation.

Interleukin-32 regulates downstream molecules and promotes the invasion of pancreatic cancer cells.

Pancreatic cancer is a malignant neoplasm with high invasiveness and poor prognosis. In a previous study, a highly invasive pancreatic cancer cell line was established and found to feature enhanced interleukin-32 (IL-32) expression. However, whether IL-32 promotes the invasiveness by enhancing or suppressing the expression of IL-32 through regulating downstream molecules was unclear. To investigate the effect of IL-32, cells were established with high levels of expression or downregulated IL-32; their invasive ability was measured using a real-time measurement system and the expression of some candidate downstream molecules involved in invasion was evaluated in the two cell types. The morphological changes in both cell types and the localization of IL-32 expression in pancreatic cancer tissues were studied using immunohistochemistry. Among the several splice variants of IL-32, cells transfected with the ε isoform had increased invasiveness, whereas the IL-32-suppressed cells had reduced invasiveness. Several downstream molecules, whose expression was changed in the two cell types, were monitored. Notably, changes of E-cadherin, CLDN1, CD44, CTGF and Wnt were documented. The morphologies of the two cell types differed from the original cell line. Immunohistochemically, the expression of IL-32 was observed only in tumor cells and not in normal pancreatic cells. In conclusion, IL-32 was found to promote the invasiveness of pancreatic cancer cells by regulating downstream molecules.

Effect of Continuous Feeding of Ayu-Narezushi on Lipid Metabolism in a Mouse Model of Metabolic Syndrome.

Ayu-narezushi, a traditional Japanese fermented food, comprises abundant levels of lactic acid bacteria (LAB) and free amino acids. This study aimed to examine the potential beneficial effects of ayu-narezushi and investigated whether ayu-narezushi led to improvements in the Tsumura Suzuki obese diabetes (TSOD) mice model of spontaneous metabolic syndrome because useful LAB are known as probiotics that regulate intestinal function. In the present study, the increased body weight of the TSOD mice was attenuated in those fed the ayu-narezushi-comprised chow (ayu-narezushi group) compared with those fed the normal rodent chow (control group). Serum triglyceride and cholesterol levels were significantly lower in the Ayu-narezushi group than in the control group at 24 weeks of age. Furthermore, hepatic mRNA levels of carnitine-palmitoyl transferase 1 and acyl-CoA oxidase, which related to fatty acid oxidation, were significantly increased in the ayu-narezushi group than in the control group at 24 weeks of age. In conclusion, these results suggested that continuous feeding with ayu-narezushi improved obesity and dyslipidemia in the TSOD mice and that the activation of fatty acid oxidation in the liver might contribute to these improvements.

Intensive surveillance endoscopy for multiple gastrointestinal tumors in a patient with constitutional mismatch repair deficiency: case report.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is an extremely rare autosomal recessive hereditary disease characterized by the absence of mismatch repair gene activity from birth, which results in brain tumors, colonic polyposis, gastrointestinal cancers, and lymphomas later in life. An aggressive approach, including colectomy or proctocolectomy, is recommended for the treatment of colorectal cancer. Additionally, partial colectomy with subsequent endoscopic surveillance may be an alternative strategy due to poor patient's condition, although there is no evidence of surveillance endoscopy after partial colectomy for CMMRD. CASE PRESENTATION: A 13-year-old male patient with a history of T-lymphoblastic lymphoma underwent total gastrointestinal endoscopy, which revealed rectal cancer, colorectal polyposis, and duodenal adenoma. Differential diagnosis included constitutional mismatch repair deficiency according to its scoring system and microsatellite instability, and subsequent germline mutation testing for mismatch repair genes confirmed the diagnosis of constitutional mismatch repair deficiency based on a homozygous mutation in mutS homolog 6 (MSH6). The patient and his family refused colectomy due to the high risk of malignancies other than colorectal cancer, which could require radical surgery. Therefore, the patient underwent low anterior resection of the rectosigmoid colon for rectal cancer and intensive surveillance endoscopy for the remaining colon polyposis. During the 3-year period after initial surgery, 130 polyps were removed and the number of polyps gradually decreased during 6-months interval surveillance endoscopies, although only one polyp was diagnosed as invasive adenocarcinoma (pT1). CONCLUSIONS: Our experience of short surveillance endoscopy illustrates that this strategy might be one of options according to patient's condition.

Prognosis of Immune-related Adverse Events in Patients With Advanced Gastric Cancer Treated With Nivolumab or Pembrolizumab: A Multicenter Retrospective Analysis.

BACKGROUND: Immune-checkpoint inhibitors (ICI), including nivolumab and pembrolizumab, are among the standard treatments for previously treated advanced gastric cancer (AGC). This study aimed to evaluate the frequency of immune-related adverse events (irAEs) and the correlation between irAEs and their efficacy in AGC cases. PATIENTS AND METHODS: Patients were divided into two groups according to irAE occurrence. The frequency of irAEs and the treatment outcome (response rate [RR], progression-free survival [PFS], and overall survival [OS]) were evaluated. The survival rates were evaluated by landmark analysis considering lead-time bias. RESULTS: Among 108 patients who received nivolumab or pembrolizumab, 17 (15.7%) had irAEs. In a 4-week landmark analysis, the RR, median PFS, and median OS were 28.5%, 3.9 months (95% CI=2.8-9.3), and 12.2 months (95% CI=3.8-NA) in patients with irAEs, while 3.0% (2/65), 1.8 months (95% CI=1.4-2.1), and 3.5 months (95% CI, 2.9-5.1) in patients without irAEs, respectively. In multivariate analysis, irAEs were associated with better PFS (HR=2.08, 95% CI=1.34-3.21). CONCLUSION: The occurrence of irAEs was associated with a better clinical outcome of ICIs in patients with AGC.

Diagnosis by molecular pathology of an early and atypical histoplasmosis lesion in the duodenum of an immunocompromised patient: A case report.

Histoplasmosis is a fungal infection caused by Histoplasma capsulatum (HC), which can occasionally be aggressive resulting in the formation of granulomatous lesions. These are usually located in the lungs; however, immunocompromised patients may occasionally develop disseminated lesions in other organs as well. Human immunodeficiency virus (HIV) primarily infects cells of the immune system expressing CD4 molecules. Not only does HIV multiply within these cells, but it can also kill them or otherwise cause loss of cellular function, leading to an immunocompromised state. As a result, in an immunocompromised patient, infection with HC can have serious implications, often the development of visceral histoplasmosis in different organs. Although several types of lesions are formed in HC-infected organs, it may be difficult to distinguish the causative organism from other pathogens based on morphology alone. The present case report describes the case of a 57-year-old woman, from South America, who may have been infected with HC >20 years previously, remaining asymptomatic over the years. She later developed a lesion in the duodenum associated with immunodeficiency caused by HIV infection. The differential diagnosis of this case was made on the basis of several specific morphological findings using histopathological analysis and molecular pathological techniques. The pathogenesis of characteristic lesions caused by HC in the presence of HIV infection was also reviewed.

Expression of laminin-5 gamma 2 chain predicts invasion of extramammary Paget's disease cell.

Extramammary Paget's disease (EMPD) is a rare malignant skin neoplasm characterized by intraepidermal proliferation of tumor cells. The tumor cells of EMPD may sometimes invade into the dermis or metastasize into the regional lymph nodes. Several studies have proposed mechanisms underlying the increased invasiveness of EMPD; however, molecular markers indicating invasiveness have yet to be well characterized. Laminin-5 (Lam-5), a heterotrimer composed of three chains (α3, ß3, and γ2), is a major component of the basement membrane in many tissues. One of the chains, Lam-5 γ2, is a marker of invasion, because it often develops as a monomer in malignant neoplasms. We investigated the expression of Lam-5 γ2 and its role for the invasiveness in EMPD. Paraffin-embedded specimens of EMPD obtained from 36 patients were examined immunohistochemically for Lam-5 γ2. The cases adopted into this study comprised 16 cases of intraepidermal lesions and 20 cases with dermal invasion. The basement membrane seen in normal skin disappeared in one-third of non-invasive cases and in most invasive cases. The disappearance of Lam-5 γ2 in the basement membrane and its cytoplasmic expression was more observed in the invasive cases than non-invasive cases. Expression of Lam-5 γ2 may be a biological marker to predict invasiveness of EMPD.

Small intestinal mucosal injury and its risk factors in patients with gastrointestinal cancer who developed complicated fluoropyrimidine-induced diarrhea.

BACKGROUND: Diarrhea is a common adverse event of fluoropyrimidine-based chemotherapy. However, limited data are available on the frequency and risk factors of complicated chemotherapy-induced diarrhea (CID) and small intestinal mucosal damage. In this current study, we aimed to determine the incidence of complicated CID and mucosal injury among patients with complicated CID receiving fluoropyrimidine via small bowel capsule endoscopy (CE) and determined baseline risk factors associated with complicated CID. METHODS: In total, 536 patients with advanced or recurrent gastrointestinal cancer who received fluoropyrimidine-based chemotherapy were retrospectively analyzed. Diarrhea was evaluated using the Common Terminology Criteria for Adverse Events version 4. Complicated CID was defined according to the American Society of Clinical Oncology guidelines. To evaluate small intestinal mucosal injury in patients with complicated CID, CE was performed. Multivariate analysis was performed to identify risk factors for complicated CID. RESULTS: Total number of 32 (6%) patients developed complicated CID. Complicating symptoms were noted in 25 (78%) patients, with cramping, vomiting, and sepsis being observed in 15 (60%), 8 (32%), and 3 (12%) patients, respectively. Among the 13 patients who underwent CE, 11 (85%) showed abnormal findings. Multivariate analysis revealed that oral fluoropyrimidine administration was a risk factor for complicated CID (odds ratio 2.95; 95% confidence interval 1.06-8.19). CONCLUSIONS: Despite the relatively low incidence of complicated CID, mucosal injury of small intestine was common in patients with complicated fluoropyrimidine-induced diarrhea and oral fluoropyrimidine was an independent risk factor.

Mucoepidermoid carcinoma of parotid gland and membranous nephropathy - differentiation between sclerosing mucoepidermoid carcinoma with eosinophilia and Kimura's disease.

BACKGROUND: When we encounter patients who present with both a neck mass and nephrotic syndrome, both malignancy and Kimura's disease need to be evaluated as the therapeutic strategies differ vastly between them. CASE PRESENTATION: We present the case of a 27-year-old male patient with neck mass and nephrotic syndrome. The presence of both eosinophilia and elevated immunoglobulin E levels were concerning for Kimura's disease, which is an allergic syndrome defined by eosinophilic granulomas of neck soft tissue along with peripheral eosinophilia. The eventual final diagnosis, however, was sclerosing mucoepidermoid carcinoma of parotid gland with both eosinophilia and membranous nephropathy. Following the surgical resection of the mass, the nephrotic syndrome completely resolved. CONCLUSION: Detailed histopathological assessments of both the parotid gland and renal tissue were key aspects of the diagnosis and management to exclude Kimura's disease.

Establishment of highly invasive pancreatic cancer cell lines and the expression of IL-32.

Compared to tumors of other organs, pancreatic cancer is highly aggressive; with one of its biological features being that, despite a prominent fibrotic stroma, there is remarkable infiltration of tumor cells. This characteristic is considered to be the main reason for the poor prognosis of patients with pancreatic cancer. Therefore, in order to elucidate the factors that contribute to this high invasiveness, a selective invasion method was used to establish four highly invasive subclones from six human pancreatic cancer cell lines. The results demonstrated that two cell lines did not exhibit enhanced invasiveness. Microarray analysis revealed that, in the highly invasive cell lines, several genes were expressed at high levels, compared with the original cell lines. These highly expressed genes were recognized only in highly invasive cells. Among them, IL-32 was most strongly upregulated in the highly invasive cells, compared with cells with a low invasive potential, as well as the original cells. RT-qPCR and western blot analysis confirmed the high levels of expression of IL-32 in highly invasive cells at the RNA and protein levels. In addition, immunohistochemical analysis of resected surgical materials revealed that the tumor cells expressed IL-32 and, in particular, many IL-32 positive cells were seen at the invasive front of the tumor tissue. IL-32 is a cytokine that is widely involved in the development of cancer and has recently received considerable attention. This cytokine has multiple splice variants and shows a wide variety of behaviors, depending on the tumor type and primary organ. Although some hypotheses have been proposed to explain the activity of IL-32, a unified view has not been agreed. In the present study, through the establishment of highly invasive cells from pancreatic cancer and a comprehensive gene analysis, it is suggested that IL-32 may serve an important role as a molecule involved in the invasiveness of this neoplasm.

Clinicopathological and molecular features of hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinomas.

AIMS: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH). Affected families have an increased risk of renal cell carcinoma (RCC). HLRCC-associated RCC (HLRCC-RCC) is highly aggressive. Clinicopathological information of genetically diagnosed patients with HLRCC-RCC contributes to the establishment of effective therapies. METHODS: Ten Japanese patients with HLRCC-RCC were enrolled in the study. Genetic testing for FH was carried out. Somatic mutations in FH and immunohistochemical analyses of FH and B7 family ligands (PD-L1 and B7-H3) were investigated in 13 tumours. Copy number variations were evaluated in two tumours. RESULTS: All patients had FH germline mutations. Regarding histology, most tumours had type 2 papillary architecture or tubulocystic pattern or both. All tumours were FH deficient by immunohistochemistry. Ten tumours were positive for PD-L1, and 12 tumours were positive for B7-H3. Somatic mutation analysis demonstrated loss of heterozygosity of FH in 10 tumours. Copy number variation analysis revealed uniparental disomy between 1q24.2 and 1q44 encompassing FH; gain of chromosome 2 p was also common. All patients had either metastases or residual tumours. Three patients died of HLRCC-RCC and one of colon cancer, whereas the other six are currently alive, including two without recurrence. CONCLUSIONS: HLRCC-RCCs appear to have unique molecular profiles, including PD-L1 expression. One patient had complete response to immunotherapy, which may be an option for HLRCC-RCC.

CDKN2A, CDK1, and CCNE1 overexpression in sebaceous gland carcinoma of eyelid.

PURPOSE: To investigate the overexpression of genes in sebaceous gland carcinoma (SGC) of the eyelid compared to sebaceous adenoma of the eyelid in order to elucidate the molecular mechanism underlying pathogenesis. METHODS: We performed histopathological examination of eyelid tissues surgically removed from four patients diagnosed with SGC (cases 1-3) and sebaceous adenoma (case 4) of the eyelid. Next, we performed global gene expression analysis of surgical tissue samples using a GeneChip® system and the Ingenuity Pathways Knowledge Base. The results of the GeneChip® analysis were explored with quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RESULTS: In the SGC samples, we found that 211, 199, and 199 genes, respectively, showed ≥ 2.0-fold higher expression than those in the sebaceous adenoma sample (case 4); 194 genes were common to all three SGC samples. For the 194 genes with upregulated expression, functional category analysis showed that SGC of the eyelid employed a unique gene network, including cyclin-dependent kinase inhibitor 2A (CDKN2A), cyclin-dependent kinase 1 (CDK1), and cyclin E1 (CCNE1), which are related to cell cycle progression, incidence of tumor, and cell viability. Furthermore, qRT-PCR analysis showed that the expression levels of CDKN2A, CDK1, and CCNE1 were significantly upregulated in all SGC cases compared to those in the sebaceous adenoma case. These data were similar to the results of microarray analysis. CONCLUSION: Overexpression of cell cycle-related genes CDKN2A, CDK1, CCNE1, and their gene network may help elucidate the pathogenic pathway of SGC of the eyelid at the molecular level.

Lymphoepithelial carcinoma of the maxillary sinus: A case report and review of the literature.

RATIONALE: Most cases of lymphoepithelial carcinoma (LEC) occur in the nasopharynx, and LEC in the sinonasal tract is extremely rare; thus, the clinical characteristics of sinonasal LEC are not well known. PATIENT CONCERNS: A 63-year-old Japanese man presented with a three-week history of left cheek pain, nasal obstruction and cheek swelling. DIAGNOSES: Enhanced CT and MRI revealed a tumor of the left maxillary sinus that invaded the left orbit and hard palate, with multiple swollen left cervical lymph nodes. Open biopsy was performed, and the specimen was diagnosed as LEC. INTERVENTIONS: Alternating chemoradiotherapy (ALCRT) followed by salvage surgery was performed. OUTCOMES: Our patient has been disease free for 5 years. LESSONS: A literature review of the epidemiology, etiology, clinical course and management of sinonasal LEC is highlighted. We believe ALCRT followed by salvage surgery to be a highly optimal treatment for sinonasal LEC from the viewpoint of a balance between quality of life and a high curative effect.

Endoglin (CD105) and SMAD4 regulate spheroid formation and the suppression of the invasive ability of human pancreatic cancer cells.

In this study, we investigated the ability of pancreatic cancer cell lines to form spheroids with the aim of identifying factors involved in cell invasiveness, a property that leads to a poor prognosis in pancreatic cancer. For this purpose, 8 cell lines derived from human pancreatic cancer tissues were cultured in non-adherent culture conditions to form spheroids, as well as normal monolayers. The morphology of the cells was observed and spheroid diameters measured. mRNA expression was compared between cells cultured under both culture conditions. The gene knockdown of endoglin (ENG) and SMAD4, components of the transforming growth factor-ß (TGF-ß) signaling system, using siRNAs was conducted in spheroids in order to identify affected protein signaling factors, determine the morphological changes occurring over time and to measure the invasive capacity of the cells constituting spheroids. The cell lines exhibited differences in their spheroid-forming abilities. The expression of SMAD4 and ENG concomitantly increased in the cells that formed spheroids. SMAD4 was transported into the nucleus when spheroids were formed. The expression of ENG was decreased in the cells in which SMAD4 was knocked down; by contrast, the expression of BMP and activin membrane-bound inhibitor (BAMBI) and noggin (NOG), further components of the TGF-ß signaling system, increased. In the cells in which ENG was knocked down, the decreased mRNA expression of TGF-ß receptor type 2 (TGFBR2) and SMAD9 was observed, as well as a change in the expression of pSMAD1/5/9, and a tendency of spheroids to decrease in size. Spheroids cultured on Matrigel exhibited a tendency towards a reduction in size over time, as well as a tendency to invade into the Matrigel. In particular, the cells in which ENG was knocked down exhibited spheroids which were reduced in size, and also exhibited an increase in invasiveness, and a decrease in adhesiveness. Thus, our data indicate that in pancreatic cancer cells, the expression of ENG may be controlled by a pathway mediated by SMAD4. In addition, ENG was found to be related to the spheroid-forming ability of cells and to be involved in the invasive capacity of pancreatic cancer cells.

Spontaneous Remission of Diffuse Large B Cell Lymphoma in the Stomach and the Continuation of Remission for 10 Years.

According to the literature, spontaneous remission of aggressive lymphomas is extremely rare; gastric non-Hodgkin lymphomas, such as mucosa-associated lymphoid tissue lymphomas, often regress due to Helicobacter pylori treatment or no progression, even in a watch-and-wait strategy. Although spontaneous remission of diffuse large B cell lymphomas in the stomach was very rarely reported, the follow-up periods of the cases of spontaneous remission are within 2 years and most cases are likely to relapse after the first remission. Here, we report that a diffuse large B cell lymphoma in the stomach showed spontaneous remission within 2 months after the initial diagnosis and the remission is still continuing for 10 years without any specific treatments against this aggressive lymphoma.

A B-cell lymphoma case that is unclassifiable, and intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma of lacrimal gland.

A 60-year-old woman presented with acute eyelid swelling and a subcutaneous hemorrhage in the right eye. Magnetic resonance imaging showed a spherical tumor of the lacrimal gland. The tumor was removed by the Kroenlein method. We diagnosed as a B-cell lymphoma that is unclassifiable, and intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) (intermediate DLBCL/BL) based on its immunohistopathological examination and c-MYC/IgH rearrangement. We administered six cycles of dose-adjusted-EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin hydrochloride, and rituximab) therapy, and remission of the lymphoma was obtained. This is the first case of an intermediate DLBCL/BL of a lacrimal gland.

Aberrant iron metabolism might have an impact on progression of diseases in Tsumura Suzuki obese diabetes mice, a model of spontaneous metabolic syndrome.

Tsumura Suzuki obese diabetes (TSOD) mice spontaneously develop obesity and type 2 diabetes with aberrant accumulation of excessive iron in the spleen. Aberrantly accumulated iron may cause oxidative stress and result in various symptoms of metabolic syndrome in the mice. We investigated iron metabolism and oxidative stress in TSOD mice. Male TSOD and control mice were killed at 2, 3, 6, and 8 months of age, and blood and tissue samples were collected. The serum levels of ferritin and oxidized low-density lipoprotein (OxLDL) were measured. Total glutathione concentrations of liver and spleen were also measured. Serum ferritin and OxLDL were higher in TSOD mice than in control mice at 2 and 6 months. In addition, the glutathione concentrations in TSOD mice were lower in the liver and higher in the spleen at 3 and 6 months than those in control mice. These results suggest that abnormal iron metabolism and imbalanced oxidative stress occurs in young and old TSOD mice. We propose herein that TSOD mice might be a unique and valuable model for investigating the role of iron metabolism in pathogenesis of metabolic syndrome.