Trends in Treatment for Patients with Late-onset Rheumatoid Arthritis in Japan: Data from the NinJa Study.

OBJECTIVES: To investigate trends in the treatment of patients with late-onset rheumatoid arthritis (LORA) using data from the National Database of Rheumatic Diseases in Japan (NinJa). METHODS: Patients registered in the NinJa were classified according to disease onset: at <65 years (young-onset rheumatoid arthritis [YORA]); at 65-74 years (early LORA); and at ≥75 years (late LORA). Chronological changes in the treatment and disease activity were compared. RESULTS: A total of 7,178, 13,171, 15,295, and 15,943 patients were evaluated in 2010, 2013, 2016, and 2019, respectively. In all groups, the use of methotrexate gradually decreased, whereas that of biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs) increased; the use of tumor necrosis factor inhibitors (TNFi) decreased, whereas that of non-TNFi increased. LORA was characterized by more single DMARD use, and less methotrexate and biological/targeted synthetic DMARD use. TNFi and interleukin-6 inhibitors were used less frequently, whereas abatacept was utilized more frequently in late versus early LORA. Conventional synthetic DMARD (excluding methotrexate) and glucocorticoid use was higher in late versus early LORA. CONCLUSIONS: This analysis revealed chronological changes in the treatment of LORA in Japan. Differences between early and late LORA suggest that patients are not a homogeneous population.

Effect of prednisolone and saireito co-administration on T-cells of rheumatoid arthritis patients.

OBJECTIVES: Rheumatoid arthritis (RA) is an autoimmune disease. Methotrexate (MTX) and prednisolone (PSL) are used in combination for severe RA therapy. However, it can increase the risk of osteoporosis and osteonecrosis. Saireito (114) can be used to reduce PSL dose owing to its immunosuppressive effects. However, the effect of combination therapy of PSL+114 on the immune system of RA patients remains unknown. This study compared the effect of PSL alone and PSL+114 on peripheral blood mononuclear cell (PBMC) proliferation, T-cell subsets, and cytokine production in adult RA patients receiving MTX monotherapy. METHODS: We isolated PBMCs from 14 consenting RA patients, and cultured them with PSL (0.0001-1.0 µM) in combination with or without 114 (300 µg/mL) for 96 h in the presence of concanavalin A. We measured the proliferation rates of PBMC, proportions of CD4+, CD8+, and CD4+CD25+Foxp3+T-cells (induced T-regulatory cells), and concentrations of interferon-γ, interleukin (IL)-6, IL-10, IL-17A, and tumour necrosis factor in the culture supernatant. RESULTS: Compared to the blank, the PBMC proliferation rate significantly decreased at a reduced PSL concentration after 114 administration. The 50% inhibition concentration was 0.43 µM PSL for the PSL-only group as compared to 0.29 µM PSL for the PSL+114 co-administration group. The PSL+114 co-administration group had a significantly higher concentration of IL-6 compared to the PSL-only group. CONCLUSIONS: The use of 114 in combination with low-concentration PSL intensified its immunosuppressive effect. However, the concentration of IL-6 was elevated in the co-administration group, suggesting exacerbation of RA activity.

Nephrotic Syndrome as an Extramuscular Manifestation of Anti-EJ Antibody-Positive Dermatomyositis: A Case Report and Review of the Literature.

Renal involvement is underestimated as an extramuscular manifestation of dermatomyositis (DM). Here, we describe a 67-year-old woman with anti-glycyl-transfer ribonucleic acid synthetase (anti-EJ) antibody and anti-ribonucleoprotein antibody-positive DM complicated by systemic sclerosis, who developed nephrotic syndrome concurrently with the exacerbation of DM, as indicated by incremental serum creatine kinase levels, high-intensity lesions on muscle magnetic resonance imaging, and active interstitial pneumonitis on chest computed tomography. Renal biopsy revealed the presence of immune-deposition in the glomerulus by immunofluorescence. To our knowledge, this is the first report describing the coexistence of anti-EJ antibody-positive DM and nephrotic syndrome. More reports of similar cases are warranted to substantiate the association.

Autotaxin is a potential link between genetic risk factors and immunological disturbances of plasmacytoid dendritic cells in systematic lupus erythematosus.

BACKGROUND: The importance of autotaxin, an enzyme that catalyzes lysophospholipid production, has recently been recognized in various diseases, including cancer and autoimmune diseases. Herein, we examined the role of autotaxin in systemic lupus erythematosus (SLE), utilizing data from ImmuNexUT, a comprehensive database consisting of transcriptome data and expression quantitative trait locus (eQTL) data of immune cells from patients with immune-mediated disorders. METHODS: Serum autotaxin concentrations in patients with SLE and healthy controls (HCs) were compared. The transcriptome data of patients with SLE and age- and sex-matched HCs were obtained from ImmuNexUT. The expression of ENPP2, the gene encoding autotaxin, was examined in peripheral blood immune cells. Next, weighted gene correlation network analysis (WGCNA) was performed to identify genes with expression patterns similar to ENPP2. The ImmuNexUT eQTL database and public epigenomic databases were used to infer the relationship between autotaxin and pathogenesis of SLE. RESULTS: Autotaxin levels were elevated in the serum of patients with SLE compared to HCs. Furthermore, the expression of ENPP2 was higher in plasmacytoid dendritic cells (pDCs) than in other immune cell subsets, and its expression was elevated in pDCs of patients with SLE compared to HCs. In WGCNA, ENPP2 belonged to a module that correlated with disease activity. This module was enriched in interferon-associated genes and included genes whose expression was influenced by single-nucleotide polymorphisms associated with SLE, suggesting that it is a key module connecting genetic risk factors of SLE with disease pathogenesis. Analysis utilizing the ImmuNexUT eQTL database and public epigenomic databases suggested that the increased expression of ENPP2 in pDCs from patients with SLE may be caused by increased expression of interferon-associated genes and increased binding of STAT3 complexes to the regulatory region of ENPP2. CONCLUSIONS: Autotaxin may play a critical role in connecting genetic risk factors of SLE to disease pathogenesis in pDCs.

Detection of salivary citrullinated cytokeratin 13 in healthy individuals and patients with rheumatoid arthritis by proteomics analysis.

The immune response to citrullinated peptides in the mucosa has been suggested to play an important role in the transition from pre-onset rheumatoid arthritis (RA) to clinically evident RA. Although there are reports indicating the presence of anti-citrullinated peptide antibodies in the saliva, few studies have reported citrullinated peptide detection in human saliva. This study aimed to identify citrullinated peptides in human saliva and discuss their clinical significance. Saliva samples were collected from 11 patients with RA and from 20 healthy individuals. Citrullinated peptides were detected using an anti-modified citrulline (AMC) antibody. Saliva from the healthy individuals was subjected to two-dimensional protein electrophoresis to isolate citrullinated peptides, which were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and mass spectrometry by peptide mass fingerprinting. The results were corroborated by immunoprecipitation (IP)-western blotting. The signal intensities of the bands precipitated with anti-cytokeratin 13 (CK13) and AMC antibodies were quantified. The signal intensity ratio of the band produced by the AMC antibody was divided by that of the band produced by the anti-CK13 antibody to calculate the citrullinated CK13 (Cit-CK13) ratio. A citrullinated peptide band corresponding to a molecular weight of approximately 50 kDa was detected in the saliva of healthy individuals, and identified as CK13 via mass spectrometry and IP-western blotting. No significant difference was observed between the salivary Cit-CK13 ratios of patients with RA and healthy participants (p = 0.605). This is the first study to show that Cit-CK13 is present in human saliva, and that there is no significant difference between the Cit-CK13 ratios of patients with RA and healthy individuals, suggesting that salivary Cit-CK13 content and RA development may not be associated. The physiological and pathological roles of Cit-CK13 in the oral cavity, and its responsiveness to mucosal immunity, remain unknown and will be the subject of further investigation.

[A Case of Metastatic and Recurrent Colon Cancer Whose QOL Kept Longly by Multidisciplinary Treatment Including Six Times Surgical Operation].

The patient was 75-year-old male, he has been diagnosed as ascending colon cancer resected by rt. hemicolectomy in September 2010. Final diagnosis was tub2, T4b, N1, Cy1, M0, pStage Ⅲc. Despite adjuvant chemotherapy, a lung metastasis was found in April 2012, and it was treated by thoracoscopic partial lung resection. In July 2012, pelvic lymph node recurrence was found, and treated by radiation therapy. In August 2013, right testicular metastasis was resected. After 2 years chemotherapy free intervals, it was resumed by S-1→irinotecan(CPT-11)→regorafenib due to peritoneal disseminations. In July 2016, transverse colostomy was performed due to obstruction caused by peritoneal dissemination. Although, chemotherapy was continued after surgery by trifluridine plus bevacizumab(Bev)→CPT-11, recurrent tumor in rt spermatic cord was enlarged, which resected to reduce its pain. While continuing chemotherapy with CPT-11 plus Bev, rapid growth of peritoneal disseminated tumor with its rapture has induced peritonitis and sepsis, so it was forced to be resected by involving rectum, ileum, and ureter in February 2019. Finally, with totally 6 times these operations, continuing chemotherapy may be maintaining his QOL and prognosis.

Development of Eosinophilic Temporal Arteritis and Digital Ischemia in a Patient with Hypereosinophilic Syndrome.

We describe a case of eosinophilic temporal arteritis in a 61-year-old woman with hypereosinophilic syndrome, who developed subcutaneous nodules in the temporal areas and digital cyanosis with small nodules on the sides of her fingers. Ultrasound revealed occlusion and corkscrew-like changes of the temporal and digital arteries, respectively. Temporal artery biopsy revealed eosinophilic vasculitis without giant cell formation. Angiography showed occlusion of the ulnar and digital arteries. Administration of low-dose corticosteroid improved the temporal artery swelling and digital cyanosis. More reports of similar cases are required to characterize this type of non-giant cell eosinophilic vasculitis that affects the peripheral arteries.

Induction of Trop-2 expression through the binding of galectin-3 to MUC1.

Both mucin 1 (MUC1) and trophoblast cell surface antigen 2 (Trop-2) are overexpressed in various epithelial tumor cells, and their high expression is correlated with a poor prognosis. Both proteins were expressed in a human breast cancer cell line, MCF-7 cells, but neither was in a human colon cancer cell line, HCT116 cells. When MUC1 cDNA was introduced into HCT116 cells (HCT116/MUC1), expression of Trop-2 was induced. Reciprocally, treatment of MCF-7 cells with MUC1 siRNA reduced the level of Trop-2. Mithramycin A, an inhibitor of specificity protein 1 (Sp1) transcription factor, effectively inhibited the expression of Trop-2. Consistently, treatment with Sp1 siRNA reduced the expression of Trop-2. To reveal the relationship between MUC1 and Sp1, coimmunoprecipitation assays were performed. Sp1 was coimmunoprecipitated with MUC1 and the level of coimmunoprecipitated Sp1 increased in relation to the level of induced Trop-2. It is known that galectin-3 is an endogenous ligand of MUC1. Binding of galectin-3 to MUC1 elevated the recruitment of Sp1 to MUC1, and knockdown of galectin-3 reduced the level of Trop-2. These results suggest that the binding of galectin-3 to MUC1 enhances the recruitment of Sp1, leading to promotion of the transcription of Trop-2.

Granulomatosis with Polyangiitis Complicated by Hypertrophic Pachymeningitis Presenting with Simultaneous Multiple Intracerebral Hemorrhages.

Central nervous system (CNS) involvement in granulomatosis with polyangiitis (GPA), including pachymeningitis and CNS vasculitis, is uncommon. Although intracerebral hemorrhage (ICH) has been reported in GPA, simultaneous multiple ICH (SMICH) is rare. We describe the case of a 50-year-old woman with a history of a limited form of GPA with chronic pachymeningitis who presented with acute-onset headache accompanied by nausea and vomiting, and who developed consciousness impairment. Computed tomography revealed bilateral subcortical ICH. Sinus thrombosis was not apparent on angiography. The patient was treated with high-dose corticosteroid therapy. The cause of the steroid-responsive SMICH in this case was unknown, but it might have been CNS vasculitis. Patients with GPA may present with SMICH, which is considered an indication for immunosuppressive therapy.

Decreased severity of experimental autoimmune arthritis in peptidylarginine deiminase type 4 knockout mice.

BACKGROUND: Peptidylarginine deiminase type 4 (PADI4) has been identified as a susceptibility gene for rheumatoid arthritis (RA) by genome-wide association studies. PADI4 is highly expressed in the bone marrow, macrophages, neutrophils, and monocytes. Peptidyl citrulline is an interesting molecule in RA because it is a target antigen for anti-citrullinated peptide antibodies, and only PADs (translated proteins from PADI genes) can provide peptidyl citrulline via the modification of protein substrates. The aim of this study was to evaluate the importance of the PADI4 gene in the progression of RA. METHODS: We generated Padi4 knockout (Padi4(-/-)) DBA1J mice. The Padi4(-/-) DBA1J and wild-type mice were immunized with bovine type II collagen (CII) to develop collagen-induced arthritis (CIA). The expression of various inflammatory cytokines and Padi genes in immune cells was detected by the real-time TaqMan assay. Cytokine concentrations in sera were measured by enzyme-linked immunosorbent assays. Localization of the PAD4 and PAD2 proteins was indicated by immunohistochemistry. RESULTS: We demonstrated that the clinical disease score was significantly decreased in the Padi4(-/-) mice and Padi4 expression was induced by CII immunization. In the Padi4(-/-) mice, serum anti-type II collagen (CII) immunoglobulin M (IgM), IgG, and inflammatory cytokine levels were significantly decreased compared with those in the wild-type mice. Padi2 expression was induced in the immune cells of the Padi4(-/-) mice as a compensation for the defect in Padi4. CONCLUSIONS: Padi4 affected disease severity in the CIA mice and was involved in the enhancement of the collagen-initiated inflammatory responses.

Binding of Galectin-3, a ß-Galactoside-binding Lectin, to MUC1 Protein Enhances Phosphorylation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2) and Akt, Promoting Tumor Cell Malignancy.

Both mucin 1 (MUC1) and galectin-3 are known to be overexpressed in various malignant tumors and associated with a poor prognosis. It has been extensively reported that MUC1 is involved in potentiation of growth factor-dependent signal transduction. Because some carbohydrate moieties carried on MUC1 change to preferable ones for binding of galectin-3 in cancer cells, we speculated that MUC1-mediated signaling may occur through direct binding of galectin-3. Immunochemical studies showed that the distribution of galectin-3 coincided with that of MUC1 in various human tumor tissues but not in human nonmalignant tissues, and the level of galectin-3 retained on the surface of various cancer cells paralleled that of MUC1. Treatment of MUC1-expressing cells with galectin-3 induced phosphorylation of ERK1/2 and Akt following enhanced phosphorylation of MUC1 C-terminal domain, consistently promoting tumor cell malignancy. It is also noted that this enhanced phosphorylation occurred independently of EGF receptor-mediated signaling in both EGF receptor- and MUC1-expressing cells, and multivalency of galectin-3 was important for initiation of MUC1-mediated signaling. Expectedly, both silencing of endogenous galectin-3 and treatment with galectin-3 antagonists down-regulated cell proliferation of MUC1-expressing cells. These results suggest that the binding of galectin-3 to MUC1 plays a key role in MUC1-mediated signaling. Thus, constitutive activation of MUC1-mediated signaling in an autocrine/paracrine manner caused by ligation of galectin-3 promotes uncontrolled tumor cell malignancy. This signaling may be another MUC1-mediated pathway and function in parallel with a growth factor-dependent MUC1-mediated signaling pathway.

Alteration of CD4 T cell subsets in metastatic lymph nodes of human gastric cancer.

Studies of tumor-infiltrating immune cells have revealed that immune escape plays an important role in tumor growth. The aim of the present study was to investigate the impact of metastasis affecting CD4+ T cell subsets in human clinical samples. Single-cell suspensions derived from tumor-draining lymph node (TDLN) and primary cancer specimens were assessed by flow cytometry, qRT-PCR and immunohistochemistry. In the CD4+ T cell subsets detected in TDLN, effector T cells (TE) in metastatic TDLN (mTDLN) was significantly lower than that in metastatic-free TDLN (mfTDLN). TE in mfTDLN were increased compared with normal controls. Similarly, effector memory T cells (TEM) in mTDLN was significantly lower than in control and mfTDLN. There was a significantly positive correlation between the proportion of TEM in TDLN and number of tumor-infiltrating CD4+ and CD8+ T cells. Th1 to Th2 ratio was lower in mTDLN, and Treg in mTDLN was significantly higher than in mfTDLN. CD4+ T cell and TE subsets in TDLN were significantly affected by metastasis. Immunosuppressive cells exhibit increased migration to TDLN, in which a subset of CD4+ TE is skewed towards immune tolerance in the tumor microenvironment.

Head-to-head comparison of the safety of tocilizumab and tumor necrosis factor inhibitors in rheumatoid arthritis patients (RA) in clinical practice: results from the registry of Japanese RA patients on biologics for long-term safety (REAL) registry.

INTRODUCTION: The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice. METHODS: This prospective cohort study included RA patients starting TCZ [TCZ group, n=302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n=304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis. RESULTS: Patients in the TCZ group had longer disease duration (P<0.001), higher disease activity (P=0.019) and more frequently used concomitant corticosteroids (P<0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37). CONCLUSIONS: The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.

New molecular staging with G-factor supplements TNM classification in gastric cancer: a multicenter collaborative research by the Japan Society for Gastroenterological Carcinogenesis G-Project committee.

BACKGROUND: The G-Project committee was erected by the Japan Society for Gastroenterological Carcinogenesis with an aim of establishing a new classification scheme based on molecular biological characteristics that would supplement the conventional TNM classification to better predict outcome. METHODS: In a literature search involving 822 articles on gastric cancer, eight molecules including p53, vascular endothelial growth factor (VEGF)-A, VEGF-C, matrix metalloproteinase-7 (MMP-7), human epidermal growth factor receptor 2, Regenerating islet-derived family, member 4, olfactomedin-4 and Claudin-18 were selected as candidates to be included in the new molecular classification scheme named G-factor. A total of 210 cases of gastric cancer who underwent curative R0 resection were registered from four independent facilities. Immunohistochemical staining for the aforementioned molecules was performed for the surgically resected specimens of the 210 cases to investigate the correlation between clinicopathological factors and expression of each molecule. RESULTS: No significant correlation was observed between the immunostaining expression of any of the eight factors and postoperative recurrence. However, the expressions of p53 and MMP-7 were significantly correlated with overall survival (OS). When 210 gastric cancer patients were divided into three groups based on the expression of p53 and MMP-7 (G0 group: negative for both p53 and MMP-7, n = 69, G1 group: positive for either p53 or MMP-7, n = 97, G2 group: positive for both of the molecules, n = 44), G2 group demonstrated significantly higher recurrence rate (59%) compared to 38% in G0 (p = 0.047). The multivariate regression analysis revealed that G2 group was independently associated with a shorter disease-free survival (DFS) (hazard ratio 1.904, 95% CI 1.098-3.303; p = 0.022), although the association with OS was not significant. Stage II patients among the G2 group had significantly inferior prognosis both in terms of OS and DFS when compared with those among the G0/G1 group, with survival curves similar to those of Stage III cases. CONCLUSIONS: G-factor based on the expression of p53 and MMP-7 was found to be a promising factor to predict outcome of Stage II/III gastric cancer, and possibly to help select the treatment for Stage II cancer, thus supplementing the conventional TNM system.

[Percutaneous Transhepatic Cholangiodrainage to Alleviate Symptoms of Afferent Loop Obstruction--A Case Report].

The patient, a 78-year-old man, had undergone distal gastrectomy for a gastric ulcer 35 years previously. As melena was observed, he was referred to our department, and was subsequently diagnosed with residual gastric cancer and ascending colon cancer. Peritoneal metastasis of gastric cancer was found, and palliative surgeries, including right hemicolectomy, total gastrectomy, and Roux-en-Y reconstruction were performed. Although postoperative chemotherapy was commenced, side effects led to a decreased performance status (PS), which resulted in the patient shifting to the best supportive care (BSC). Five months after surgery, the patient was urgently transferred to the hospital with upper abdominal pain, and underwent computed tomography (CT) scan. The patient was diagnosed with acute afferent loop obstruction due to peritoneal metastases. It was not possible to perform endoscopic drainage because of the stenosis; therefore, percutaneous transhepatic cholangiodrainage (PTCD) was performed to reduce the pressure in the duodenal afferent loop. Herein, we report on a case of afferent loop obstruction, for which we performed decompression of the afferent loop with PTCD, allowing the patient to continue BSC for approximately 3 months.

A positive correlation between neutrophils in regional lymph nodes and progression of gastric cancer.

UNLABELLED: BACKGROND/AIM: Recent evidence indicates that inflammation is a hallmark of cancer. Tumor-associated neutrophils (TANs) contribute to tumor invasion. However, whether TANs and lymph node metastasis are related is unknown. Intranodal lymphatic vessel density (LVD) is significantly correlated with tumor progression, lymph node metastasis in gastric cancer. Herein, we investigated the effects of TANs in regional lymph nodes. MATERIALS AND METHODS: We investigated the association of the density of TANs in regional lymph nodes with clinicopathological features by immunohistochemistry. Furthermore, we examined the prognostic value of TANs in lymph nodes. RESULTS: The number of TANs in regional lymph nodes was positively correlated with intranodal LVD and micrometastases. Patients with higher cluster of differentiation 15(+) TAN counts had significantly poorer prognosis than those with lower counts. CONCLUSION: Our results suggest that TANs in regional lymph nodes promote the invasion of lymph nodes by cancer cells via augmentation of lymphangiogenesis and thereby contribute to tumor progression.

MUC1 protein induces urokinase-type plasminogen activator (uPA) by forming a complex with NF-κB p65 transcription factor and binding to the uPA promoter, leading to enhanced invasiveness of cancer cells.

Mucin 1 (MUC1) is overexpressed in various human malignant tumors and its expression is correlated with a poor prognosis. MUC1 engages in signal transduction by interacting with receptors for growth and differentiation factors, which contributes to the growth and survival of cancer cells. However, the mechanism by which MUC1 promotes cancer cell invasion remains unclear. Microarray analysis revealed that expression of urokinase-type plasminogen activator (uPA) was elevated in MUC1-overexpressing cells. Furthermore, up- and down-modulation of MUC1 expression was clearly correlated with the change of uPA expression. An immunochemical study showed that the distribution of uPA coincided with that of MUC1 in various human cancer tissues. The MUC1 C-terminal domain (MUC1-CD) was associated with nuclear factor-κB (NF-κB) p65 in MUC1-expressing cells. Chromatin immunoprecipitation (ChIP) assays demonstrated that MUC1-CD existed with NF-κB p65 on the uPA promoter. Luciferase assays indicated that the uPA transcriptional activity was correlated with the level of MUC1 expression and that this MUC1-enhancing effect on the uPA transcription was abolished by introduction of mutations into the NF-κB binding sites on the uPA promoter. These results indicate that formation of the MUC1-CD and NF-κB p65 complex enhanced nuclear translocation of NF-κB p65 and subsequent occupancy of NF-κB binding region on the uPA promoter, leading to elevated transcription of uPA. We also demonstrated that uPA induced by MUC1 enhanced the matrix metalloproteinase (MMP)-2 and -9 activities, and consequently promoted cancer cell invasion. Thus, a MUC1 co-operating NF-κB signaling pathway plays a critical role in cancer cell invasion in MUC1-expressing cells.

[Advanced gastric cancer(Stage IV)leading to perforation during chemotherapy with S-1 plus cisplatin].

A 60-year-old man was diagnosed with advanced gastric cancer(Type 3)with multiple liver and lymph node metastases. The clinical stage was determined to be T3(SS), N2, M1, P0, H1, Stage IV, and a chemotherapy regimen of S-1 plus cisplatin (CDDP)was selected for treatment. During 3 courses of chemotherapy, the patient complained of severe abdominal pain, and an urgent laparotomy was performed with a tentative diagnosis of perforated gastric cancer. Surgical findings revealed a 5-mm perforation in the upper part of the anterior wall of the stomach, from the center of the tumor. Although we detected a metastasis only in S6 of the liver, we decided to perform total gastrectomy, D1 lymphadenectomy, and Roux-en-Y reconstruction. Pathological findings demonstrated that cancer cells were replaced by fibrosis, and tumor response after treatment was determined to be Grade 2. No lymph node metastasis was observed. The patient received chemotherapy with S-1 4 weeks after the operation, without any perioperative complications. The patient is alive 12 months after the operation, without any enlargement of the liver metastasis.

[A case of Stage IV gastric cancer in which a partial response was maintained for four years with multidisciplinary treatment].

The patient was a 63-year-old man with Stage IV gastric cancer (cT3, cNX, cM1[LYN]). After chemotherapy with S-1 plus paclitaxel (PTX), a partial response was achieved, and distal gastrectomy was subsequently performed. During continued chemotherapy with S-1 plus PTX after surgery, enlarged lymph nodes (#16) were observed. Metastasis was detected and treated with radiation therapy. Ten months after the cervical and Virchow lymph node metastases were detected, lymph node dissection was performed. After the second surgery, chemotherapy with S-1 plus cisplatin (CDDP) was selected, but the regimen was changed to S-1 alone because of cerebral infarction. This treatment resulted in the maintenance of a partial response for one year. However, lymph node metastases around the right iliac artery and left cervix subsequently appeared, and lymph node dissection was performed. Since the metastatic lesions remained inside the left parotid gland, radiation therapy to the cervical region was performed again. However, the right inguinal and iliac lymph node metastases enlarged, and we again attempted to treat them with radiation therapy. The patient died due to peritoneal dissemination four years and two months after his first visit.

Laparoscopy-assisted total gastrectomy: a simplified approach.

Laparoscopy-assisted total gastrectomy (LATG), esophagojejunostomy is an effective but difficult procedure to perform. We describe a simple modification that substantially facilitates insertion of the anvil into the esophagus and avoids oral injuries and complications. After mobilization of the stomach and esophagus, a semicircumferential esophagotomy is made at the anterior esophageal wall. An OrVil anvil (Orvil, Covidien, Norwalk, CT, USA) is delivered laparoscopically and secured with a POLYSORB (Covidien) suture to the esophagus. The suture is advanced anteriorly so that the center rod penetrates the esophageal wall. The esophagus is transected with the stapler at this point. A circular-stapled esophagojejunostomy is then performed using the hemidouble stapling technique. Laparoscopy-assisted total gastrectomies were performed for 40 patients with gastric cancers (T1N0M0). All procedures were completed laparoscopically without any complications. The time required to place the anvil averaged 5 min compared with 9 min reported by others. There were no major complications or mortality in this series. The major advantage of this technique is that circular stapling is much easier than linear stapling, allowing surgeons without advanced surgical skills in LATG to perform the procedure effectively and safely.