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Background Over 30% of the population of Okinawa Prefecture have a high body mass index. The incidence of hypertension and dyslipidaemia has also increased in recent years. We found that Ooitabi (Ficus pumila L.), a plant native to Okinawa, was useful for hypertension. During ancient times, the extracts of Ooitabi leaves were used for making Ishimaki tea in some areas of Okinawa Prefecture. The plants in Okinawa are rich in antioxidants, and four flavonoid glycosides, including rutin, have been identified in Ooitabi. Methods In the present study, we conducted clinical verification tests on the effects of drinking Ishimaki tea on outpatients with hypertension and dyslipidaemia. Of 3814 Japanese patients who underwent medical check‐ups in Okinawa, 38 individuals with high blood pressure, dyslipidaemia, liver dysfunction and gout visited our hospital as outpatients and were asked to drink Ishimaki tea. Results After 3 months, there were significant reductions in body mass index, systolic and diastolic blood pressure, total cholesterol, low‐density lipoprotein cholesterol, γ‐glutamyltrans peptidase, uric acid and ratio of blood vessel insulin resistance. Conclusions Ooitabi extract can lower blood pressure and improve lipid abnormalities and has likely contributed to the well‐known health and longevity of the population in Okinawa., Shisa is Okinawan lion (or lion dog) statue placed as talisman against evil at entrances, on roofs and on stone walls. Shisa holds Ooitabi leaves in its mouth (Fig. 2a).

Ovarian cancer is the most common malignant disease leading to death among women. IL (interleukin)-17A is the most well-studied member of the IL-17 family, and has been demonstrated to play a critical role in host defenses against various microbial pathogens, as well as against tissue inflammation. T-helper (Th)17 cells that produce interleukin (IL)-17A are of particular importance, because IL-17A exerts a wide variety of biological functions, particularly related to inflammation and the resultant carcinogenesis, as well as immune suppression in patients with cancer, and IL-17A-targeted therapy has been proven to be effective in the treatment of some autoimmune diseases. The pathogenic features of Th17 and IL-17A cells in cancer are still controversial, and Th17 cells appear to promote disease progression, as well as be present in the vicinity of many types of malignant diseases. In cancer patients, MDSC (myeloid-derived suppressor cells), one of the major immunosuppressive immature cells, and VEGF (vascular endothelial growth factor) are reported to correlate each other and strongly connected to IL-17-driven inflammation and malnutrition. In the present review, the latest advances are presented about the basic features of IL-17A and Th17. The function of IL-17A has not been clarified especially in ovarian cancer. This review overview the basic features of IL-17A and the functions in ovarian cancer as well as in other malignant and non-malignant diseases. Increasing our understanding of the interactions between IL-17A and ovarian cancer could lead to new therapeutic strategies in oncology.

Human T-cell leukemia virus type 1 was isolated as the retrovirus to be identified in humans. Here, we focused on Ficus pumila L. as a factor that be effective against human T-cell leukemia virus type 1. The significant and novel findings is that symptoms of patients with drinking Ficus pumila L. extracts did not worsen despite a lack of aggressive pharmacotherapy against adult T-cell leukemia, a human T-cell leukemia virus type 1-associated myelopathy, or T-cell leukemia virus type 1 uveitis. Twenty-eight of the 194 inpatients who underwent showed high levels of human T-cell leukemia virus type 1.Among human T-cell leukemia virus type 1-infected patients, those who were administered Ficus pumila L. extracts had no human T-cell leukemia virus type 1-related symptoms, while those who were not administered Ficus pumila L. extracts had human T-cell leukemia virus type 1-related diseases and a significantly poorer prognosis. This suggests that the Ficus pumila L. extracts may show some utility against virus infection.

Continuous blood pressure monitoring is essential in the management of patients in critical conditions, as well as those under anesthesia. However, continuous blood pressure monitoring requires insertion of a catheter into the radial artery. Thus, continuous noninvasive arterial blood pressure monitoring would be ideal.We designed and built a continuous noninvasive arterial blood pressure monitoring device with a pressure sensor diaphragm using microelectromechanical system technology, a square with 4 mm sides that were 0.4 mm thick. Comparisons between a continuous noninvasive arterial blood pressure monitoring device and a sphygmomanometer were carried out on 92 volunteers, and comparisons between noninvasive and invasive blood pressure monitoring were performed on three patients perioperatively at Fukushima Medical University Hospital.In the comparisons of arterial blood pressure measurements between a sphygmomanometer and our device, the differences became gradually greater over time after starting continuous monitoring in conscious participants. In the comparisons of arterial blood pressure measurements between the invasive and noninvasive methods in unconscious subjects under general anesthesia, the results of noninvasive monitoring were consistent with those of invasive arterial blood pressure monitoring.Continuous noninvasive arterial monitoring with a pressure sensor diaphragm using microelectromechanical system technology is a possible alternative to conventional invasive arterial pressure monitoring by an arterial catheter.

Background: It has been hypothesized that flavonoid ingestion stimulates immunity, promotes health, and prevents human illness. The aim of this analysis was to evaluate the association of the levels of immunoglobulin A (IgA) with the prevention of influenza infections and with the polyphenols contained in Okinawan vegetables. Methods: IgA, immunoglobulin G (IgG), immunoglobulin M (IgM), and soluble interleukin-2 receptor (sIL-2R) levels were measured in 44 outpatients who regularly ingested vegetables grown on Okinawa Island (200–300 g/day for ≥ 300 days/year) with no history of influenza infection and in 73 patients who ingested the vegetables irregularly or not at all with a history of influenza infection. Results: The patients who regularly ate Okinawan vegetables had higher IgA, IgG, and IgM levels than those who did not. On the other hand, patients who did not consume Okinawan vegetables and had influenza had lower IgA, IgG, and IgM levels. In addition, the IgA and IgG levels showed significant positive correlations with the sIL-2R levels in both groups. Conclusions: It may be beneficial to eat vegetables abundant in polyphenols every day. Secretory IgA antibodies are an important part of the immune defense against viral diseases. People who ingest Okinawan vegetables have high IgA levels and might be more likely to develop immunity against influenza RNA viruses.

Objectives The standard strategy for advanced rectal cancer (RC) is preoperative short-course radiotherapy (SCRT)/chemoradiotherapy (CRT) plus total mesorectal excision (TME) in Western countries; however, the survival benefit of adding chemotherapy to radiotherapy remains unclear. There is accumulating evidence that either SCRT/CRT or lateral pelvic lymph node dissection (LPND) alone may not be sufficient for local control of advanced RC. We herein retrospectively evaluated the clinical outcomes of patients who were treated by SCRT/CRT+TME+LPND, particularly focusing on the prognostic impact of lateral pelvic lymph node metastasis (LPNM). Methods Patients diagnosed as having clinical Stage II and III lower RC who received SCRT/CRT+TME+LPND between 1999 and 2012 at our hospital were enrolled. Adverse events (AEs), surgery-related complications (SRC), and therapeutic effects were retrospectively analyzed. Results Fifty cases (SCRT:25, CRT:25) were analyzed. No significant differences were observed in overall survival (OS), relapse-free survival (RFS), local recurrence (LR), AE, and SRC between the SCRT and CRT groups, although the pathological therapeutic effect was higher in the CRT group. The patients with LPNM showed significantly inferior 5-year OS and 5-year RFS than those without LPNM. Conclusions There were no significant differences in OS, RFS, or LR between SCRT and CRT, although CRT had a significantly greater histological therapeutic effect. The prognosis of the pathological LPNM-positive cases was significantly poorer than that of pathological LPNM-negative cases.

Pancreatic metastatic tumors from thyroid carcinoma are extremely rare. We report a case of an 80-year-old female with a pancreatic metastatic tumor derived from papillary thyroid carcinoma which was initially resected 158 months prior to detection of the metastatic pancreatic tumor. The patient has encountered cervical lymph-node metastasis on three occasions following the initial operation. Metastatic pancreatic lesions and cervical lymph nodes were first detected using 18-fluorodeoxyglucose positron-emission tomography/computed tomography, and she was preoperatively diagnosed using endoscopic ultrasound-guided fine-needle aspiration biopsy. A coin lesion, 10 mm in size, was detected in the left lung by chest computed tomography with no abnormal uptake in 18-fluorodeoxyglucose positron-emission tomography/computed tomography. Distal pancreatectomy and cervical lymph-node dissection were performed. Adjuvant chemotherapy with weekly paclitaxel was administered because anaplastic transformation had been detected in one of the cervical lymph nodes. The patient eventually died from multiple lung metastases 11 months after removing the metastatic pancreatic lesion. We reported a rare case of a pancreatic metastatic tumor from thyroid carcinoma, and found that 18-fluorodeoxyglucose positron-emission tomography/computed tomography and endoscopic ultrasound-guided fine-needle aspiration biopsy are useful for preoperatively diagnosing tumors.

The incidence of breast cancer increases annually, and it has become common within families of breast cancer patients. Interleukin-2 activates cytotoxic T lymphocytes, which are important for cancer immunity. To identify markers of increased familial breast cancer risk, soluble interleukin-2 receptor levels and immunologic factors were investigated in familial breast cancer and non-familial breast cancer patients. Of 106 untreated breast cancer patients in this study, 24 had familial breast cancer and 82 had non-familial breast cancer. The patients’ soluble interleukin-2 receptor, interleukin-10, vascular endothelial growth factor, interleukin-17, regulatory T cell, myeloid-derived suppressor cell, white blood cell, and C-reactive protein levels, and their neutrophil-to-lymphocyte ratios were measured, and their prognoses were compared according to the soluble interleukin-2 receptor levels. Additionally, postoperative tissues from the patients with high soluble interleukin-2 receptor levels were stained with programmed cell death ligand 1 and cluster of differentiation 8. The soluble interleukin-2 receptor level in the familial breast cancer patients was significantly higher, and it showed significantly stronger correlations with the neutrophil-to-lymphocyte ratio and the interleukin-10, vascular endothelial growth factor, interleukin-17, regulatory T cell, myeloid-derived suppressor cell, white blood cell, and C-reactive protein levels, than in the non-familial breast cancer patients. The regulatory T cell and myeloid-derived suppressor cell levels were significantly higher in the patients with high soluble interleukin-2 receptor levels, and the overall survival and disease-free-survival rates were significantly worse for the familial breast cancer patients than for the non-familial breast cancer patients. Triple-negative breast cancer tissues from the familial breast cancer patients with high soluble interleukin-2 receptor levels stained well for programmed cell death ligand 1 and cluster of differentiation 8. Soluble interleukin-2 receptor levels can be used to predict the prognosis of familial breast cancer patients. Prospectively identifying patients who are less likely to have non-familial breast cancer is vital for improving their overall survival.

Solute carrier (SLC) drug transporters exchange various molecules without energy from adenosine triphosphate hydrolysis, indicating an association with anticancer drug resistance. However, the expression and role of SLC transporters in malignant tumors has not yet been fully elucidated. Therefore, in the current study, the expression of SLC37A family genes was evaluated in patients with colorectal cancer (CRC), and it was revealed that SLC family 37 member 1 (SLC37A1) expression was significantly increased in tumorous tissues compared with that in non-tumorous tissues. The cases with upregulated expression of SLC37A1 by immunohistochemical staining were significantly associated with positive venous invasion and liver metastasis. Furthermore, upregulated SLC37A1 expression was associated with poor overall survival time in the present cohort. These results indicated that SLC37A1 is involved in the hematogenous metastasis of CRC. To investigate whether SLC37A1 is associated with hematogenous metastasis and glycolipid metabolism, SLC37A1 was knocked down in colon cancer cells, and the expression of sialyl Lewis A and sialyl Lewis X was observed to be decreased. In summary, upregulation of SLC37A1 was observed in patients with CRC, and was associated with poor patient outcomes and survival. To the best of our knowledge, the present study is the first to propose a key role of SLC37A1 in CRC, and additional studies are warranted to reveal the functional role of SLC37A1 in CRC development.

Relationships between inflammation and innate immunity in cancer are widely accepted today; however, the precise cell mechanisms mediating these relationships have not yet been elucidated. Interleukin (IL)-17 is a proinflammatory cytokine that has been reported to induce inflammation in patients with autoimmune diseases. Myeloid-derived suppressor cells (MDSC) may contribute to the negative regulation of immune responses during cancer and inflammation. Vascular endothelial growth factor (VEGF) is reported to have multiple biological actions including increasing vascular permeability, neovascularization, and possible inhibition of immune function in malignant diseases. This study investigated the status of systemic inflammation and immune suppression associated with IL-17 and VEGF in patients with breast cancer. IL-17 production and the serum levels of VEGF were also increased in advanced stages of the disease. The production of IL-12, which induces Th1 cells, and the stimulation index (SI), which is a marker of cell-mediated immune function, were both shown to decrease along with disease advancement. Also, the production of IL-17 and the VEGF levels were both positively correlated with the levels of MDSC, the neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), and were inversely correlated with IL-12 production and the SI. Nutritional markers, including prealbumin (PA), transferrin (TF), and retinol-binding protein (RBP), were also shown to be significantly lower in patients with high production of IL-17 or high levels of VEGF. These data clearly showed that IL-17 and VEGF, whose levels correlated with each other and with those of MDSC, were significantly associated with disease advancement, systemic inflammation, suppression of cell-mediated immunity including Th1 induction, and malnutrition.

Acinar cell cystadenocarcinoma is a rare malignant epithelial neoplasm of the pancreas with a diffusely cystic, gross architecture in which the cysts are lined with neoplastic epithelial cells that demonstrate evidence of pancreatic exocrine enzyme production. This is the 10th case that has been reported in the literature. A 77-year-old male complaining of left hypochondrial pain was referred to our hospital for treatment of a pancreatic tumor. A huge, honeycomb-structured tumor was detected in the pancreatic tail. Distal pancreatectomy with total resection of the residual stomach and partial resection of the transverse colon were performed. Microscopically, there were variably sized cystic lesions in the tumor. Immunohistochemical examinations revealed that tumor cells were positive for alpha 1-antichymotrypsin and alpha 1-trypsin, showing that tumor cells had features of pancreatic acinar cells. Thus, the tumor was diagnosed as acinar cell cystadenocarcinoma. Herein, we report a rare case with acinar cell cystadenocarcinoma, which is the 10th case reported in the literature based on a PubMed search. We managed to resect the tumor completely by distal pancreatectomy with total resection of the residual stomach and partial resection of the transverse colon. The patient is still alive 26 months after surgery without any recurrence after 1 year of adjuvant chemotherapy with S-1.

Metastasis represents the leading cause of breast cancer deaths, necessitating strategies for its treatment. Although radiotherapy is employed for both primary and metastatic breast cancers, the difference in their ionizing radiation response remains incompletely understood. This study is the first to compare the radioresponse of a breast cancer cell line with its metastatic variants and report that such metastatic variants are more radioresistant. A luciferase expressing cell line was established from human basal-like breast adenocarcinoma MDA-MB-231 and underwent in vivo selections, whereby a cycle of inoculations into the left cardiac ventricle or the mammary fat pad of athymic nude mice, isolation of metastases to the bone, lung and lymph nodes visualized with bioluminescence imaging, and expansion of obtained cells was repeated twice or three times. The established metastatic cell lines were assessed for cell proliferation, wound healing, invasion, clonogenic survival, and apoptosis. The established metastatic cell lines possessed an increased proliferative potential in vivo and were more chemotactic, invasive, and resistant to X‑ray-induced clonogenic inactivation and apoptosis in vitro. Breast cancer metastasis to the bone, lung, and lymph nodes promotes radioresistance.

Lung adenocarcinoma (LADC) is a cancer treatable using targeted therapies against driver gene aberrations. EGFR mutations and ALK fusions are frequent gene aberrations in LADC, and personalized therapies against those aberrations have become a standard therapy. These targeted therapies have shown significant positive efficacy and tolerable toxicity compared to conventional chemotherapy, so it is necessary to identify additional druggable genetic aberrations. Other than EGFR mutations and ALK fusions, mutations in KRAS, HER2, and BRAF, and driver fusions involving RET and ROS1, have also been identified in LADC. Interestingly, the frequency of driver gene aberrations differs according to ethnicity, sex, and smoking, which leads to differences in treatment efficacy. To date, several molecular-targeted drugs against driver genes have been developed, and several clinical trials have been conducted to evaluate the efficacy. However, targeted therapies against driver-gene-negative cases have not yet been well developed. Efforts to identify a new druggable target for such cases are currently underway. Furthermore, immune checkpoint blockade therapy might be effective for driver-negative cases, especially those with accumulated mutations.

Objective Emerging studies have focused on the association between non-alcoholic fatty liver disease (NAFLD) and the risk of type 2 diabetes mellitus (T2DM). We aimed to investigate whether NAFLD diagnosed by ultrasonography could predict the risk of future T2DM in a Japanese middle-aged health check population. Methods We conducted a 10-year observational study in a health checkup population of middle-aged Japanese men and women at Hidaka Hospital from 2004 to 2013. We excluded cases with an alcohol intake exceeding 20 g/day and those with impaired glucose tolerance. The remaining 1,544 men and 864 women were classified into fatty liver and non-fatty liver groups based on the findings of abdominal ultrasonography. Both groups were followed for the development of diabetes. A multiple regression analysis was performed for each variable to predict the risk of future diabetes. Results The median age of the participants was 46.0 years at the entry, and the follow-up period was 10 years. The incidence of diabetes in the fatty liver group was 12.5% (29/232) in men and 26.3% (10/38) in women, whereas the incidence of diabetes in the non-fatty liver group was 2.5% (34/1,312) in men and 1.8% (15/826) in women. The relative risk of diabetes associated with fatty liver was 4.8 [95% confidence interval (CI) 3.0 -7.8, p

Background Autosomal dominant polycystic kidney disease is defined as an inherited disorder characterized by renal cyst formation due to mutations in the PKD1 or PKD2 gene, whereas tuberous sclerosis complex is an autosomal dominant neurocutaneous syndrome caused by mutation or deletion of the TSC2 gene. A TSC2/PKD1 contiguous gene syndrome, which is caused by a chromosomal mutation that disrupts both the TSC2 and PKD1 genes, has been identified in patients with tuberous sclerosis complex and severe early-onset autosomal dominant polycystic kidney disease. The tumor tissue of patients with breast cancer with contiguous gene syndrome has a high mutation burden and produces several neoantigens. A diffuse positive immunohistochemistry staining for cluster of differentiation 8+ in the T cells of breast cancer tissue is consistent with neoantigen production due to high mutation burden. Case presentation A 61-year-old Japanese woman who had been undergoing dialysis for 23 years because of end-stage renal failure secondary to autosomal dominant polycystic kidney disease was diagnosed as having triple-negative breast cancer and underwent mastectomy in 2015. She had a history of epilepsy and skin hamartoma. Her grandmother, mother, two aunts, four cousins, and one brother were also on dialysis for autosomal dominant polycystic kidney disease. Her brother had epilepsy and a brain nodule. Another brother had a syndrome of kidney failure, intellectual disability, and diabetes mellitus, which seemed to be caused by mutation in the CREBBP gene. Immunohistochemistry of our patient’s breast tissue showed cluster of differentiation 8 and programmed cell death ligand 1 positivity. Conclusions Programmed cell death ligand 1 checkpoint therapy may be effective for recurrence of triple-negative breast cancer in a patient with autosomal dominant polycystic kidney disease and tuberous sclerosis complex.

Background: The incidence of breast cancer has been increasing annually, and breast cancer-related diseases, such as breast cancer in the young, ovarian cancer, prostate cancer, and pancreatic cancer, have clearly and steadily increased in number and have become common among the family members of patients with breast cancer. Accordingly, an increase in the incidence of familial breast cancer (FBC) is anticipated in the future. Interleukin (IL)-2 is one of the cytokines that activate cytotoxic T lymphocytes (CTLs), which are important for cancer immunity. To identify the markers of increased risk for FBC, soluble IL-2 receptor (sIL-2R) levels and immunologic factors were investigated in patients with FBC and non-familial breast cancer (NFBC).Methods: Of the 106 untreated breast cancer patients who gave consent to participate in this study, 24 had FBC and 82 had NFBC. There were 11 healthy individuals included in this study. Serum and peripheral blood mononuclear cells were collected from all patients for measurement of sIL-2R, IL-10, Vascular endothelial growth factor (VEGF), IL-17, regulatory T cells (Tregs), Myeloid derived suppressor cells (MDSCs), neutrophil to lymphocyte ratio (NLR), white blood cell (WBC) and C-reactive protein (CRP) levels. Prognosis was assessed and compared according to sIL-2R levels (low vs. high). Tissue samples from postoperative patients with high sIL-2R levels were stained with programmed cell death ligand 1 (PD-L1) and Cluster of Differentiation (CD) 8.Results: sIL-2R level was significantly higher and had significantly stronger correlation with IL-10, VEGF, IL-17, Tregs, MDSCs levels, NLR, WBC count and CRP in FBC, than in NFBC. In cases with high sIL-2R levels, Tregs and MDSCs levels were significantly higher and the overall survival (OS) and disease free survival (DFS) rates were significantly worse in FBC than in NFBC. Among the FBC cases with high sIL-2R levels, triple negative breast cancer tissues stained well for PD-L1and CD8.Conclusions: Compared with NFBC, FBC was associated with higher sIL-2R level, Th2 predominance, and less aggressive cancer immunosuppressive cells. In the present study, sIL-2R was identified as a biomarker that can predict the prognosis of FBC. The ability to prospectively identify patients who are less likely to have NFBC is a vital step in improving the overall survival of this population.

Among advanced gastric cancer cases, peritoneal dissemination is a life-threatening mode of metastasis, and any strategy to control peritoneal metastasis will significantly improve treatment outcomes. Since intraperitoneal administration of anticancer drugs can induce an extremely high concentration of drugs in the peritoneal cavity, intraperitoneal chemotherapy would appear to be a reasonable and promising strategy to control the peritoneal dissemination. However, it has been reported in the past that intraperitoneal administration of mitomycin C or cisplatin resulted in no significant clinical effects against peritoneal metastasis of gastric cancer. In contrast, intraperitoneal paclitaxel is expected to remain inside the peritoneal cavity due to its large molecular weight and fat solubility, leading to a high concentration of the drug in the peritoneal cavity. In fact, promising results in several phase II clinical trials using intraperitoneal paclitaxel have been reported, including a median survival time of 16.2-24.6 months and a 1-year overall survival rate of 69-78 %. Thereafter, a phase III randomized control study (PHOENIX-GC trial) with intraperitoneal paclitaxel plus systemic S-1 and intravenous paclitaxel in comparison to systemic S-1 plus cisplatin was conducted in Japan. Moreover, a phase II clinical trial of combination chemotherapy of intraperitoneal paclitaxel with systemic capecitabine plus oxaliplatin is currently ongoing in Singapore. In this review, based on clinical experience from Singapore and Japan, the clinical significance of intraperitoneal chemotherapy for gastric cancer with peritoneal disease is discussed.

To develop prognostic biomarkers that can discriminate stage II-III colorectal cancer patients with high risk of postoperative recurrence, we conducted a genome-wide screening of relapse-related genes utilizing multiple microarray cohorts. Among differentially expressed genes between tumor and nontumor, we identified eight candidate genes associated with relapse in two datasets of stage II-III patients (n = 94 and 145, respectively, P < 0.05). Using datasets of laser-microdissected samples and FACS-purified cell populations, the localization of candidate genes, including COL4A2, COL4A1, VCAN and SERPINE1, were found predominantly in cancer stroma rather than epithelial components. Among those relapse-related stromal genes, VCAN mRNA, specifically expressed in cancer-associated fibroblasts, was further validated to be a prognostic factor in two additional independent datasets, consisting of 453 (P = 0.0334) and 89 (P = 0.0041) stage II-III patients. Furthermore, in our large set of formalin-fixed paraffin-embedded cohort (n = 338), VCAN protein was detected exclusively in cancer stroma by immunohistochemistry, demonstrating a stepwise increase of stromal VCAN from normal tissues through stage 0 to stage IV tumors. Stromal VCAN protein was associated with shorter relapse-free survival (RFS) in stage II-III colon cancer, independent of other clinical factors by multivariate analysis (P = 0.004). Stratified analyses revealed that stromal VCAN was a strong prognostic indicator particularly in stage II colon cancer (P = 0.0029). In all five analyzed cohorts, the expression of VCAN, in transcript or protein levels, was associated with poor RFS in stage II-III patients. We conclude that VCAN is a promising biomarker to identify stage II-III patients at high risk of relapse who may benefit from intensive postoperative management.

Objective The aim of this study was to examine the associations between the visceral fat area (VFA) and the subcutaneous fat area (SFA) as estimated by the dual impedance method with a body composition monitor (BCM) and the diagnostic components of metabolic syndrome in a middle-aged Japanese population. Methods The subjects included 303 men (average age 51.3±9.0 years old) and 345 women (average age 40.0±9.4 years old). The VFA and SFA were estimated by BCM, and the associations among the components of metabolic syndrome (waist circumference, blood pressure and related blood sample tests) were evaluated. Results VFA showed positive correlations with waist circumference, HbA1c, high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol, triglyceride and uric acid level in men, while showing positive correlations with waist circumference, HDL cholesterol, triglyceride and HbA1c in women. The estimated SFA showed positive correlations with systolic blood pressure, HDL/LDL cholesterol and triglyceride in men, and HDL cholesterol and triglyceride in women. A receiver operating characteristic (ROC) analysis showed the estimated VFA to be as effective as WC to identify subject with metabolic syndrome. Conclusion By estimating the VFA using BCM, it may be possible to identify patients at risk of developing metabolic syndrome and hyperuricemia.

Aquaporin 1 (AQP1), which functions as a water transporter, is associated with cancer cell proliferation, invasion, metastasis and angiogenesis in numerous types of solid cancer, including colorectal cancer (CRC). The focus of the present study was to address the potential clinical use of AQP1 expression in CRC as a prognostic and predictive biomarker for disease recurrence and therapeutic outcomes. The current study investigated the expression of AQP1 in surgically resected specimens from 268 patients with stage 0–IV CRC. AQP1 expression was positive in 112 (41.8%) patients, and was significantly associated with left-sided tumors (P

The objective of this study is to diminish postoperative complications after pylorus-preserving pancreaticoduodenectomy. Pylorus-preserving pancreaticoduodenectomy is still associated with major complications, especially leakage at pancreatojejunostomy and delayed gastric emptying. Traditional pylorus-preserving pancreaticoduodenectomy was performed in group A, while the novel procedure, an antecolic vertical duodenojejunostomy and internal pancreatic drainage with omental wrapping, was performed in group B (n = 40 each). We compared the following characteristics between the 2 groups: operation time, blood loss, time required before removal of nasogastric tube and resumption of food intake, length of hospital stay, and postoperative complications. The novel procedure required less time and was associated with less blood loss (both P < 0.0001). In the comparison of the 2 groups, group B showed less time for removal of nasogastric tubes and resumption of food intake, shorter hospital stays, and fewer postoperative complications (all P < 0.0001). The novel procedure appears to be a safe and effective alternative to traditional pancreaticoduodenectomy techniques.

In this study, we present a case of developmental delay, epilepsy and neonatal diabetes (DEND) syndrome in a young male patient with the R50P mutation located in the Kir6.2 subunit of the ATP-sensitive K(+) (KATP) channel. Whereas most patients with DEND syndrome are resistant to sulfonylurea therapy, our patient was responsive to sulfonylurea, lacked the most common neurological symptoms, such as epilepsy, but refused to drink water. His serum electrolytes and plasma osmolarity were normal but the serum vasopressin level was increased. To investigate the underlying mechanism of his water intake disorder, a 5 μL aliquot of 340 μM KATP channel opener diazoxide or 100 μM KATP channel inhibitor glibenclamide was injected into the third ventricle of the rat brain, and water intake was monitored. Although the injection of glibenclamide had no effect, injection of diazoxide significantly increased water intake by about 1.5 fold without affecting food intake. This result indicates that the KATP channel activity in the brain may have an influence on water intake. Here, we present the first case of a DEND syndrome-afflicted patient with water intake disorder and increased serum vasopressin level, possibly related to altered KATP channel activity.

Homeobox A (HOXA) cluster genes, members of the HOX family, perform an important role in normal organ development. It has previously been reported that HOXA gene expression in various types of cancer is associated with poor patient outcomes. However, the role of HOXA genes, as well as their expression, in colorectal cancers (CRC) remains unknown. Therefore, the present study investigated HOXA gene expression in patients with CRC and revealed that HOXA9 expression was significantly increased in tumor tissues compared with non-tumor tissues. Additionally, the functional role of HOXA9 was assessed by knocking down the HOXA9 gene in CRC cells and by evaluating cell growth. Regarding gene expression, cases with positive HOXA9 expression (as detected by immunohistochemical staining) were significantly associated with higher TNM stage and positive lymph node metastasis, although no association was observed between increased HOXA9 levels and the rate of overall survival in the present cohort. Regarding the functional role, HOXA9 expression was demonstrated to be upregulated in patients with CRC and was associated with lymph node metastasis.

Kinesin family member 4A (KIF4A) is a member of the kinesin 4 subfamily of kinesin-related proteins and serves an important role in cell division. The expression levels of KIF4A have been investigated in numerous types of cancer, including cervical, lung, oral, and breast cancer, and are established to be associated with poor patient prognosis. However, the role of KIF4A, as well as its expression in colorectal cancer (CRC), remains to be elucidated. Therefore, the current study investigated KIF4A expression levels in patients with CRC and demonstrated that its levels were increased in tumor tissues compared with non-tumor tissues. To investigate the functional role of KIF4A, KIF4A was knocked down in CRC cells and cell viability was evaluated. CRC cells with KIF4A knockdown exhibited lower cell proliferation compared with control cells. In addition, KIF4A expression levels, as determined by immunohistochemistry, were compared with the expression of Ki-67, but no significant associations were observed in the patients with CRC. Therefore, KIF4A was found to be upregulated in patients with CRC and downregulation of KIF4A reduced cell proliferation in CRC cells. These results suggest that KIF4A may be a potential therapeutic target, which may improve the outcomes of patients with CRC.

Enhancement of antibody-dependent cellular cytotoxicity (ADCC) with some modalities may be a promising approach to enhance the efficacy of therapeutic monoclonal antibodies (mAbs). It has previously been demonstrated that the removal of fucose from antibody oligosaccharides (defucosylation) leads to augmentation of ADCC activity. To establish clinically relevant evidence of this procedure, the present study evaluated trastuzumab- and cetuximab-mediated ADCC by comparing defucosylated mAbs with conventional mAbs using peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 20 patients with gastrointestinal tract cancer and 10 healthy volunteers. ADCCs were measured using PBMCs as effector cells and two gastric cancer cell lines as target cells. ADCCs were significantly enhanced with defucosylated mAbs compared with conventional mAbs using PBMC from the healthy donors and patients with cancer. The results confirmed that the cetuximab- and trastuzumab-mediated ADCCs in advanced disease were impaired in comparison to those in early disease or healthy individuals. However, when the defucosylated mAbs were used instead of the conventional mAbs, the ADCC activities in the advanced cases were almost comparable with those in early disease or healthy individuals. Furthermore, the expression of ADCC associated molecules were modified toward immunosuppressive status with a mitogen-activated protein kinase inhibitor in vitro, the conventional cetuximab- and trastuzumab-mediated ADCC was downregulated, and the defucosylated mAbs overcome the downregulation of ADCC. In conclusion, defucosylated therapeutic mAbs may enhance ADCC activities in patients with cancer, which may lead to more effective anti-cancer treatments.

It has been reported that chemo-radiotherapy can induce immunogenic tumor cell death (ICD), which triggers T-cell immunity mainly mediated by high-mobility group box 1 protein (HMGB1) and calreticulin. However, there is still limited information to support this theory relating to chemotherapy alone. In the present study, the expression of HMGB1 and calreticulin was evaluated by immunohistochemistry in pre-treatment biopsy specimens and surgically resected specimens, which were obtained from patients with breast cancer (n=52) and esophageal squamous cell carcinoma (ESCC) (n=8) who had been treated with neoadjuvant chemotherapy (NAC). We also analyzed HMGB1 and calreticulin expression in breast cancer cell lines treated with chemotherapeutic drugs. As a result, both HMGB1 and calreticulin expression levels were significantly upregulated after NAC in both breast cancer and ESCC tissues. However, no significant correlation was observed between HMGB1 expression and pathological response after NAC or between HMGB1 expression and patient survival. Furthermore, although overall survival in the high infiltration group of CD8-positive T cells was significantly superior to that in the low infiltration group in breast cancer patients, there were no correlations between the number of CD8-positive T cells and HMGB1 or calreticulin expression levels. In addition, chemotherapeutic drugs induced upregulation of HMGB1 and calreticulin in all tested cell lines. Our findings indicate that chemotherapy alone can significantly induce ICD regardless of the degree of pathological response after chemotherapy.

Background: We previously developed a prognostic classifier using the expression levels of BRCA1, HIF1A, DLC1, and XPO1 that identified stage I lung adenocarcinoma patients with a high risk of relapse. That study evaluated patients in five independent cohorts from various regions of the world. In an attempt to further validate the classifier, we have used a meta-analysis–based approach to study 12 cohorts consisting of 1,069 tumor–node–metastasis stage I lung adenocarcinoma patients from every suitable, publically available dataset. Methods: Cohorts were obtained through a systematic search of public gene expression datasets. These data were used to calculate the risk score using the previously published 4-gene risk model. A fixed effect meta-analysis model was used to generate a pooled estimate for all cohorts. Results: The classifier was associated with prognosis in 10 of the 12 cohorts (P < 0.05). This association was highly consistent regardless of the ethnic diversity or microarray platform. The pooled estimate demonstrated that patients classified as high risk had worse overall survival for all stage I [HR, 2.66; 95% confidence interval (CI), 1.93–3.67; P < 0.0001] patients and in stratified analyses of stage IA (HR, 2.69; 95% CI, 1.66–4.35; P < 0.0001) and stage IB (HR, 2.69; 95% CI, 1.74–4.16; P < 0.0001) patients. Conclusions: The 4-gene classifier provides independent prognostic stratification of stage IA and stage IB patients beyond conventional clinical factors. Impact: Our results suggest that the 4-gene classifier may assist clinicians in decisions about the postoperative management of early-stage lung adenocarcinoma patients. Cancer Epidemiol Biomarkers Prev; 23(12); 2884–94. ©2014 AACR.

We report a case of malignant melanoma of unknown primary origin presenting metastasis in various organs as well as intraluminal gallbladder bleeding due to gallbladder metastasis. A 58-year-old woman was diagnosed with stage IV metastatic malignant melanoma. Because she exhibited acute cholecystitis and hemobilia due to malignant melanoma of the gallbladder, laparoscopic cholecystectomy was performed to relieve the symptoms. The resected gallbladder specimen showed a pedunculated black mass indicating malignant melanoma. Pathologic examination and immunohistochemical analysis revealed malignant melanoma of the gallbladder. Only a few cases of gallbladder malignant melanoma presenting hemobilia have been reported; here we present our case, including the experience of multidisciplinary treatment.

Background Immune checkpoint inhibitors have been reported to be ineffective in patients with high levels of MDSC (myeloid-derived suppressor cells) and MDSC has been proven to be stimulated by inflammation involving VEGF and IL-17. We have reported that MDSC, IL-17 and VEGF are closely associated with immunosuppression and poor prognosis. Methods Stimulation index (SI) obtained by PHA-blastogenic response of lymphocyte was used as a marker of cell-mediated immunity and was tested in 658 patients with unresectable diseases including 260 esophageal, 110 gastric and 288 colorectal cancers. These patients received chemotherapy and SI were analyzed in correlation with nutritional status, treatment outcome (RECIST) and prognosis. These patients were divided into 2 groups with a median level of SI and, chemotherapy outcome and overall survival were compared between these groups (Study 1). To characterize the mechanisms of immunosuppression, PBMC (peripheral blood cells) were separated from the patients and the production of IL-17 (ELISA) by PBMC. Circulating levels of MDSC (CD14-CD11b+CD33+/flow cytometry), serum levels of VEGF (ELISA) were measured and analyzed in 43 patients with gastric cancer and 64 with colorectal cancer (Study 2). Results (Study 1) The overall survival was significantly worse in patients with lower SI than in those with higher SI in each disease, and the responses (RECIST) to chemotherapy were significantly better in patients with higher SI than those with lower SI. SI were significantly inversely correlated with NLR (neutrophil/lymphocyte ratio: inflammatory parameter) and nutritional factors including prealbumin, retinol-binding protein and transferrin. (Study 2) SI were significantly and inversely correlated with the levels of MDSC, the production of IL-17, and the levels of VEGF. The levels of MDSC, VEGF, IL-17 were significantly correlated with each other and inversely with nutritional parameters. Conclusion The key mechanisms of immunosuppression in these patients are systemic inflammation involving MDSC, VEGF and IL-17. Immune checkpoint inhibitors might be more effective with a decreased MDSC by controlling VEGF and IL-17. Legal entity responsible for the study Masahiko Shibata. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

e14204 Background: Although a causal relationship for inflammation and immunity of cancer is more widely accepted today, the precise cell mechanisms mediating this relationship have not been elucidated. Accumulating evidence suggests that myeloid-derived suppressor cells (MDSC), may contribute to the negative regulation of immune responses during cancer and inflammation. IL-17 is a pro-inflammatory cytokine that is primarily secreted by T helper (Th)17 cells and we have reported that IL-17 correlates with immunosuppressive conditions in patients with cancer. Methods: PBMC (peripheral blood mononuclear cells) were harvested from 106 patients including 43 with gastric and 63 with colorectal cancer. PBMC were stimulated with PHA (phytohemagglutinin) and the production of IL-17 was measured by ELISA. MDSC were detected by flow cytometry (CD11b+,CD14-,CD33+). The levels of CRP (C-reacting protein) and NLR (neutrophil to lymphocyte ratio) were used as inflammatory markers. Results: Both of MDSC and IL-17 production were increased in patients with advanced stages, and correlated with each other, inflammatory markers and immune suppression. The patients were divided with average levels of MDSC and IL-17 production and the prognosis were analyzed with Kaplan-Meier method. The overall survival of patients with high MDSC or high IL-17 production were significantly worse than those with low MDSC or low IL-17 production, respectively, in patients with stages III and IV, although the differences were not significant in patients with stages I and II. Conclusions: Thus these inflammatory markers are closely related with systemic inflammation involving IL-17 and with immunosuppression driven by MDSC, and are effective prognostic indicators in patients with stages III and IV gastric and colorectal cancer.

Poor nutritional status is common in ovarian cancer. It is well known that the nutritional status of a patient with malignant disease is associated with survival, and that it can be assessed by serum levels of rapid turnover proteins (RTPs), such as retinol binding protein, prealbumin and transferrin. Systemic inflammation, usually observed in the form of elevated C-reactive protein (CRP) or neutrophil/lymphocyte ratio (NLR), occurs by various mechanisms involving numerous pro-inflammatory cytokines. These include interleukin (IL)-17 and other soluble protein mediators, such as soluble IL-2 receptor (sIL-2R) and vascular endothelial growth factor (VEGF). In this study, circulating levels of RTP were decreased in advanced stages of ovarian cancer, and significant inverse correlations were found between RTP levels and serum levels of CRP or NLR. CRP levels were also correlated with serum levels of VEGF and sIL-2R. Moreover, NLR, VEGF and sIL-2R levels, and IL-17 production, were all inversely correlated with RTP levels. These findings indicate that chronic inflammation may be associated with compromised immune function, such as an impaired T-cell response, via various inflammatory proteins, including sIL-2R, VEGF and IL-17. The key mechanisms leading to cancer cachexia, in which nutritional impairment is a major clinical issue, appear to be primarily immune reactions caused by chronic inflammation. Anti-inflammatory treatments may be effective in clinically improving various symptoms associated with these mechanisms.