[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to evaluate preoperative variables predictive of lethal morbidities in critically ill surgical patients at a national level.There is no report of risk stratification for morbidities associated with mortality in critically ill patients with acute diffuse peritonitis (ADP).We examined data from 16,930 patients operated during 2011 and 2012 in 1546 different hospitals for ADP identified in the National Clinical Database of Japan. We analyzed morbidities significantly associated with operative mortality. Based on 80% of the population, we calculated independent predictors for these morbidities. The risk factors were validated using the remaining 20%.The operative mortality was 14.1%. Morbidity of any grade occurred in 40.2% of patients. Morbidities correlated with mortality, including septic shock, progressive renal insufficiency, prolonged ventilation >48 hours, systemic sepsis, central nervous system (CNS) morbidities, acute renal failure and pneumonia, and surgical site infection (SSI), were selected for risk models. A total of 18 to 29 preoperative variables were selected per morbidity and yielded excellent C-indices for each (septic shock: 0.851; progressive renal insufficiency: 0.878; prolonged ventilation >48 h: 0.849; systemic sepsis: 0.839; CNS morbidities: 0.848; acute renal failure: 0.868; pneumonia: 0.830; and SSI: 0.688).We report the first risk stratification study on lethal morbidities in critically ill patients with ADP using a nationwide surgical database. These risk models will contribute to patient counseling and help predict which patients require more aggressive surgical and novel pharmacological interventions.
Medicine 07/2015; 94(30):e1224. DOI:10.1097/MD.0000000000001224 · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While murine CD4(+) CD39(+) Treg co-express CD73 and hydrolyze exogenous (e) ATP to immunosuppressive adenosine (ADO), surface co-expression of CD73 on human circulating CD4(+) CD39(+) Treg is rare. Therefore, the ability of human Treg to produce and utilize ADO for suppression remains unclear. Using mass spectrometry, we measured nucleoside production by subsets of human CD4(+) CD39(+) and CD4(+) CD39(-)CD73(+) T cells or CD19(+) B cells isolated from blood of 30 volunteers and 14 cancer patients. CD39 and CD73 expression was evaluated by flow cytometry, western-blots, confocal microscopy or RT-PCR. Circulating CD4+CD39+ Treg which hydrolyzed eATP to 5'-AMP contained few intracytoplasmic granules and had low CD73 mRNA levels. Only ∼1% of these Treg were CD39+CD73+. In contrast, CD4(+) CD39(neg) CD73(+) T cells contained numerous CD73(+) granules in the cytoplasm and strongly expressed surface CD73. In vitro-generated Treg (Tr1) and most B cells were CD39(+) CD73(+) . All these CD73(+) T cell subsets and B cells hydrolyzed 5'-AMP to ADO. Exosomes isolated from plasma of NC or cancer patients carried enzymatically-active CD39 and CD73(+) and, when supplied with eATP hydrolyzed it to ADO. Only CD4+CD39+ Treg co-incubated with CD4(+) CD73(+) T cells, B cells or CD39(+) CD73(+) exosomes produced ADO. Thus, contact with membrane-tethered CD73 was sufficient for ADO production by CD4+CD39+ Treg. In microenvironments containing CD4(+) CD73(+) T cells, B cells or CD39(+) CD73(+) exosomes, CD73 is readily available to CD4(+) CD39(+) CD73(neg) Treg for the production of immunosuppressive ADO.
[Show abstract][Hide abstract] ABSTRACT: Regulatory T cells (Treg) accumulate in tumor tissues and the peripheral blood of cancer patients and may persist after therapies. This cross-sectional study examines effects of adjuvant chemo-radiotherapy (CRT) on Treg numbers and function in head and neck squamous cell carcinoma (HNSCC) patients.
The frequency and absolute numbers of CD4+, ATP-hydrolyzing CD4+CD39+ and CD8+ T cells and expression levels of CD39, CD25, TGF-β-associated LAP and GARP on Treg were measured by flow cytometry in 40 healthy donors (NC) and 71 HNSCC patients (29 untreated with active disease (AD); 22 treated with surgery; 20 treated with CRT). All treated subjects had no evident disease (NED) at the time of phlebotomy. In an additional cohort of 40 subjects with AD (n=15), NED (n=10) and NC (n=15), in vitro sensitivity of CD4+ T cell subsets to cisplatin and activation-induced cell death (AICD) was tested in Annexin V- binding assays.
CRT decreased the frequency of circulating CD4+ T cells (p<0.002) but increased that of CD4+CD39+ Treg (p≤0.001) compared to untreated or surgery-only patients. Treg frequency remained elevated for >3 years. CRT increased surface expression of LAP, GARP and CD39 on Treg. In vitro, Treg were resistant to AICD or cisplatin but conventional CD4+ T cells (Tconv) were not. CRT-induced Treg from AD or NC subjects up-regulated pro-survival proteins, while Tconv up-regulated pro-apoptotic Bax.
Highly suppressive, cisplatin-resistant Treg increase in frequency and persist after CRT and could be responsible for suppression of anti-tumor immune responses and recurrence in HNSCC.
Clinical Cancer Research 10/2013; 19(23). DOI:10.1158/1078-0432.CCR-13-0900 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The role of the adenosine (ADO) suppression pathway, specifically CD39-expressing and CD73-expressing CD4 T cells in HIV-1 infection is unclear.
We evaluated the frequency and numbers of CD4CD39 and CD4CD73 T cells, activated T cells, and plasma C reactive protein (CRP) levels in 36 HIV-1-positive individuals and 10 normal controls (NC). Low-level plasma viremia was evaluated using single copy assay. Mass spectrometry was used to measure hydrolysis of ATP by ectoenzyme-expressing CD4 T cells, whereas cyclic adenosine monophosphate (cAMP) levels were measured using enzyme immunoassay. Suppression of T-cell function by exogenous ADO and CD4CD73 T cells was tested by flow cytometry.
CD39 and CD73 are expressed in different CD4 T-cell subsets. CD4CD73 T cells do not express CD25 and FOXP3, and their frequency and numbers were lower in HIV-1-positive individuals regardless of virologic suppression (P = 0.005 and P < 0.001, respectively). CD4CD73 numbers inversely correlated with CD4CD38DR (P = 0.002), CD8CD38DR T-cell frequency (P = 0.05), and plasma CRP levels (P = 0.01). Both subsets are required for hydrolysis of exogenous ATP to ADO and can increase CD4 T-cell cAMP levels when incubated with exogenous ATP. Low-level viremia did not correlate with activated T-cell frequency. In vitro, ADO suppressed T-cell activation and cytokine expression. CD4CD73 T cells suppressed T-cell proliferation only in the presence of exogenous 5'-AMP.
The ADO-producing CD4CD73 subset of T cells is depleted in HIV-1-positive individuals regardless of viral suppression and may play a key role in controlling HIV-1-associated immune activation.
AIDS (London, England) 06/2013; 27(10):1545-1555. DOI:10.1097/QAD.0b013e328360c7f3 · 5.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antibody-independent role of B cells in modulating T-cell responses is incompletely understood. Freshly-isolated or cultured B cells isolated from the peripheral blood of 30 normal donors were evaluated for CD39 and CD73 co-expression, the ability to produce 5'-AMP and adenosine (ADO) in the presence of exogenous(e) ATP as well as A1, A2A, A2B and A3 adenosine receptor (ADOR) expression. Human circulating B cells co-express ectonucleotidases, CD39 and CD73, hydrolyze exogenous ATP to 5'-AMP and ADO and express mRNA for A1R, A2AR and A3R. 2-chloroadenosine (CADO) inhibited B-cell proliferation and cytokine expression, and only A3R selective antagonist restored B-cell functions. This suggested that B cells utilize the A3R for autocrine signaling and self-regulation. mediated effects on B-cell growth ± ADOR antagonists or agonists were tested in CFSE assays. In co-cultures, resting B cells up-regulated functions of CD4(+) and CD8(+) T-cells. However, in vitro-activated B cells down-regulated CD73 expression, mainly produced 5'-AMP and inhibited T-cell proliferation and cytokine production. These B cells acquire the ability to restrict potentially harmful effects of activated T cells. Thus, B cells emerge as a key regulatory component of T cell-B cell interactions, and their dual regulatory activity is mediated by the products of ATP hydrolysis, 5'-AMP and ADO.
[Show abstract][Hide abstract] ABSTRACT: The sonic hedgehog (SHH) signaling pathway is critical in fetal organogenesis. Activation of the SHH pathway has been associated with several types of human cancer; however, the clinical impact of SHH activation in patients with gastric cancer is still unknown.
The present study included 41 patients with gastric cancer who underwent gastrectomy between 2000 and 2004. SHH, Patched-1 (PTCH1), Smoothened (SMO) and Glioma-associated oncogene-1 (GLI1) were examined immunohistochemically, and these of mRNAs from the cancer lesions were evaluated using real-time quantitative RT-PCR.
Immunohistological expressions of SHH-related molecules were relatively intense in cancer tissue, but no significant correlation was found with any clinicopathological factors of tumor. PTCH1 was only the molecule associated with poor prognosis of patients with differentiated type of tumor. For mRNA analysis, a significant correlation was demonstrated between certain clinicopathological factors and PTCH1, SMO or/and GLI1 mRNA levels. High levels of SHH and PTCH1 mRNA were associated with poor prognosis. Multivariate analysis demonstrated the PTCH1 mRNA level and liver metastasis as significant independent prognostic factors.
PTCH1 expression in the SHH pathway was possibly involved in gastric cancer tumor progression, and could be a useful indicator for the prognosis of gastric cancer.
Digestive surgery 03/2012; 29(2):115-23. DOI:10.1159/000336949 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells (DCs) are potent antigen-presenting cells that are central to the regulation, maturation, and maintenance of the cellular immune response against cancer. In contrast, CD4(+)CD25(+) regulatory T cells (Tregs) play a central role in self-tolerance and suppress antitumor immunity. In this study, we investigated the clinical significance of mature CD83(+) DCs and Foxp3(+) Tregs in the primary tumor and regional lymph nodes from the viewpoint of the two opposing players in the immune responses.
We investigated, immunohistochemically, the density of CD83(+) DCs and Foxp3(+) Tregs in primary lesions of gastric cancer (n = 123), as well as in regional lymph nodes with (n = 40) or without metastasis (n = 40).
Decreased density of CD83(+) DCs and increased density of Foxp3(+) Tregs were observed in the primary tumor and metastatic lymph nodes. Density was significantly correlated with certain clinicopathological features. Poor prognosis was observed in patients with a low density of CD83(+) DCs and a high density of Foxp3(+) Tregs in primary lesions. For patients with metastatic lymph nodes, the density of CD83(+) DCs in negative lymph nodes was found to be an independent prognostic factor by multivariate analysis.
The density of CD83(+) DCs and Foxp3(+) Tregs was inversely correlated with tumor progression and reflected the prognosis of gastric cancer.
Gastric Cancer 11/2011; 15(2):144-53. DOI:10.1007/s10120-011-0090-9 · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This is a randomized phase II trial to evaluate non-inferiority of progression-free surviva(l PFS) by comparing S-1 and S-1/PSK for advanced or recurrent gastric cancer. Sample size was calculated to be 120. However, the trial was terminated because of slow accrual. This exploratory analysis was done by collecting the minimum data.
Only 8 patients were enrolled. Four patients were randomly assigned to S-1 and the others to S-1/PSK. Performance status was 0 in all 8 patients. Median age was 64. Median overall survival was 13.7 months in all 8 patients, 8 . 9 months in S-1 group, and 13 . 7 months in S-1/PSK group.
When considering PS 0 in 8 patients enrolled, an overall survival was comparable to that observed in S-1 group of other phase III trials. Standard chemotherapy for advanced gastric cancer was changed to S-1/CDDP by SPIRITS phase III trial which was presented just after this trial was initiated, which would be a major cause of slow accrual. When conducting phase III trial, we should carefully determine design and standard arm by considering on-going phase III trial.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2011; 38(12):1909-11.
[Show abstract][Hide abstract] ABSTRACT: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract that are diagnosed by c-kit staining in most cases. A lysosomal cysteine proteinase termed cathepsin L has been commonly associated with malignancy in several cancer types, but this finding has not been reported for GISTs. We analyzed the cathepsin L mRNA and protein expression in GISTs. Real-time reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that cathepsin L levels were higher in GISTs than those in gastric or colorectal tumors; this finding was supported by results of the Western blot analysis. Immunohistochemistry revealed that cathepsin L was localized to the cytoplasm of GIST cells as an intense granular signal, which was not observed in the cells of leiomyoma, a mesenchymal tumor that was analyzed as a control specimen. Double immunofluorescence microscopy revealed that a portion of the granular signal colocalized with lysosome-associated membrane protein-1 (LAMP-1), which is a lysosomal marker. Moreover, immunohistochemical analysis of 43 tumor specimens revealed that 86.0% (n=37) were cathepsin-L positive, and this positivity was significantly correlated with c-kit positivity but not with other clinicopathological factors, including gender, age, region, size, mitosis and risk of recurrence. From these results, we conclude that cathepsin L is highly expressed in GISTs compared to its expression in other cancerous lesions; this identifies cathepsin-L as a new diagnostic marker for GISTs.
International Journal of Oncology 07/2011; 39(5):1109-15. DOI:10.3892/ijo.2011.1127 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Immunosuppressive acidic protein (IAP) suppresses several immune responses in vivo and in vitro , and high preoperative IAP levels could predict the impairment of the host's immunity. In this study prognostic significance of preoperative IAP levels was investigated in 68 esophageal cancer patients with curative resection and eight with non-curative resection. The curative group had significantly lower levels than the non-curative group (432 +/- 183 mg/mL vs. 739 +/- 235 mg/mL, P < 0.0001). The IAP levels were associated with T-status (P < 0.0001), lymphatic invasion (P < 0.05), and p-stages (P < 0.0001). When 5-year survival rate of patients with curative resection was compared by setting various cutoff values of IAP between high and low IAP groups, several cutoff points (400-580 mg/mL) were revealed to be significantly associated with survival. Setting cutoff value of IAP to 560 mg/mL resulted in a most significant difference of 5-year survival rate of patients between the high and low IAP groups (13.9% and 61.5%, P < 0.0001). These data indicate that pre-operative IAP level is a useful parameter to predict the prognosis of esophageal cancer patients after curative resection.
Diseases of the Esophagus 05/2008; 21(3):214-9. DOI:10.1111/j.1442-2050.2007.00754.x · 1.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adjuvant chemotherapy for advanced gastric cancer has not yet been established. We report a patient with advanced gastric cancer responding remarkably to neo-adjuvant combination chemotherapy consisting of CPT-11 and S-1. The patient was a 69-year-old woman diagnosed with large type 3 advanced gastric cancer with esophageal invasion and having No.3 lymph node metastasis (cT3, cN1, cM0, cStage IIIA), treated with 2 courses of CPT-11 plus S-1 as neo-adjuvant chemotherapy. Computed tomography after neo-adjuvant chemotherapy showed improvement of gastric wall thickness and reduction of lymph node metastasis. Subsequently, she underwent an operation. There was no lymph node swelling,so we performed curative surgery consisting of total gastrectomy, splenectomy, cholecystectomy, and D 2 lymph node dissection. Histological diagnosis was pT2 (MP), pN1, pStage II, and estimation of the histological change by chemotherapy was Grade 2. The course after surgery was good, and she was treated by S-1 after discharge. To date, 8 months after surgery, there is no evidence of recurrence. Combination chemotherapy consisting of CPT-11 plus S-1 can be performed safely as a neo-adjuvant treatment, and may be an effective treatment modality for advanced gastric cancer.
Gan to kagaku ryoho. Cancer & chemotherapy 10/2007; 34(9):1473-6.
[Show abstract][Hide abstract] ABSTRACT: Present status and problems in diagnostic procedure combination (DPC) for treatment of gastric cancer are reviewed in this article. DPC for gastric malignancies are subgrouped by the presence or absence of operation, operative procedures and adjuvant treatment such as intensive care, radiotherapy and chemotherapy. In a comparison between prospective payment and medical cost invested, most investments can be recovered by DPC in patients who underwent mucosal resection or gastrectomy without major complications. However, in patients with postoperative complications who required intensive treatment,considerable investments can not be recovered by DPC. In patients given chemotherapy, most of the investments in conventional chemotherapy can be recovered by current DPC. The clinical pathway appears to be a useful tool to control homogeneously well-qualified investments in DPC.
Gan to kagaku ryoho. Cancer & chemotherapy 02/2007; 34(1):35-40.
[Show abstract][Hide abstract] ABSTRACT: Dihydropyrimidine dehydrogenase (DPD) is a reducing enzyme for fluoropyrimidine which is a widely-used anti-cancer agent, and its deficiency leads to serious toxicities. We report a rare patient with a DPD deficiency. A 39-year-old man was suspected to have a gastric cancer recurrence from the elevation of CEA. Although TS-1 was administered for five days, it was stopped due to the development of grade 2 anorexia and nausea. Although we administered UFT at his request after a one-month drug rest, grade 1 stomatorrhagia besides the former adverse events developed after five days. Therefore he discontinued it and was admitted to our hospital. After 19 days, he died from multiple brain hemorrhage despite the intensive therapies. We considered that the congenital DPD deficiency caused the development of these adverse events because the DPD value was less than 5 pmol/mg/min in mononuclear cells of peripheral blood.
Gan to kagaku ryoho. Cancer & chemotherapy 08/2006; 33(7):985-8.
[Show abstract][Hide abstract] ABSTRACT: As the frequency of chemotherapy was increasing at an out-patient clinic, chemotherapy centers for an outpatient clinic have been established. When chemotherapy was carried out for 25 patients in a day at an outpatient clinic, the mean time was 27.6 minutes from ordering the drugs to the drugs' arrival. When the line was crowded, the drug arrival time was more than one hour, and at least 90 minutes was necessary to begin the chemotherapy. As the number of patients increases, it is necessary to have the effective use of a chemotherapy room and the patients have to be divided according to the duration of time required for chemotherapy. It appears that a continuation of infusion chemotherapy will be frequently carried out and the chemotherapy with an IVH port and a portable pump system will be popular in the future. It is necessary to make the system which supports a continuous infusion like this.
Gan to kagaku ryoho. Cancer & chemotherapy 01/2006; 32 Suppl 1:12-4.