Background The earthworm fibrinolytic enzyme （EFE） is a complex protein enzyme that is widely distributed in the earthworm＇s digestive cavity. Possessing strong protein hydrolysis activity, EFE not only has a direc...Background The earthworm fibrinolytic enzyme （EFE） is a complex protein enzyme that is widely distributed in the earthworm＇s digestive cavity. Possessing strong protein hydrolysis activity, EFE not only has a direct effect on fibrin, but also can activate plasminogen. Its therapeutic and preventative effects on thrombosis-related disease have been confirmed clinically. Recently, there has been increased interest in the anti-tumor activity of EFE. In this study, the anti-tumor activity of EFE, isolated from Eisenia foetida, on human hepatoma cells was evaluated in vitro and in vivo. The potential mechanisms involved were also studied. Methods In vitro experiments were performed in four human hepatoma cell lines： HLE, Huh7, PLC/PRF/5 and HepG2. After treatment with EFE in various concentrations, the inhibition of the rate of cell proliferation was measured. For the in vivo studies, tumor-bearing models xenografted with Huh7 cells were developed in nude mice, and then the mice were fed with EFE once a day for 4 weeks, and the control group received only saline. An inhibitory effect on tumor growth was observed. Also, apoptosis was observed with flow cytometric assay and fluorescent dye staining with acridine orange and ethidium bromide （AO/EB）. The expression of matrix metalloproteinase 2 （MMP-2） were detected by Western blotting assay. Results After treatment with various concentrations of EFE, the proliferation of all hepatoma cell lines was suppressed to varying degrees in vitro. The IC50 for HLE, Huh7, PLC/PCF/5 and HepG2 were 2.11, 5.87, 25.29 and 17.30 uku/ml, respectively. After administration of EFE orally for 4 weeks, the growth of tumor xenograft of Huh7 cells in nude mice was significantly inhibited in vivo. The tumor inhibitory rates in the EFE 500 uku/（kg·d） and 1000 uku/（kg·d） groups were 46.08% （compared with control group, P=0.026） and 57.52% （compared with control group, P=0.002） respectively. Meanwhile, the average weight of body, spleen or thymus did not show any 展开更多
Hepatocellular carcinoma(HCC), with its high incidence and mortality rate, is one of the most common malignant tumors. Despite recent development of a diagnostic and treatment method, the prognosis of HCC remains poor...Hepatocellular carcinoma(HCC), with its high incidence and mortality rate, is one of the most common malignant tumors. Despite recent development of a diagnostic and treatment method, the prognosis of HCC remains poor. Therefore, to provide optimal treatment for each patient with HCC, more precise and effective biomarkers are urgently needed which could facilitate a more detailed individualized decision-making during HCC treatment, including the following; risk assessment, early cancer detection, prediction of treatment or prognostic outcome. In the blood of cancer patients, accumulating evidence about circulating tumor cells and cell-free nucleic acids has suggested their potent clinical utilities as novel biomarker. This concept, so-called "liquid biopsy" is widely known as an alternative approach to cancer tissue biopsy. This method might facilitate a more sensitive diagnosis and better decision-making by obtaining genetic and epigenetic aberrations that are closely associated with cancer initiation and progression. In this article, we review recent developments based on the available literature on both circulating tumor cells and cell-free nucleic acids in cancer patients, especially focusing on Hepatocellular carcinoma.展开更多
AIM: To determine the optimal method of endoscopic preoperative biliary drainage for malignant distal biliary obstruction.METHODS: Multicenter retrospective study was conducted in patients who underwent plastic stent ...AIM: To determine the optimal method of endoscopic preoperative biliary drainage for malignant distal biliary obstruction.METHODS: Multicenter retrospective study was conducted in patients who underwent plastic stent (PS) or nasobiliary catheter (NBC) placement for resectable malignant distal biliary obstruction followed by surgery between January 2010 and March 2012. Procedure-related adverse events, stent/catheter dysfunction (occlusion or migration of PS/NBC, development of cholangitis, or other conditions that required repeat endoscopic biliary intervention), and jaundice resolution (bilirubin level < 3.0 mg/dL) were evaluated. Cumulative incidence of jaundice resolution and dysfunction of PS/NBC were estimated using competing risk analysis. Patient characteristics and preoperative biliary drainage were also evaluated for association with the time to jaundice resolution and PS/NBC dysfunction using competing risk regression analysis.RESULTS: In total, 419 patients were included in the study (PS, 253 and NBC, 166). Primary cancers included pancreatic cancer in 194 patients (46%), bile duct cancer in 172 (41%), gallbladder cancer in three (1%), and ampullary cancer in 50 (12%). The median serum total bilirubin was 7.8 mg/dL and 324 patients (77%) had ≥ 3.0 mg/dL. During the median time to surgery of 29 d [interquartile range (IQR), 30-39 d]. PS/NBC dysfunction rate was 35% for PS and 18% for NBC [Subdistribution hazard ratio (SHR) = 4.76; 95%CI: 2.44-10.0, P < 0.001]; the pig-tailed tip was a risk factor for PS dysfunction. Jaundice resolution was achieved in 85% of patients and did not depend on the drainage method (PS or NBC).CONCLUSION: PS has insufficient patency for preoperative biliary drainage. Given the drawbacks of external drainage via NBC, an alternative method of internal drainage should be explored.展开更多
AIM： To assess histochemical expression of KL-6 and its clinicopathological significance in carcinoma of the ampulla of Vater. METHODS： Ampullary carcinoma tissues were collected from 38 patients who underwent pancr...AIM： To assess histochemical expression of KL-6 and its clinicopathological significance in carcinoma of the ampulla of Vater. METHODS： Ampullary carcinoma tissues were collected from 38 patients who underwent pancreatoduodenectomy or local resection. Tissues were subjected to immunohistochemical analysis using KL-6 antibody. RESULTS： Positive staining of ampullary carcinoma cells was observed in 26 （68.4%） cases. Staining was not found in the surrounding non-cancer regions of the ampullary tissues. Remarkable KL-6 expression was observed in invasive carcinoma cells in pancreatic and duodenal tissues and in metastatic carcinoma cells in lymph nodes. Positive KL-6 expression was related to lymph node metastasis （P = 0.020）, pancreatic invasion （P = 0.016）, duodenal invasion （P = 0.034）, and advanced stage of TNM clinical classification （P = 0.010）. Survival analysis showed that positive expression of KL-6 was related to a poorer prognosis （P = 0.029）. CONCLUSION： The aberrant expression of KL-6 mucin is significantly related to unfavorable behaviors of cardnoma of the ampulla of Vater.展开更多
A 72-year-old woman with a sigmoid colon cancer and a synchronous colorectal liver metastasis(CRLM),which involved the right hepatic vein(RHV)and the inferior vena cava(IVC),was referred to our hospital.The metastatic...A 72-year-old woman with a sigmoid colon cancer and a synchronous colorectal liver metastasis(CRLM),which involved the right hepatic vein(RHV)and the inferior vena cava(IVC),was referred to our hospital.The metastatic lesion was diagnosed as initially unresectable because of its invasion into the confluence of the RHV and IVC.After she had undergone laparoscopic sigmoidectomy for the original tumor,she consequently had 3 courses of modified 5-fluorouracil,leucovorin,and oxaliplatin(m FOLFOX6)plus cetuximab.Computed tomography revealed a partial response,and the confluence of the RHV and IVC got free from cancer invasion.After 3 additional courses of m FOLFOX6 plus cetuximab,preoperative percutaneous transhepatic portal vein embolization(PTPE)was performed to secure the future remnant liver volume.Finally,a right hemihepatectomy was performed.The postoperative course was uneventful.The patient was discharged from the hospital on postoperative day 13.She had neither local recurrence nor distant metastasis 18 mo after the last surgical intervention.This multidisciplinary strategy,consisting of conversion chemotherapy using FOLFOX plus cetuximab and PTPE,could contribute in facilitating curative hepatic resection for initially unresectable CRLM.展开更多
Despite recent advances in surgical techniques and perioperative management, the prognosis of pancreatic cancer(PCa) remains extremely poor. To provide optimal treatment for each patient with Pca, superior biomarkers ...Despite recent advances in surgical techniques and perioperative management, the prognosis of pancreatic cancer(PCa) remains extremely poor. To provide optimal treatment for each patient with Pca, superior biomarkers are urgently needed in all phases of management from early detection to staging, treatment monitoring, and prognosis. In the blood of patients with cancer, circulating tumor cells(CTCs) and cell-free nucleic acids(cf NAs), such as DNA, m RNA, and noncoding RNA have been recognized. In the recent years, their presence in the blood has encouraged researchers to investigate their potential use as novel blood biomarkers, and numerous studies have demonstrated their potential clinical utility as a biomarker for certain types of cancer. This concept, called "liquid biopsy" has been focused on as a less invasive, alternative approach to cancer tissue biopsy for obtaining genetic and epigenetic aberrations that contribute to oncogenesis and cancer progression. In this article, we review the available literature on CTCs and cfN As in patients with cancer, particularly focusing on PCa, and discuss future perspectives in this field.展开更多
Recent advances in localization techniques,such as the selective arterial secretagogue injection test(SASI test) and somatostatin receptor scintigraphy have promoted curative resection surgery for patients with pancre...Recent advances in localization techniques,such as the selective arterial secretagogue injection test(SASI test) and somatostatin receptor scintigraphy have promoted curative resection surgery for patients with pancreatic neuroendocrine tumors(PNET).For patients with sporadic functioning PNET,curative resection surgery has been established by localization with the SASI test using secretin or calcium.For curative resection of functioning PNET associated with multiple endocrine neoplasia type 1(MEN 1) which are usually multiple and sometimes numerous,resection surgery of the pancreas and/or the duodenum has to be performed based on localization by the SASI test.As resection surgery of PNET has increased,several important pathological features of PNET have been revealed.For example,in patients with Zollinger-Ellison syndrome(ZES),duodenal gastrinoma has been detected more frequently than pancreatic gastrinoma,and in patients with MEN 1 and ZES,gastrinomas have been located mostly in the duodenum,and pancreatic gastrinoma has been found to co-exist in 13% of patients.Nonfunctioning PNET in patients with MEN 1 becomes metastatic to the liver when it is more than 1 cm in diameter and should be resected after careful observation.The most important prognos-tic factor in patients with PNET is the development of hepatic metastases.The treatment strategy for hepatic metastases of PNET has not been established and aggressive resection with chemotherapy and trans-arterial chemoembolization have been performed with significant benefit.The usefulness of octreotide treatment and other molecular targeting agents are currently being assessed.展开更多
Bone is one of the preferred sites for the metastasis of malignant tumours,such as breast cancer,lung cancer and malignant melanoma.Tumour cells colonizing bone have the capacity to induce the expression of receptor a...Bone is one of the preferred sites for the metastasis of malignant tumours,such as breast cancer,lung cancer and malignant melanoma.Tumour cells colonizing bone have the capacity to induce the expression of receptor activator of nuclear factor-κB ligand(RANKL),which promotes osteoclast differentiation and activation.Tumour-induced osteoclastic bone resorption leads to a vicious cycle between tumours and bone cells that fuels osteolytic tumour growth,causing bone pain and hypercalcaemia.Furthermore,RANKL contributes to bone metastasis by acting as a chemoattractant to bone for tumour cells that express its receptor,RANK.Thus inhibition of the RANKL–RANK pathway is a promising treatment for bone metastasis,and a human monoclonal anti-RANKL antibody,denosumab,has been used in the clinic.However,orally available drugs targeting RANKL must be developed to increase the therapeutic benefits to patients.Here we report the efficacy of the small-molecule RANKL inhibitor AS2676293 in treating bone metastasis using mouse models.Oral administration of AS2676293 markedly inhibited bone metastasis of human breast cancer cells MDA-MB-231-5a-D-Luc2 as well as tumour-induced osteolysis.AS2676293 suppressed RANKLmediated tumour migration in the transwell assay and inhibited bone metastasis of the murine cell line B16F10,which is known not to trigger osteoclast activation.Based on the results from this study,RANKL inhibition with a small-molecule compound constitutes a promising therapeutic strategy for treating bone metastasis by inhibiting both osteoclastic bone resorption and tumour migration to bone.展开更多
AIM: To test protracted irinotecan infusion plus a low-dose cisplatin in this Phase Ⅱ trial to decrease its toxic-ity. METHODS: The eligibility criteria were: (1) histologi-cally proven measurable gastric cancer; (2)...AIM: To test protracted irinotecan infusion plus a low-dose cisplatin in this Phase Ⅱ trial to decrease its toxic-ity. METHODS: The eligibility criteria were: (1) histologi-cally proven measurable gastric cancer; (2) performance status of 0 or 1; (3) no prior chemotherapy or comple-tion of prior therapy at least 4 wk before enrollment; (4) adequate function of major organs; (5) no other active malignancy; and (6) written informed consent. The regi-men consisted of irinotecan (60 mg/m2) on d 1 and 15 by 24-h infusion and cisplatin (10 mg/m2) on d 1, 2, 3, 15, 16, and 17. Treatment was repeated every 4 wk. RESULTS: Thirty-one patients were registered between April 2000 and January 2001. The response rate for all 31 patients, 20 patients without prior chemotherapy, and 11 patients with prior chemotherapy was 52% (16/31), 60% (12/20), and 36% (4/11), respectively. The median survival time was 378 d. The median number of courses given to all patients was 2. Grade 4 neutropenia oc-curred in 11 (35%) patients, while grade 3 to 4 diarrhea or nausea occurred in 1 (3%) and 3 (10%) patients, respectively. Fatigue was minimal as grade 1 fatigue was found only in 3 (10%) patients. Other adverse events were mild and no treatment-related deaths occurred.CONCLUSION: This regimen showed a high level of ac-tivity and acceptable toxicity in patients with metastatic gastric cancer.展开更多
This report presents a case of highly advanced gastric cancer that achieved a histologically complete response (CR) to preoperative chemoradiotherapy with S-1 plus low-dose Cisplatin. A 60-year-old male patient underw...This report presents a case of highly advanced gastric cancer that achieved a histologically complete response (CR) to preoperative chemoradiotherapy with S-1 plus low-dose Cisplatin. A 60-year-old male patient underwent FDG positron emission tomography (PET) during a routine health examination. The patient was found to have swollen paraaortic lymph nodes. Shortly thereafter, he was diagnosed with gastric carcinoma with a type 2 tumor in the antrum with paraaortic lymph node metastases based on FDG-PET, endoscopic examination and abdominal computed tomography. After the completion of chemoradiation therapy (CRT), the tumor and the paraaortic lymph node metastases disappeared. The patient underwent surgery 5 wk after the completion of CRT, including a subtotal gastrectomy with Rouxen-Y reconstruction, D3 lymph node dissection and a left adrenalectomy. No cancer cells were detected in the resected specimen either in the primary lesion or lymph nodes, thus confirming a pathologically CR to CRT (CR grade 3). The patient has been stable and well without any evidence of recurrence for 48 mo after surgery. Such a preoperative CRT regimen might therefore be very effective for treatment of some advanced gastric cancers.展开更多
The Tohoku Regional Bureau(TRB) of the Ministry of Land, Infrastructure, Transport and Tourism(MLIT) performed various actions in response to the 2011 Great East Japan Earthquake and Tsunami. The total disaster recove...The Tohoku Regional Bureau(TRB) of the Ministry of Land, Infrastructure, Transport and Tourism(MLIT) performed various actions in response to the 2011 Great East Japan Earthquake and Tsunami. The total disaster recovery and reconstruction period is expected to last for 10 years, of which the first five years are regarded as the concentrated reconstruction period. As of 2013, a majority of the mega projects that involved restoration actions have been completed, which indicates a more effective rate of completion compared with the MLIT projects performed in normal non-disaster situations. This short article explains the management process of the recovery and reconstruction utilized by the TRB—an interorganizational process—from a business process management(BPM) perspective and creates a simple organization construction diagram of the entire process. The study focused on the transactions and actor roles to identify their strengths. The findings indicate the utilization of different operational procedures in some parts of the process, the importance of liaison role, as well as some obstacles. The lessons learned from this analysis can assist managers and researchers in designing and managing restoration processes for future disasters.展开更多
AIM： To search for the optimal surgery for gastrinoma and duodenopancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1. METHODS： Sixteen patients with genetically confirmed multiple e...AIM： To search for the optimal surgery for gastrinoma and duodenopancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1. METHODS： Sixteen patients with genetically confirmed multiple endocrine neoplasia type 1 （MEN 1） and Zollinger-Ellison syndrome （ZES） underwent resection of both gastrinomas and duodenopancreatic neuroendocrine tumors （NETs） between 1991 and 2009. For localization of gastrinoma, selective arterial secretagogue injection test （SASI test） with secretin or calcium solution was performed as well as somatostatin receptor scintigraphy （SRS） and other imaging methods such as computed tomography （CT） or magnetic resonance imaging （MRI）. The modus of surgery for gastrinoma has been changed over time, searching for the optimal surgery： pancreaticoduodenectomy （PD） was first performed guided by localization with the SAST test, then local resection of duodenal gastrinomas with dissection of regional lymph nodes （LR）, and recently pancreas-preserving total duodenectomy （PPTD） has been performed for multiple duodenal gastrinomas. RESULTS： Among various types of preoperative localizing methods for gastrinoma, the SASI test was the most useful method. Imaging methods such as SRS or CT made it essentially impossible to differentiate functioning gastrinoma among various kinds of NETs. However, recent imaging methods including SRS or CT were useful for detecting both distant metastases and ectopic NETs; therefore they are indispensable for staging of NETs. Biochemical cure of gastrinoma was achieved in 14 of 16 patients （87.5%）; that is, 100% in 3 patients who underwent PD, 100% in 6 patients who underwent LR （although in 2 patients （33.3%） second LR was performed for recurrence of duodenal gastri- noma）, and 71.4% in 7 patients who underwent PPTD. Pancreatic NETs more than 1 cm in diameter were resected either by distal pancreatectomy or enucleations, and no hepatic metastases have developed postoperatively. Pathological s展开更多
BACKGROUND As the aging population grows worldwide,the rates of endoscopic retrograde cholangiopancreatography(ERCP)for common bile duct stones(CBDS)in older patients with a poor performance status(PS)have been increa...BACKGROUND As the aging population grows worldwide,the rates of endoscopic retrograde cholangiopancreatography(ERCP)for common bile duct stones(CBDS)in older patients with a poor performance status(PS)have been increasing.However,the data on the safety and efficacy of ERCP for CBDS in patients with a PS score of 3 or 4 are lacking,with only a few studies having investigated this issue among patients with poor PS.AIM To examine the safety and efficacy of ERCP for CBDS in patients with a PS score of 3 or 4.METHODS This study utilized a retrospective multi-centered design of three institutions in Japan for 8 years to identify a total of 1343 patients with CBDS having native papillae who underwent therapeutic ERCP.As a result,1113 patients with a PS 0-2 and 230 patients with a PS 3-4 were included.One-to-one propensity-score matching was performed to compare the safety and efficacy of ERCP for CBDS between patients with a PS 0-2 and those with a PS 3-4.RESULTS The overall ERCP-related complication rates in all patients and propensity score-matched patients with a PS 0-2 and 3-4 were 9.0%(100/1113)and 7.0%(16/230;P=0.37),and 4.6%(9/196)and 6.6%(13/196;P=0.51),respectively.In the propensity score-matched patients,complications were significantly more severe in the group with a PS 3-4 than in the group with a PS 0-2 group(P=0.042).Risk factors for complications were indications of ERCP and absence of antibiotics in the multivariate analysis.Therapeutic success rates,including complete CBDS removal and permanent biliary stent placement,in propensity score-matched patients with a PS 0-2 and 3-4 were 97.4%(191/196)and 97.4%(191/196),respectively(P=1.0).CONCLUSION ERCP for CBDS can be effectively performed in patients with a PS 3 or 4.Nevertheless,the indication for ERCP in such patients should be carefully considered with prophylactic antibiotics.展开更多
Longitudinal bone growth relies on endochondral ossification in the cartilaginous growth plate,where chondrocytes accumulate and synthesize the matrix scaffold that is replaced by bone.The chondroprogenitors in the re...Longitudinal bone growth relies on endochondral ossification in the cartilaginous growth plate,where chondrocytes accumulate and synthesize the matrix scaffold that is replaced by bone.The chondroprogenitors in the resting zone maintain the continuous turnover of chondrocytes in the growth plate.Malnutrition is a leading cause of growth retardation in children;however,after recovery from nutrient deprivation,bone growth is accelerated beyond the normal rate,a phenomenon termed catch-up growth.Although nutritional status is a known regulator of long bone growth,it is largely unknown whether and how chondroprogenitor cells respond to deviations in nutrient availability.Here,using fate-mapping analysis in Axin2CreERT2 mice,we showed that dietary restriction increased the number of Axin2+chondroprogenitors in the resting zone and simultaneously inhibited their differentiation.Once nutrient deficiency was resolved,the accumulated chondroprogenitor cells immediately restarted differentiation and formed chondrocyte columns,contributing to accelerated growth.Furthermore,we showed that nutrient deprivation reduced the level of phosphorylated Akt in the resting zone and that exogenous IGF-1 restored the phosphorylated Akt level and stimulated differentiation of the pooled chondroprogenitors,decreasing their numbers.Our study of Axin2CreERT2 revealed that nutrient availability regulates the balance between accumulation and differentiation of chondroprogenitors in the growth plate and further demonstrated that IGF-1 partially mediates this regulation by promoting the committed differentiation of chondroprogenitor cells.展开更多
Background:Antiangiogenic tyrosine kinase inhibitors(TKIs)provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma(HCC).However,patients with HCC often develop resistance toward a...Background:Antiangiogenic tyrosine kinase inhibitors(TKIs)provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma(HCC).However,patients with HCC often develop resistance toward antiangiogenic TKIs,and the underlying mechanisms are not understood.The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC.Methods:We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients.We evaluated the prognosis,therapeutic response,and serum insulin-like growth factor-binding protein-1(IGFBP-1)levels of 31 lenvatinib-treated HCC patients.Based on the array of results,a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted.Additionally,in vivo genetic and pharmacological gain-and loss-of-function experiments were performed.Results:In the patient cohort,IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival.Mechanistically,antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling.IGFBP-1 stimulated angiogenesis through activation of the integrinα5β1-focal adhesion kinase pathway.Consequently,loss of IGFBP-1 and integrinα5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment.Conclusions:Together,our data shed light onmechanisms underlying acquired resistance of HCC to antiangiogenic TKIs.Antiangiogenic TKIs induced an increase of tumor IGFBP-1,which promoted angiogenesis through activating the IGFBP-1-integrinα5β1 pathway.These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.展开更多
AIM: To assess the clinical features of hepatoduodenal lymph node(HDLN) metastasis and to clarify the optimal indication of HDLN dissection.METHODS: We investigated a total of 276 patients who underwent gastrectomy wi...AIM: To assess the clinical features of hepatoduodenal lymph node(HDLN) metastasis and to clarify the optimal indication of HDLN dissection.METHODS: We investigated a total of 276 patients who underwent gastrectomy with extended lymphadenectomy,including HDLN dissection,for gastric cancer between 1999 and 2012. Of these,26 patients(9.4%) had HDLN metastasis. First,we investigated the clinicopathological characteristics,their perioperative clinical outcomes,such as postoperative complications,and prognostic outcomes between patients with and without HDLN metastasis. Second,we detected the prognostic factors,particularly in patients with HDLN metastasis. Third,we assessed the therapeutic value of HDLN dissection to determine its optimal indication.RESULTS: The five-year overall survival rate of the patients with HDLN metastasis was 29%. Univariate and multivariate logistic regression analyses revealed that the tumour location(the middle or lower stomach [P = 0.005,OR = 5.88(95%CI: 1.61-38.1)] and p T category [T3 or T4,P = 0.017,OR = 4.45(95%CI: 1.28-21.3)] were independent risk factors for HDLNmetastasis. Cox proportional hazard analysis identified p N3 as an independent poor prognostic factor in the patients with HDLN metastasis [P = 0.021,HR = 5.17(95%CI: 1.8-292)]. For patients who underwent radical HDLN dissection,HDLN metastasis was a prognostic indicator in p N3 gastric cancer(P < 0.0001),but not p N1-2(P = 0.602). Furthermore,the index of therapeutic value of HDLN dissection for gastric cancer in the middle or lower stomach and the upper stomach was 3.4 and 0.0,respectively.CONCLUSION: We suggest that HDLN dissection should be indicated for p N1 or p N2 gastric cancers located at the middle or lower stomach.展开更多
Pancreatic cancer continues to be a leading cause of cancer-related death worldwide and there is an urgent need to develop novel diagnostic and therapeutic strategies to reduce the mortality of patients with this dise...Pancreatic cancer continues to be a leading cause of cancer-related death worldwide and there is an urgent need to develop novel diagnostic and therapeutic strategies to reduce the mortality of patients with this disease. In pancreatic cancer, some tight junction proteins, including claudins, are abnormally regulated and therefore are promising molecular targets for diagnosis, prognosis and therapy. Claudin-4 and-18 are overexpressed in human pancreatic cancer and its precursor lesions. Claudin-4 is a high affinity receptor of Clostridium perfringens enterotoxin(CPE). The cytotoxic effects of CPE and monoclonal antibodies against claudin-4 are useful as novel therapeutic tools for pancreatic cancer. Claudin-18 could be a putative marker and therapeutic target with prognostic implications for patients with pancreatic cancer. Claudin-1,-7, tricellulin and marvelD3 are involved in epithelial to mesenchymal transition(EMT) of pancreatic cancer cells and thus might be useful as biomarkers during disease. Protein kinase C is closely related to EMT of pancreatic cancer and regulates tight junctions of normal human pancreatic duct epithelial cells and the cancer cells. This review focuses on the regulation of tight junctions via protein kinase C during EMT in human pancreatic cancer for the purpose of developing new diagnostic and therapeutic modalities for pancreatic cancer.展开更多
AIM： To determine the relationship between the subfoveal choroidal thickness（CT） and intraocular pressure（IOP） following idiopathic epiretinal membrane（ERM） surgery.METHODS： Retrospective observational case se...AIM： To determine the relationship between the subfoveal choroidal thickness（CT） and intraocular pressure（IOP） following idiopathic epiretinal membrane（ERM） surgery.METHODS： Retrospective observational case series of patients who had undergone 23-gauge vitrectomy for an ERM. The measurements of CT and IOP were done at the baseline and 1 d, 1 wk, 1, 3, 6, and 12 mo after the surgery.RESULTS： Forty-four eyes of 43 patients with a mean age of 69.8±9.5 y were studied. The CT was 200.8±86.3 μm at the baseline, 210.1±83.5 μm at 1 d, 213.2±85.4 μm at 1 wk, 203.1±84.0 μm at 1 mo, 197.5±85.5 μm at 3 mo, 197.7±84.0 μm at 6 mo, and 191.2±86.8 μm at 12 mo after surgery. The CT on day 1 and week 1 after the surgery was significantly thicker than that at the baseline CT（P=0.0023 and P〈0.0001）. The CT at 12 mo after surgery was significantly thinner than the baseline（P=0.0062）. The IOP on day 1 and week 1 were significantly lower than the baseline（P〈0.0001 and P=0.0042）. The IOP at 1, 3, 6, and 12 mo after surgery were significantly higher than the baseline IOP（P=0.0087, P=0.0023, P〈0.00051, and P〈0.0001）. The rates of changes in the CT between baseline and day 1 and week 1 were significantly and negatively correlated with the rates of change in the IOP（P〈0.0001 and P=0.046）. In the group with the IOP change rate of-30% or less at 1 d postoperatively, the change rate of CT was-21.1% to 31.2%（9.8%±12.4%） and in the group of-29% or more, it was-8.9% to 28.0%（2.6%±8.9%）. The change rate of CT in the group with the IOP change rate of-30% or less was significantly higher than the group of-29% or more（P=0.016）.CONCLUSION： CT increases soon after the ERM surgery which is probably due to the transient hypotony, showing that IOP may be a significant confounding factor for CT.展开更多
Current guidelines for treating asymptomatic common bile duct stones(CBDS)recommend stone removal,with endoscopic retrograde cholangiopan-creatography(ERCP)being the first treatment choice.When deciding on ERCP treatm...Current guidelines for treating asymptomatic common bile duct stones(CBDS)recommend stone removal,with endoscopic retrograde cholangiopan-creatography(ERCP)being the first treatment choice.When deciding on ERCP treatment for asymptomatic CBDS,the risk of ERCP-related complications and outcome of natural history of asymptomatic CBDS should be compared.The incidence rate of ERCP-related complications,particularly of post-ERCP pancreatitis for asymptomatic CBDS,was reportedly higher than that of symptomatic CBDS,increasing the risk of ERCP-related complications for asymptomatic CBDS compared with that previously reported for biliopancreatic diseases.Although studies have reported short-to middle-term outcomes of natural history of asymptomatic CBDS,its long-term natural history is not well known.Till date,there are no prospective studies that determined whether ERCP has a better outcome than no treatment in patients with asymptomatic CBDS or not.No randomized controlled trial has evaluated the risk of early and late ERCP-related complications vs the risk of biliary complications in the wait-and-see approach,suggesting that a change is needed in our perspective on endoscopic treatment for asymptomatic CBDS.Further studies examining long-term complication risks of ERCP and wait-and-see groups for asymptomatic CBDS are warranted to discuss whether routine endoscopic treatment for asymptomatic CBDS is justified or not.展开更多
AIM： To assess whether a 24-wk course of interferon （IFN） could prevent hepatocellular carcinoma （HCC） recurrence and worsening of liver function in patients with hepatitis C virus （HCV）-infected patients after...AIM： To assess whether a 24-wk course of interferon （IFN） could prevent hepatocellular carcinoma （HCC） recurrence and worsening of liver function in patients with hepatitis C virus （HCV）-infected patients after receiving curative treatment for primary HCC.METHODS： Outcomes in 42 patients with HCV infection treated with IFN-α, after curative treatment for primary HCC （IFN group）, were compared with 42 matched curatively treated historical controls not given IFN （non- IFN group）.RESULTS： Although the rate of initial recurrence did not differ significantly between ]FN group and non-IFN group （0%, 44%, 61~, and 67% ys 4.8%, 53~, 81%, and 87% at 1, 3, 5, and 7 years, P = 0.153, respectively）, ]FN group showed a lower rate than the non-IFN group for second recurrence （0%, 10.4%, 28%, and 350/0 ys 0%, 30~ , 59%, and 66% at 1, 3, 5 and 7 years, P = 0.022, respectively）. Among the ]FN group, patients with sustained virologic response （SVR） were less likely to have a second HCC recurrence than ]FN patients without an SVR, or non-IFN patients. Multivariate analysis identified the lack of SVR as the only independent risk factor for a second recurrence, while SVR and Child-Pugh class A independently favored overall survival.CONCLUSION： Most intrahepatic recurrences of HCV-related HCC occurred during persistent viral infection. Eradication of HCV is essential for the prevention of HCC recurrence and improvement of survival.展开更多
文摘Background The earthworm fibrinolytic enzyme （EFE） is a complex protein enzyme that is widely distributed in the earthworm＇s digestive cavity. Possessing strong protein hydrolysis activity, EFE not only has a direct effect on fibrin, but also can activate plasminogen. Its therapeutic and preventative effects on thrombosis-related disease have been confirmed clinically. Recently, there has been increased interest in the anti-tumor activity of EFE. In this study, the anti-tumor activity of EFE, isolated from Eisenia foetida, on human hepatoma cells was evaluated in vitro and in vivo. The potential mechanisms involved were also studied. Methods In vitro experiments were performed in four human hepatoma cell lines： HLE, Huh7, PLC/PRF/5 and HepG2. After treatment with EFE in various concentrations, the inhibition of the rate of cell proliferation was measured. For the in vivo studies, tumor-bearing models xenografted with Huh7 cells were developed in nude mice, and then the mice were fed with EFE once a day for 4 weeks, and the control group received only saline. An inhibitory effect on tumor growth was observed. Also, apoptosis was observed with flow cytometric assay and fluorescent dye staining with acridine orange and ethidium bromide （AO/EB）. The expression of matrix metalloproteinase 2 （MMP-2） were detected by Western blotting assay. Results After treatment with various concentrations of EFE, the proliferation of all hepatoma cell lines was suppressed to varying degrees in vitro. The IC50 for HLE, Huh7, PLC/PCF/5 and HepG2 were 2.11, 5.87, 25.29 and 17.30 uku/ml, respectively. After administration of EFE orally for 4 weeks, the growth of tumor xenograft of Huh7 cells in nude mice was significantly inhibited in vivo. The tumor inhibitory rates in the EFE 500 uku/（kg·d） and 1000 uku/（kg·d） groups were 46.08% （compared with control group, P=0.026） and 57.52% （compared with control group, P=0.002） respectively. Meanwhile, the average weight of body, spleen or thymus did not show any
文摘Hepatocellular carcinoma(HCC), with its high incidence and mortality rate, is one of the most common malignant tumors. Despite recent development of a diagnostic and treatment method, the prognosis of HCC remains poor. Therefore, to provide optimal treatment for each patient with HCC, more precise and effective biomarkers are urgently needed which could facilitate a more detailed individualized decision-making during HCC treatment, including the following; risk assessment, early cancer detection, prediction of treatment or prognostic outcome. In the blood of cancer patients, accumulating evidence about circulating tumor cells and cell-free nucleic acids has suggested their potent clinical utilities as novel biomarker. This concept, so-called "liquid biopsy" is widely known as an alternative approach to cancer tissue biopsy. This method might facilitate a more sensitive diagnosis and better decision-making by obtaining genetic and epigenetic aberrations that are closely associated with cancer initiation and progression. In this article, we review recent developments based on the available literature on both circulating tumor cells and cell-free nucleic acids in cancer patients, especially focusing on Hepatocellular carcinoma.
基金Supported by The grant from the Japanese Foundation for Research and Promotion of Endoscopy,No.12-042
文摘AIM: To determine the optimal method of endoscopic preoperative biliary drainage for malignant distal biliary obstruction.METHODS: Multicenter retrospective study was conducted in patients who underwent plastic stent (PS) or nasobiliary catheter (NBC) placement for resectable malignant distal biliary obstruction followed by surgery between January 2010 and March 2012. Procedure-related adverse events, stent/catheter dysfunction (occlusion or migration of PS/NBC, development of cholangitis, or other conditions that required repeat endoscopic biliary intervention), and jaundice resolution (bilirubin level < 3.0 mg/dL) were evaluated. Cumulative incidence of jaundice resolution and dysfunction of PS/NBC were estimated using competing risk analysis. Patient characteristics and preoperative biliary drainage were also evaluated for association with the time to jaundice resolution and PS/NBC dysfunction using competing risk regression analysis.RESULTS: In total, 419 patients were included in the study (PS, 253 and NBC, 166). Primary cancers included pancreatic cancer in 194 patients (46%), bile duct cancer in 172 (41%), gallbladder cancer in three (1%), and ampullary cancer in 50 (12%). The median serum total bilirubin was 7.8 mg/dL and 324 patients (77%) had ≥ 3.0 mg/dL. During the median time to surgery of 29 d [interquartile range (IQR), 30-39 d]. PS/NBC dysfunction rate was 35% for PS and 18% for NBC [Subdistribution hazard ratio (SHR) = 4.76; 95%CI: 2.44-10.0, P < 0.001]; the pig-tailed tip was a risk factor for PS dysfunction. Jaundice resolution was achieved in 85% of patients and did not depend on the drainage method (PS or NBC).CONCLUSION: PS has insufficient patency for preoperative biliary drainage. Given the drawbacks of external drainage via NBC, an alternative method of internal drainage should be explored.
基金Supported by Grants-in-aid From the Ministry of Education, Science, Sports, and Culture of Japan and a grant for Hi-Tech Research from Tokai University
文摘AIM： To assess histochemical expression of KL-6 and its clinicopathological significance in carcinoma of the ampulla of Vater. METHODS： Ampullary carcinoma tissues were collected from 38 patients who underwent pancreatoduodenectomy or local resection. Tissues were subjected to immunohistochemical analysis using KL-6 antibody. RESULTS： Positive staining of ampullary carcinoma cells was observed in 26 （68.4%） cases. Staining was not found in the surrounding non-cancer regions of the ampullary tissues. Remarkable KL-6 expression was observed in invasive carcinoma cells in pancreatic and duodenal tissues and in metastatic carcinoma cells in lymph nodes. Positive KL-6 expression was related to lymph node metastasis （P = 0.020）, pancreatic invasion （P = 0.016）, duodenal invasion （P = 0.034）, and advanced stage of TNM clinical classification （P = 0.010）. Survival analysis showed that positive expression of KL-6 was related to a poorer prognosis （P = 0.029）. CONCLUSION： The aberrant expression of KL-6 mucin is significantly related to unfavorable behaviors of cardnoma of the ampulla of Vater.
文摘A 72-year-old woman with a sigmoid colon cancer and a synchronous colorectal liver metastasis(CRLM),which involved the right hepatic vein(RHV)and the inferior vena cava(IVC),was referred to our hospital.The metastatic lesion was diagnosed as initially unresectable because of its invasion into the confluence of the RHV and IVC.After she had undergone laparoscopic sigmoidectomy for the original tumor,she consequently had 3 courses of modified 5-fluorouracil,leucovorin,and oxaliplatin(m FOLFOX6)plus cetuximab.Computed tomography revealed a partial response,and the confluence of the RHV and IVC got free from cancer invasion.After 3 additional courses of m FOLFOX6 plus cetuximab,preoperative percutaneous transhepatic portal vein embolization(PTPE)was performed to secure the future remnant liver volume.Finally,a right hemihepatectomy was performed.The postoperative course was uneventful.The patient was discharged from the hospital on postoperative day 13.She had neither local recurrence nor distant metastasis 18 mo after the last surgical intervention.This multidisciplinary strategy,consisting of conversion chemotherapy using FOLFOX plus cetuximab and PTPE,could contribute in facilitating curative hepatic resection for initially unresectable CRLM.
文摘Despite recent advances in surgical techniques and perioperative management, the prognosis of pancreatic cancer(PCa) remains extremely poor. To provide optimal treatment for each patient with Pca, superior biomarkers are urgently needed in all phases of management from early detection to staging, treatment monitoring, and prognosis. In the blood of patients with cancer, circulating tumor cells(CTCs) and cell-free nucleic acids(cf NAs), such as DNA, m RNA, and noncoding RNA have been recognized. In the recent years, their presence in the blood has encouraged researchers to investigate their potential use as novel blood biomarkers, and numerous studies have demonstrated their potential clinical utility as a biomarker for certain types of cancer. This concept, called "liquid biopsy" has been focused on as a less invasive, alternative approach to cancer tissue biopsy for obtaining genetic and epigenetic aberrations that contribute to oncogenesis and cancer progression. In this article, we review the available literature on CTCs and cfN As in patients with cancer, particularly focusing on PCa, and discuss future perspectives in this field.
文摘Recent advances in localization techniques,such as the selective arterial secretagogue injection test(SASI test) and somatostatin receptor scintigraphy have promoted curative resection surgery for patients with pancreatic neuroendocrine tumors(PNET).For patients with sporadic functioning PNET,curative resection surgery has been established by localization with the SASI test using secretin or calcium.For curative resection of functioning PNET associated with multiple endocrine neoplasia type 1(MEN 1) which are usually multiple and sometimes numerous,resection surgery of the pancreas and/or the duodenum has to be performed based on localization by the SASI test.As resection surgery of PNET has increased,several important pathological features of PNET have been revealed.For example,in patients with Zollinger-Ellison syndrome(ZES),duodenal gastrinoma has been detected more frequently than pancreatic gastrinoma,and in patients with MEN 1 and ZES,gastrinomas have been located mostly in the duodenum,and pancreatic gastrinoma has been found to co-exist in 13% of patients.Nonfunctioning PNET in patients with MEN 1 becomes metastatic to the liver when it is more than 1 cm in diameter and should be resected after careful observation.The most important prognos-tic factor in patients with PNET is the development of hepatic metastases.The treatment strategy for hepatic metastases of PNET has not been established and aggressive resection with chemotherapy and trans-arterial chemoembolization have been performed with significant benefit.The usefulness of octreotide treatment and other molecular targeting agents are currently being assessed.
基金partially supported by a grant for Practical Research Project for Rare/Intractable Diseases (JP17ek0109106) from the Japan Agency for Medical Research and Development a Grant-in-Aid for Specially Promoted Research from the Japan Society for Promotion of Science (JSPS) (15H05703)+3 种基金a Grant-in-Aid for Young Scientists A from JSPS (15H05653)a Grantin-Aid for Scientific Research (B) from JSPS (18H02919)a Grant-in-Aid for Challenging Research (Pioneering) from JSPS (17K19582)grants from Mitsui Life Social Welfare Foundation and Kobayashi Foundation for Cancer Research
文摘Bone is one of the preferred sites for the metastasis of malignant tumours,such as breast cancer,lung cancer and malignant melanoma.Tumour cells colonizing bone have the capacity to induce the expression of receptor activator of nuclear factor-κB ligand(RANKL),which promotes osteoclast differentiation and activation.Tumour-induced osteoclastic bone resorption leads to a vicious cycle between tumours and bone cells that fuels osteolytic tumour growth,causing bone pain and hypercalcaemia.Furthermore,RANKL contributes to bone metastasis by acting as a chemoattractant to bone for tumour cells that express its receptor,RANK.Thus inhibition of the RANKL–RANK pathway is a promising treatment for bone metastasis,and a human monoclonal anti-RANKL antibody,denosumab,has been used in the clinic.However,orally available drugs targeting RANKL must be developed to increase the therapeutic benefits to patients.Here we report the efficacy of the small-molecule RANKL inhibitor AS2676293 in treating bone metastasis using mouse models.Oral administration of AS2676293 markedly inhibited bone metastasis of human breast cancer cells MDA-MB-231-5a-D-Luc2 as well as tumour-induced osteolysis.AS2676293 suppressed RANKLmediated tumour migration in the transwell assay and inhibited bone metastasis of the murine cell line B16F10,which is known not to trigger osteoclast activation.Based on the results from this study,RANKL inhibition with a small-molecule compound constitutes a promising therapeutic strategy for treating bone metastasis by inhibiting both osteoclastic bone resorption and tumour migration to bone.
文摘AIM: To test protracted irinotecan infusion plus a low-dose cisplatin in this Phase Ⅱ trial to decrease its toxic-ity. METHODS: The eligibility criteria were: (1) histologi-cally proven measurable gastric cancer; (2) performance status of 0 or 1; (3) no prior chemotherapy or comple-tion of prior therapy at least 4 wk before enrollment; (4) adequate function of major organs; (5) no other active malignancy; and (6) written informed consent. The regi-men consisted of irinotecan (60 mg/m2) on d 1 and 15 by 24-h infusion and cisplatin (10 mg/m2) on d 1, 2, 3, 15, 16, and 17. Treatment was repeated every 4 wk. RESULTS: Thirty-one patients were registered between April 2000 and January 2001. The response rate for all 31 patients, 20 patients without prior chemotherapy, and 11 patients with prior chemotherapy was 52% (16/31), 60% (12/20), and 36% (4/11), respectively. The median survival time was 378 d. The median number of courses given to all patients was 2. Grade 4 neutropenia oc-curred in 11 (35%) patients, while grade 3 to 4 diarrhea or nausea occurred in 1 (3%) and 3 (10%) patients, respectively. Fatigue was minimal as grade 1 fatigue was found only in 3 (10%) patients. Other adverse events were mild and no treatment-related deaths occurred.CONCLUSION: This regimen showed a high level of ac-tivity and acceptable toxicity in patients with metastatic gastric cancer.
文摘This report presents a case of highly advanced gastric cancer that achieved a histologically complete response (CR) to preoperative chemoradiotherapy with S-1 plus low-dose Cisplatin. A 60-year-old male patient underwent FDG positron emission tomography (PET) during a routine health examination. The patient was found to have swollen paraaortic lymph nodes. Shortly thereafter, he was diagnosed with gastric carcinoma with a type 2 tumor in the antrum with paraaortic lymph node metastases based on FDG-PET, endoscopic examination and abdominal computed tomography. After the completion of chemoradiation therapy (CRT), the tumor and the paraaortic lymph node metastases disappeared. The patient underwent surgery 5 wk after the completion of CRT, including a subtotal gastrectomy with Rouxen-Y reconstruction, D3 lymph node dissection and a left adrenalectomy. No cancer cells were detected in the resected specimen either in the primary lesion or lymph nodes, thus confirming a pathologically CR to CRT (CR grade 3). The patient has been stable and well without any evidence of recurrence for 48 mo after surgery. Such a preoperative CRT regimen might therefore be very effective for treatment of some advanced gastric cancers.
文摘The Tohoku Regional Bureau(TRB) of the Ministry of Land, Infrastructure, Transport and Tourism(MLIT) performed various actions in response to the 2011 Great East Japan Earthquake and Tsunami. The total disaster recovery and reconstruction period is expected to last for 10 years, of which the first five years are regarded as the concentrated reconstruction period. As of 2013, a majority of the mega projects that involved restoration actions have been completed, which indicates a more effective rate of completion compared with the MLIT projects performed in normal non-disaster situations. This short article explains the management process of the recovery and reconstruction utilized by the TRB—an interorganizational process—from a business process management(BPM) perspective and creates a simple organization construction diagram of the entire process. The study focused on the transactions and actor roles to identify their strengths. The findings indicate the utilization of different operational procedures in some parts of the process, the importance of liaison role, as well as some obstacles. The lessons learned from this analysis can assist managers and researchers in designing and managing restoration processes for future disasters.
基金Supported by a Health and Labor Sciences Research Grant from the Ministry of Health, Labor and Welfare, Government of Japan (Grant No. H21-Nanchi-Ippan-037)
文摘AIM： To search for the optimal surgery for gastrinoma and duodenopancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1. METHODS： Sixteen patients with genetically confirmed multiple endocrine neoplasia type 1 （MEN 1） and Zollinger-Ellison syndrome （ZES） underwent resection of both gastrinomas and duodenopancreatic neuroendocrine tumors （NETs） between 1991 and 2009. For localization of gastrinoma, selective arterial secretagogue injection test （SASI test） with secretin or calcium solution was performed as well as somatostatin receptor scintigraphy （SRS） and other imaging methods such as computed tomography （CT） or magnetic resonance imaging （MRI）. The modus of surgery for gastrinoma has been changed over time, searching for the optimal surgery： pancreaticoduodenectomy （PD） was first performed guided by localization with the SAST test, then local resection of duodenal gastrinomas with dissection of regional lymph nodes （LR）, and recently pancreas-preserving total duodenectomy （PPTD） has been performed for multiple duodenal gastrinomas. RESULTS： Among various types of preoperative localizing methods for gastrinoma, the SASI test was the most useful method. Imaging methods such as SRS or CT made it essentially impossible to differentiate functioning gastrinoma among various kinds of NETs. However, recent imaging methods including SRS or CT were useful for detecting both distant metastases and ectopic NETs; therefore they are indispensable for staging of NETs. Biochemical cure of gastrinoma was achieved in 14 of 16 patients （87.5%）; that is, 100% in 3 patients who underwent PD, 100% in 6 patients who underwent LR （although in 2 patients （33.3%） second LR was performed for recurrence of duodenal gastri- noma）, and 71.4% in 7 patients who underwent PPTD. Pancreatic NETs more than 1 cm in diameter were resected either by distal pancreatectomy or enucleations, and no hepatic metastases have developed postoperatively. Pathological s
文摘BACKGROUND As the aging population grows worldwide,the rates of endoscopic retrograde cholangiopancreatography(ERCP)for common bile duct stones(CBDS)in older patients with a poor performance status(PS)have been increasing.However,the data on the safety and efficacy of ERCP for CBDS in patients with a PS score of 3 or 4 are lacking,with only a few studies having investigated this issue among patients with poor PS.AIM To examine the safety and efficacy of ERCP for CBDS in patients with a PS score of 3 or 4.METHODS This study utilized a retrospective multi-centered design of three institutions in Japan for 8 years to identify a total of 1343 patients with CBDS having native papillae who underwent therapeutic ERCP.As a result,1113 patients with a PS 0-2 and 230 patients with a PS 3-4 were included.One-to-one propensity-score matching was performed to compare the safety and efficacy of ERCP for CBDS between patients with a PS 0-2 and those with a PS 3-4.RESULTS The overall ERCP-related complication rates in all patients and propensity score-matched patients with a PS 0-2 and 3-4 were 9.0%(100/1113)and 7.0%(16/230;P=0.37),and 4.6%(9/196)and 6.6%(13/196;P=0.51),respectively.In the propensity score-matched patients,complications were significantly more severe in the group with a PS 3-4 than in the group with a PS 0-2 group(P=0.042).Risk factors for complications were indications of ERCP and absence of antibiotics in the multivariate analysis.Therapeutic success rates,including complete CBDS removal and permanent biliary stent placement,in propensity score-matched patients with a PS 0-2 and 3-4 were 97.4%(191/196)and 97.4%(191/196),respectively(P=1.0).CONCLUSION ERCP for CBDS can be effectively performed in patients with a PS 3 or 4.Nevertheless,the indication for ERCP in such patients should be carefully considered with prophylactic antibiotics.
基金partially supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R01AR062908(to MEI),R01AR056837(to MI),R01AR073181(to SO),and R21AR077654(to SO)the departmental fund of the University of Maryland(to MI,ME-I)。
文摘Longitudinal bone growth relies on endochondral ossification in the cartilaginous growth plate,where chondrocytes accumulate and synthesize the matrix scaffold that is replaced by bone.The chondroprogenitors in the resting zone maintain the continuous turnover of chondrocytes in the growth plate.Malnutrition is a leading cause of growth retardation in children;however,after recovery from nutrient deprivation,bone growth is accelerated beyond the normal rate,a phenomenon termed catch-up growth.Although nutritional status is a known regulator of long bone growth,it is largely unknown whether and how chondroprogenitor cells respond to deviations in nutrient availability.Here,using fate-mapping analysis in Axin2CreERT2 mice,we showed that dietary restriction increased the number of Axin2+chondroprogenitors in the resting zone and simultaneously inhibited their differentiation.Once nutrient deficiency was resolved,the accumulated chondroprogenitor cells immediately restarted differentiation and formed chondrocyte columns,contributing to accelerated growth.Furthermore,we showed that nutrient deprivation reduced the level of phosphorylated Akt in the resting zone and that exogenous IGF-1 restored the phosphorylated Akt level and stimulated differentiation of the pooled chondroprogenitors,decreasing their numbers.Our study of Axin2CreERT2 revealed that nutrient availability regulates the balance between accumulation and differentiation of chondroprogenitors in the growth plate and further demonstrated that IGF-1 partially mediates this regulation by promoting the committed differentiation of chondroprogenitor cells.
基金Ishibashi Foundation for the Promotion of ScienceTakeda Science Foundation+3 种基金Shinnihon Foundation of Advanced Medical Treatment Researchthe Kurume University Branding Projectthe Yasuda Medical Foundationthe JSPS KAKENHI grant。
文摘Background:Antiangiogenic tyrosine kinase inhibitors(TKIs)provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma(HCC).However,patients with HCC often develop resistance toward antiangiogenic TKIs,and the underlying mechanisms are not understood.The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC.Methods:We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients.We evaluated the prognosis,therapeutic response,and serum insulin-like growth factor-binding protein-1(IGFBP-1)levels of 31 lenvatinib-treated HCC patients.Based on the array of results,a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted.Additionally,in vivo genetic and pharmacological gain-and loss-of-function experiments were performed.Results:In the patient cohort,IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival.Mechanistically,antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling.IGFBP-1 stimulated angiogenesis through activation of the integrinα5β1-focal adhesion kinase pathway.Consequently,loss of IGFBP-1 and integrinα5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment.Conclusions:Together,our data shed light onmechanisms underlying acquired resistance of HCC to antiangiogenic TKIs.Antiangiogenic TKIs induced an increase of tumor IGFBP-1,which promoted angiogenesis through activating the IGFBP-1-integrinα5β1 pathway.These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.
文摘AIM: To assess the clinical features of hepatoduodenal lymph node(HDLN) metastasis and to clarify the optimal indication of HDLN dissection.METHODS: We investigated a total of 276 patients who underwent gastrectomy with extended lymphadenectomy,including HDLN dissection,for gastric cancer between 1999 and 2012. Of these,26 patients(9.4%) had HDLN metastasis. First,we investigated the clinicopathological characteristics,their perioperative clinical outcomes,such as postoperative complications,and prognostic outcomes between patients with and without HDLN metastasis. Second,we detected the prognostic factors,particularly in patients with HDLN metastasis. Third,we assessed the therapeutic value of HDLN dissection to determine its optimal indication.RESULTS: The five-year overall survival rate of the patients with HDLN metastasis was 29%. Univariate and multivariate logistic regression analyses revealed that the tumour location(the middle or lower stomach [P = 0.005,OR = 5.88(95%CI: 1.61-38.1)] and p T category [T3 or T4,P = 0.017,OR = 4.45(95%CI: 1.28-21.3)] were independent risk factors for HDLNmetastasis. Cox proportional hazard analysis identified p N3 as an independent poor prognostic factor in the patients with HDLN metastasis [P = 0.021,HR = 5.17(95%CI: 1.8-292)]. For patients who underwent radical HDLN dissection,HDLN metastasis was a prognostic indicator in p N3 gastric cancer(P < 0.0001),but not p N1-2(P = 0.602). Furthermore,the index of therapeutic value of HDLN dissection for gastric cancer in the middle or lower stomach and the upper stomach was 3.4 and 0.0,respectively.CONCLUSION: We suggest that HDLN dissection should be indicated for p N1 or p N2 gastric cancers located at the middle or lower stomach.
基金Supported by Ministry of Education,Culture,Sports Science,and Technology,and the Ministry of Health,Labour and Welfare of Japan
文摘Pancreatic cancer continues to be a leading cause of cancer-related death worldwide and there is an urgent need to develop novel diagnostic and therapeutic strategies to reduce the mortality of patients with this disease. In pancreatic cancer, some tight junction proteins, including claudins, are abnormally regulated and therefore are promising molecular targets for diagnosis, prognosis and therapy. Claudin-4 and-18 are overexpressed in human pancreatic cancer and its precursor lesions. Claudin-4 is a high affinity receptor of Clostridium perfringens enterotoxin(CPE). The cytotoxic effects of CPE and monoclonal antibodies against claudin-4 are useful as novel therapeutic tools for pancreatic cancer. Claudin-18 could be a putative marker and therapeutic target with prognostic implications for patients with pancreatic cancer. Claudin-1,-7, tricellulin and marvelD3 are involved in epithelial to mesenchymal transition(EMT) of pancreatic cancer cells and thus might be useful as biomarkers during disease. Protein kinase C is closely related to EMT of pancreatic cancer and regulates tight junctions of normal human pancreatic duct epithelial cells and the cancer cells. This review focuses on the regulation of tight junctions via protein kinase C during EMT in human pancreatic cancer for the purpose of developing new diagnostic and therapeutic modalities for pancreatic cancer.
基金funded by Koureisha Ganshikkan Kenkyu Zaidan in Japan
文摘AIM： To determine the relationship between the subfoveal choroidal thickness（CT） and intraocular pressure（IOP） following idiopathic epiretinal membrane（ERM） surgery.METHODS： Retrospective observational case series of patients who had undergone 23-gauge vitrectomy for an ERM. The measurements of CT and IOP were done at the baseline and 1 d, 1 wk, 1, 3, 6, and 12 mo after the surgery.RESULTS： Forty-four eyes of 43 patients with a mean age of 69.8±9.5 y were studied. The CT was 200.8±86.3 μm at the baseline, 210.1±83.5 μm at 1 d, 213.2±85.4 μm at 1 wk, 203.1±84.0 μm at 1 mo, 197.5±85.5 μm at 3 mo, 197.7±84.0 μm at 6 mo, and 191.2±86.8 μm at 12 mo after surgery. The CT on day 1 and week 1 after the surgery was significantly thicker than that at the baseline CT（P=0.0023 and P〈0.0001）. The CT at 12 mo after surgery was significantly thinner than the baseline（P=0.0062）. The IOP on day 1 and week 1 were significantly lower than the baseline（P〈0.0001 and P=0.0042）. The IOP at 1, 3, 6, and 12 mo after surgery were significantly higher than the baseline IOP（P=0.0087, P=0.0023, P〈0.00051, and P〈0.0001）. The rates of changes in the CT between baseline and day 1 and week 1 were significantly and negatively correlated with the rates of change in the IOP（P〈0.0001 and P=0.046）. In the group with the IOP change rate of-30% or less at 1 d postoperatively, the change rate of CT was-21.1% to 31.2%（9.8%±12.4%） and in the group of-29% or more, it was-8.9% to 28.0%（2.6%±8.9%）. The change rate of CT in the group with the IOP change rate of-30% or less was significantly higher than the group of-29% or more（P=0.016）.CONCLUSION： CT increases soon after the ERM surgery which is probably due to the transient hypotony, showing that IOP may be a significant confounding factor for CT.
文摘Current guidelines for treating asymptomatic common bile duct stones(CBDS)recommend stone removal,with endoscopic retrograde cholangiopan-creatography(ERCP)being the first treatment choice.When deciding on ERCP treatment for asymptomatic CBDS,the risk of ERCP-related complications and outcome of natural history of asymptomatic CBDS should be compared.The incidence rate of ERCP-related complications,particularly of post-ERCP pancreatitis for asymptomatic CBDS,was reportedly higher than that of symptomatic CBDS,increasing the risk of ERCP-related complications for asymptomatic CBDS compared with that previously reported for biliopancreatic diseases.Although studies have reported short-to middle-term outcomes of natural history of asymptomatic CBDS,its long-term natural history is not well known.Till date,there are no prospective studies that determined whether ERCP has a better outcome than no treatment in patients with asymptomatic CBDS or not.No randomized controlled trial has evaluated the risk of early and late ERCP-related complications vs the risk of biliary complications in the wait-and-see approach,suggesting that a change is needed in our perspective on endoscopic treatment for asymptomatic CBDS.Further studies examining long-term complication risks of ERCP and wait-and-see groups for asymptomatic CBDS are warranted to discuss whether routine endoscopic treatment for asymptomatic CBDS is justified or not.
文摘AIM： To assess whether a 24-wk course of interferon （IFN） could prevent hepatocellular carcinoma （HCC） recurrence and worsening of liver function in patients with hepatitis C virus （HCV）-infected patients after receiving curative treatment for primary HCC.METHODS： Outcomes in 42 patients with HCV infection treated with IFN-α, after curative treatment for primary HCC （IFN group）, were compared with 42 matched curatively treated historical controls not given IFN （non- IFN group）.RESULTS： Although the rate of initial recurrence did not differ significantly between ]FN group and non-IFN group （0%, 44%, 61~, and 67% ys 4.8%, 53~, 81%, and 87% at 1, 3, 5, and 7 years, P = 0.153, respectively）, ]FN group showed a lower rate than the non-IFN group for second recurrence （0%, 10.4%, 28%, and 350/0 ys 0%, 30~ , 59%, and 66% at 1, 3, 5 and 7 years, P = 0.022, respectively）. Among the ]FN group, patients with sustained virologic response （SVR） were less likely to have a second HCC recurrence than ]FN patients without an SVR, or non-IFN patients. Multivariate analysis identified the lack of SVR as the only independent risk factor for a second recurrence, while SVR and Child-Pugh class A independently favored overall survival.CONCLUSION： Most intrahepatic recurrences of HCV-related HCC occurred during persistent viral infection. Eradication of HCV is essential for the prevention of HCC recurrence and improvement of survival.
