Portal vein resection using the no-touch technique with a hepatectomy for hilar cholangiocarcinoma.

OBJECTIVES: To assess the safety and feasibility and discuss the oncological impact of a portal vein resection using the no-touch technique with a hepatectomy for locally advanced hilar cholangiocarcinoma. PATIENTS AND METHODS: From 2005 to March 2009, 49 patients with hilar cholangiocarcinoma underwent a major right-sided hepatectomy with curative intent. Portal vein resection was performed using the no-touch technique in 36 patients (PVR group) but the portal vein was not resected in the other 13 patients (NR group). Peri-operative data and histological findings were compared between the two groups. Moreover, tumour recurrence and survival rates after surgery were calculated and compared for each group. RESULTS: Although the tumours of the patients in the PVR group were more locally advanced, the residual tumour status and tumour recurrence rate were similar and there was no significant difference in long-term survival between the two groups: 5-year survival rates in the PVR and NR groups were 59% and 51%, respectively (P = 0.353). In-hospital mortality was encountered in 2 of the 49 patients. CONCLUSION: A portal vein resection using the no-touch technique with a right-sided hepatectomy had a positive impact on survival and is feasible in terms of long-term outcomes with acceptable mortality.

Modified duodenum-preserving pancreas head resection for low-grade malignant lesion in the pancreatic head.

BACKGROUND/OBJECTIVES: Our institution has utilized a duodenum-preserving pancreas head resection (DPPHR) procedure for management of low-grade malignant lesions within the head of the pancreas, but this has resulted in a higher rate of postoperative complications, including pancreatic fistula and ischemic bile duct injury. To avoid these complications we recently modified DPPHR to resect all the parenchyma around the pancreatic head and to preserve the epicholedochal plexus around the bile duct. The goal of this study was to investigate outcomes with postoperative complications and disease control following this modified procedure. METHODS: Twenty-one consecutive patients underwent DPPHR between 1994 and 2011. Patients were retrospectively classified into one of two groups: the conventional DPPHR group (cDPPHR) or the modified DPPHR group (mDPPHR). Perioperative factors and postoperative complications were compared between these two groups. RESULTS: The median age of the 21 patients was 61 (23-77) years, and the median follow-up period was 51 months. Intra-operational blood loss was significantly smaller and duration of hospital stay was significantly shorter in the mDPPHR group than in the cDPPHR group, respectively. The rate of pancreatic fistula was markedly lower in the mDPPHR group (2/13; 15%) than in the cDPPHR group (7/8; 88%) (P = 0.0022). For neoplastic lesions, the surgical margin was negative in all cases, and local recurrence has not occurred in either group. CONCLUSIONS: For selected patients, modified DPPHR may provide clinical benefits in terms of less complications associated with shorter hospital stay.

[Gastric ulcer and duodenal ulcer].

Peptic ulcer diseases are improved by strong acid suppression therapy. However, peptic ulcer diseases are often relapsed after discontinuing of acid suppression therapy. After discovery of Helicobacter pylori (H. pylori) in 1984, H. pylori is known as the strongest causal agent for peptic ulcer diseases. In November 2000, eradication therapy for H. pylori infection was approved under the Japanese system of health insurance. H. pylori eradication reduces ulcer recurrence dramatically. Recently, peptic ulcer diseases induced by NSAIDs and/or aspirin are increasing. In prevention of NSAIDs and/or aspirin induced peptic ulcer recurrence, H. pylori eradication plus PPI treatment is recommended. Several reports described occurrence of newly-developed gastric cancer after H. pylori eradication. Careful follow-up upper gastrointestinal endoscopy is necessary after H. pylori eradication.

The immunological impact of neoadjuvant chemotherapy on the tumor microenvironment of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal cancer is an aggressive cancer with poor prognosis. However, little is known about the immune response in the tumor microenvironment after neoadjuvant chemotherapy. PURPOSE: To investigate the immunological impact of neoadjuvant chemotherapy in the tumor microenvironment of esophageal squamous cell carcinoma. METHODS: Eighteen patients with esophageal squamous cell carcinoma with and without neoadjuvant chemotherapy were analyzed using immunohistochemical methods for human leukocyte antigen (HLA) class I heavy chain, CD4-, CD8-, and Foxp3-positive cell infiltration. RESULTS: The number of CD4 T cells in the stroma and within the cancer nest was significantly higher in the neoadjuvant chemotherapy group. The number of CD8 T cells in the stroma was significantly higher in the neoadjuvant chemotherapy group. HLA class I expression was more downregulated in the control group compared with the neoadjuvant chemotherapy group. CONCLUSION: Neoadjuvant chemotherapy utilizing 5-fluorouracil and cisplatin in esophageal squamous cell carcinoma is useful to induce CD4 and CD8 T lymphocytes in the tumor microenvironment and to maintain HLA class I expression levels in combination with its direct cytotoxic effects.

Continuous proton pump inhibitor treatment decreases upper gastrointestinal bleeding and related death in rural area in Japan.

BACKGROUND AND AIMS: Proton pump inhibitors (PPI) have been rarely used for prevention of upper gastrointestinal bleeding (UGIB) induced by non-steroidal anti-inflammatory drugs (NSAIDs) and/or aspirin in Japan. The increased incidence of UGIB in the aged society is becoming a serious problem. The aim of this study was to retrospectively evaluate whether PPI can prevent UGIB. METHODS: We examined records of 2367 patients (aged 67.9 ± 15.1 years, male 1271) attending the only hospital serving the rural area, with little population movement. We investigated the correlation between the frequency of usage of medicine (PPI, histamine 2 receptor antagonists [H2RA], NSAIDs, aspirin) and incidence of UGIB over 12 years. UGIB was defined as cases with hematemesis and/or melena and definite bleeding at upper gastrointestinal endoscopy. The annual incidence of UGIB of inhabitants (16,065 ± 375.3 persons/year) was evaluated. The frequency of usage of medicine was compared with the total number of patients prescribed any medication (1080 ± 33.2 persons/year). RESULTS: The frequency of PPI usage has increased significantly 4.6%→30.8% (P < 0.05). NSAIDs and aspirin usage increased significantly in the latter half of the survey period (P < 0.05). The annual incidence of UGIB significantly decreased 160.8 →23.6/100,000 inhabitants per annum (P ≤ 0.05) due to widespread use of PPI. No patients died due to UGIB after 2006. The incidence of UGIB and the prevalence of PPI usage were found to have a negative correlation (r = -0.804, P = 0.0016). CONCLUSIONS: By widespread use of PPI, UGIB and related death has declined significantly. This survey showed that continuous PPI treatment decreases UGIB and related death in community medicine.

Evaluation of extra capsular lymph node involvement in patients with extra-hepatic bile duct cancer.

BACKGROUND: Lymph node metastasis is one of the most important prognostic factors for extra-hepatic bile duct carcinoma (ExHBDC). Extra capsular lymph node involvement (ExCLNI) is the extension of cancer cells through the nodal capsule into the perinodal fatty tissue. The prognostic impact of ExCLNI has been shown to be significant mainly in head and neck malignancies. Recently, the prognostic impacts of ExCLNI have evaluated in gastrointestinal malignancies. However no data is available regarding the incidence and prognostic significance of extra-capsular lymph node involvement (ExCLNI) in resectable ExHBDCs. The aim of the present study is first to evaluate the incidence of ExCLNI in surgically-treated ExHBDCs and second, to determine the prognostic impact of ExCLNI in patients with surgically-treated ExHBDCs. METHODS: A total of 228 patients (110 cases of hilar cholangiocarcinoma and 118 cases of distal cholangiocarcinoma) with surgically-treated ExHBDCs were included in this retrospective study. ExCLNI was defined as the extension of cancer cells through the nodal capsule into the perinodal fatty tissue. The existence of ExCLNI and its prognostic value were analyzed as a subgroup of lymph node metastasis. RESULTS: ExCLNI was detected in only 22% of patients with lymph node metastasis of surgically-treated ExHBDC. The presence of ExCLNI correlated with distal cholangiocarcinoma (p = 0.002). On univariate analysis for survival, perineural invasion, vascular invasion, histological grade, and lymph node metastasis were statistically significant factors. On multivariate analysis, only lymph node metastasis was identified as a significant independent prognostic factor in patients with resectable ExHBDC. Subgroups of lymph node metastasis including the presence of ExCLNI, location of lymph node metastasis, and the number of lymph node metastasis had no statistically significant impact on survival. CONCLUSION: ExCLNI was present in only 22% of the LNM (7% of overall patients) in patients with surgical treated ExHBDCs. And ExCLNI would have no impact on the survival of patients with surgically-treated ExHBDCs.

The CD40-CD154 interaction would correlate with proliferation and immune escape in pancreatic ductal adenocarcinoma.

BACKGROUND: CD40 and CD154 are associated with lymphocyte signaling pathways and they are also expressed in some malignant neoplasms, but the significance in pancreatic cancer is unknown. METHODS: Eighty pancreatic cancer specimens were stained immunohistochemically, and the results were correlated with the patients' clinicopathologic features. Subsequently, in vitro analysis of CD40-CD154 signaling was performed. RESULT: Immunohistochemical analysis of tumor cells showed that 29 patients (36.3%) were positive for CD40, and 17 patients (21.3%) had very high CD154 expression. The survival of patients who had very high CD154 expression was significantly better than that of others (P = 0.0198). Univariate and multivariate analysis revealed that very high CD154 expression in cancer cells was not an independent, favorable prognostic factor (risk ratio, 0.493; P = 0.0224). On in vitro proliferation assay, the growth of PK-45P and KP-4 cells was blocked by CD40 and CD154 blocking antibodies. Moreover, on in vitro cytokine assay, Th-2 cytokines from PK-45P and SUIT-2 were blocked by CD40 or CD154 blocking antibody. CONCLUSION: These results suggest that the CD40-CD154 interaction would correlate with cell proliferation and secretion of cytokines in PDAC cells, and CD154 overexpression could be a favorable prognostic factor in PDAC patients.

Trabecular structure and composition analysis of human autogenous bone donor sites using micro-computed tomography.

OBJECTIVES: To evaluate the bone microstructure of autogenous graft bone in elderly people (mean age, 66 years), we compared the bone volume/total volume and bone mineral density of four donor sites that are commonly harvested for maxillofacial surgery and dental implant treatments, using X-ray micro-computed tomography. METHODS: Eighteen Japanese cadavers were included in this study. Overall, 66 harvested bones (mandibular symphysis, mandibular ramus, ilium, and tibia) were studied. Micro-computed tomography scans of four sites were performed to analyze the trabecular structures, bone mineral density, and bone volume/total volume in these bones. RESULTS: The mandibular symphysis bones showed the highest bone volume/total volume and bone mineral density at the four sites. There was a significant difference in the bone volume/total volume between the mandibular symphysis and tibia groups. There was also a significant difference in bone mineral density between the mandibular symphysis group and the ilium and tibia groups. In the three-dimensional observations, the structures of the mandibular trabecular were plate-type. The structures of the tibial bone were mixtures of plate- and rod-types. In the ilium, most trabecula were rod-shaped. CONCLUSIONS: Mandibular symphysis and ramus had a higher bone volume/total volume and bone mineral density of the four sites and did not show regressive changes in our findings. Mandibular bone is the most suitable source of autogenous graft bone material because of its superior bone quality and quantity.

Prognostic impact of regional lymph node micrometastasis in patients with node-negative biliary cancer.

OBJECTIVE: To immunohistochemically identify regional lymph node micrometastases in patients with regional node-negative biliary cancer who underwent curative resection, and to evaluate their clinical significance. SUMMARY BACKGROUND DATA: The clinical significance of immunohistochemically detected lymph node micrometastasis has recently been evaluated in various tumors. However, few reports have focused on this issue with regard to biliary cancer. METHODS: A total of 1421 regional lymph nodes from 151 patients with biliary cancer with negative regional nodes (as determined by conventional methods) were immunostained with antibody against cytokeratins 7 and 8 (CAM5.2). Prognostic impact was evaluated among patients with no metastasis, micrometastasis, and obvious metastasis detected by hematoxylin and eosin staining. Immunostained tumor foci were classified as small micrometastasis or large micrometastasis according to size (above or below 0.2 mm). RESULTS: CAM5.2-positive occult carcinoma cells in regional lymph nodes were detected in 33 (22%) of 151 patients and 49 (3%) of 1421 regional lymph nodes. Small micrometastases were detected in 23 patients, whereas large micrometastases were found in 10 patients. Survival for patients with micrometastasis was significantly worse than that for patients without (P = 0.0051), but was significantly better than that for patients with overt metastasis (P = 0.0092). No significant difference in postoperative survival was seen between patients with small and large micrometastases (P = 0.4221). CONCLUSIONS: Occult cancer cells were present in regional lymph nodes of 22% patients with regional node-negative biliary cancer, and were associated with significantly worse survival. Patients with micrometastases should be treated as carefully as node-positive patients.

Identification of a royal jelly glycoprotein that carries unique complex-type N-glycans harboring the T-antigen (Galß1-3GalNAc) unit.

In this study, we identified a royal jelly glycoprotein (RJG) that carries a unique complex-type N-glycans harboring the T-antigen (Galß1-3GalNAc) unit. The amino acid sequence of the tryptic glycopeptide harboring the T-antigen unit was G-E-S-L-X-K (X might be glycosylated Asn), confirmed in the major royal jelly glycoprotein 1 (MRJP1), which is also expressed in the mushroom body of the honeybee brain.

Adenovirus-mediated eukaryotic initiation factor 4E binding protein-1 in combination with rapamycin inhibits tumor growth of pancreatic ductal adenocarcinoma in vivo.

Over-expression of eIF4E indicates a poor prognosis in different tumors. In the present study, we investigated the frequency of eIF4E, 4E-BP1 and phosphorylated 4E-BP1 expression in PDAC cell lines, gastric carcinoma (GC) cell lines and human embryonic pancreatic cells, as well as gene therapy using translation repressor gene 4E-BP1 in combination with the mTOR inhibitor rapamycin. We also assessed the significance of eIF4E expression in 80 PDAC cases. Combination therapy of adenovirus vector-delivered 4E-BP1 gene and rapamycin was administered to determine their growth inhibition effect in vitro and in vivo in mice. Our study revealed that all PDAC cell lines, GC cell lines and human embryonic pancreas-derived cells expressed the 25-kDa eIF4E protein (MIAPaca-2 cells also expressed the 13-kDa protein 4E-BP1). The 80 PDAC specimens showed a heterogeneous pattern of eIF4E staining. No significant correlation between eIF4E expression and TNM classification was found. Adenovirus vectors Ad-4E-BP1 and Ad-GFP efficiently showed transgenic expression with hyperphosphorylation of 4E-BP1; however, insignificant growth inhibition of the PDAC and GC cell lines was observed. Combination therapy with rapamycin significantly inhibited proliferation and tumor growth in vitro as well as in vivo. Therefore, combination of Ad 4E-BP1 and rapamycin may be a more effective adjuvant therapy.

Activation of placenta-specific transcription factor distal-less homeobox 5 predicts clinical outcome in primary lung cancer patients.

PURPOSE AND EXPERIMENTAL DESIGN: To identify novel biomarkers and therapeutic targets for lung cancers, we screened for genes that were highly transactivated in lung cancers using a cDNA microarray representing 27,648 genes. DLX5 gene, a member of the human distal-less homeobox transcriptional factor family that is expressed during early embryonic development, was found to be overexpressed in the great majority of lung cancers. Tissue microarray consisting of archival non-small cell lung cancer samples from 369 patients was applied to examine the clinicopathologic significance of DLX5 protein. A role of DLX5 in cancer cell growth and/or survival was investigated through small interfering RNA experiments. RESULTS: Northern blot and immunohistochemical analyses detected expression of DLX5 only in placenta among 23 normal tissues examined. Immunohistochemical analysis showed that positive immunostaining of DLX5 was correlated with tumor size (pT classification; P = 0.0053) and poorer prognosis of non-small cell lung cancer patients (P = 0.0045). It was also shown to be an independent prognostic factor (P = 0.0415). Treatment of lung cancer cells with small interfering RNAs for DLX5 effectively knocked down its expression and suppressed cell growth. CONCLUSIONS: These data implied that DLX5 is useful as a target for the development of anticancer drugs and cancer vaccines as well as for a prognostic biomarker in clinic.

Activation of Holliday junction recognizing protein involved in the chromosomal stability and immortality of cancer cells.

We identified a novel gene HJURP (Holliday junction-recognizing protein) whose activation seemed to play a pivotal role in the immortality of cancer cells. HJURP was considered a possible downstream target for ataxia telangiectasia mutated signaling, and its expression was increased by DNA double-strand breaks (DSB). HJURP was involved in the homologous recombination pathway in the DSB repair process through interaction with hMSH5 and NBS1, which is a part of the MRN protein complex. HJURP formed nuclear foci in cells at S phase and those subjected to DNA damage. In vitro assays implied that HJURP bound directly to the Holliday junction and rDNA arrays. Treatment of cancer cells with small interfering RNA (siRNA) against HJURP caused abnormal chromosomal fusions and led to genomic instability and senescence. In addition, HJURP overexpression was observed in a majority of lung cancers and was associated with poor prognosis as well. We suggest that HJURP is an indispensable factor for chromosomal stability in immortalized cancer cells and is a potential novel therapeutic target for the development of anticancer drugs.

Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis.

Through genome-wide gene expression analysis of lung carcinomas, we detected in the great majority of lung cancer samples cotransactivation of cell division cycle associated 8 (CDCA8) and aurora kinase B (AURKB), which were considered to be components of the vertebrate chromosomal passenger complex. Immunohistochemical analysis of lung cancer tissue microarrays showed that overexpression of CDCA8 and AURKB was significantly associated with poor prognosis of lung cancer patients. AURKB directly phosphorylated CDCA8 at Ser(154), Ser(219), Ser(275), and Thr(278) and seemed to stabilize CDCA8 protein in cancer cells. Suppression of CDCA8 expression with small interfering RNA against CDCA8 significantly suppressed the growth of lung cancer cells. In addition, functional inhibition of interaction between CDCA8 and AURKB by a cell-permeable peptide corresponding to 20-amino acid sequence of a part of CDCA8 (11R-CDCA8(261-280)), which included two phosphorylation sites by AURKB, significantly reduced phosphorylation of CDCA8 and resulted in growth suppression of lung cancer cells. Our data imply that selective suppression of the CDCA8-AURKB pathway could be a promising therapeutic strategy for treatment of lung cancer patients.

Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas.

Gene expression profile analysis of lung and esophageal carcinomas revealed that Dikkopf-1 (DKK1) was highly transactivated in the great majority of lung cancers and esophageal squamous cell carcinomas (ESCC). Immunohistochemical staining using tumor tissue microarrays consisting of 279 archived non-small cell lung cancers (NSCLC) and 280 ESCC specimens showed that a high level of DKK1 expression was associated with poor prognosis of patients with NSCLC as well as ESCC, and multivariate analysis confirmed its independent prognostic value for NSCLC. In addition, we identified that exogenous expression of DKK1 increased the migratory activity of mammalian cells, suggesting that DKK1 may play a significant role in progression of human cancer. We established an ELISA system to measure serum levels of DKK1 and found that serum DKK1 levels were significantly higher in lung and esophageal cancer patients than in healthy controls. The proportion of the DKK1-positive cases was 126 of 180 (70.0%) NSCLC, 59 of 85 (69.4%) SCLC, and 51 of 81 (63.0%) ESCC patients, whereas only 10 of 207 (4.8%) healthy volunteers were falsely diagnosed as positive. A combined ELISA assays for both DKK1 and carcinoembryonic antigen increased sensitivity and classified 82.2% of the NSCLC patients as positive whereas only 7.7% of healthy volunteers were falsely diagnosed to be positive. The use of both DKK1 and ProGRP increased sensitivity to detect SCLCs up to 89.4%, whereas false-positive rate in healthy donors was only 6.3%. Our data imply that DKK1 should be useful as a novel diagnostic/prognostic biomarker in clinic and probably as a therapeutic target for lung and esophageal cancer.

Rh(I)-catalyzed reaction of 2-(chloromethyl)phenylboronic acids and alkynes leading to indenes.

The reaction of 2-(chloromethyl)phenylboronic acid (1) with alkynes in the presence of a Rh(I) complex gave indene derivatives in high yields. The regioselectivity depends on the steric nature of the substituent on the alkynes. A bulky group favors the alpha-position of indenes.

Increased expression of insulin-like growth factor-II messenger RNA-binding protein 1 is associated with tumor progression in patients with lung cancer.

PURPOSE: To identify novel biomarkers and therapeutic targets for lung cancers, we screened for genes that were highly transactivated in a large proportion of non-small cell lung cancers (NSCLC) using a cDNA microarray representing 27,648 genes. EXPERIMENTAL DESIGN: A gene encoding insulin-like growth factor-II mRNA-binding protein 1 (IMP-1) was selected as a candidate (> or =3-fold expression than in normal lung tissue in about 70% of NSCLCs). Tumor tissue microarray was applied to examine expression of IMP-1 protein in archival lung cancer samples from 267 patients and investigated its clinicopathologic significance. A role of IMP-1 in cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of IMP-1 on mammalian cells was examined using Matrigel assays. mRNAs associated with IMP-1 in cancer cells were also isolated by RNA immunoprecipitation followed by cDNA microarray analysis. RESULTS: Positive immunostaining of IMP-1 was correlated with male (P = 0.0001), tumor size (P = 0.0003), non-adenocarcinoma histology (P < 0.0001), smoking history (P = 0.0005), non-well-differentiated tumor grade (P = 0.0001), and poor prognosis (P = 0.0053). Suppression of IMP-1 expression with small interfering RNA effectively suppressed growth of NSCLC cells. In addition, we identified that exogenous expression of IMP-1 increased the migratory activity of mammalian cells. IMP-1 was able to bind to mRNAs encoding a variety of proteins involved in signal transduction, cell cycle progression, cell adhesion and cytoskeleton, and various types of enzymatic activities. CONCLUSIONS: These results suggest that IMP-1 expression is likely to play important roles in lung cancer development and progression, and that IMP-1 is a prognostic biomarker and a promising therapeutic target for lung cancer.

Frequency scale for symptoms of gastroesophageal reflux disease predicts the need for addition of prokinetics to proton pump inhibitor therapy.

BACKGROUND AND AIM: Proton pump inhibitor (PPI) monotherapy cannot cure all cases of gastroesophageal reflux disease (GERD), and combination therapy with prokinetics and PPI achieves symptomatic improvement for some GERD patients. Few studies have been performed to predict the need for prokinetics. METHODS: Subjects were 163 patients (64 male, mean age 53.1 +/- 16.6 years) with GERD symptoms. They were evaluated using the frequency scale for the symptoms of GERD (FSSG), a GERD-specific questionnaire developed in Japan(1) and endoscopy. They were administered with rabeprazole 10 mg daily. At 12 and 24 weeks of treatment, subjects were offered a choice of four treatment regimens according to their degree of satisfaction (1, no need for further treatment; 2, opt for continued PPI treatment; 3, step-down to H2RA; 4, dissatisfied with present treatment, so opt for combination treatment with prokinetics, mosapride 5 mg tid). RESULTS: The choice of treatment after 12 weeks of treatment placed 79.1% of subjects in the satisfied group (1, 21; 2, 98; 3, 10). After 24 weeks, 98.2% of subjects were in the satisfied group. Pretreatment FSSG scores were significantly higher in the dissatisfied group (4, 17.4 +/- 1.4) than in the satisfied group (1, 12.3 +/- 1.3; 2, 12.8 +/- 0.8; 3, 10.2 +/- 1.8) (P < 0.05). CONCLUSIONS: The satisfaction rate with these treatment regimens was 98.2% at 24 weeks, suggesting that combination therapy with prokinetics was effective for patients dissatisfied with PPI monotherapy. The FSSG is a useful predictor of the necessity for combination therapy.

High incidence of newly-developed gastroesophageal reflux disease in the Japanese community: a 6-year follow-up study.

BACKGROUND AND AIM: We conducted a community-based study to assess the incidence of newly-developed gastroesophageal reflux disease (GERD). We also analyzed the risk factors of GERD occurrence. METHODS: A total of 322 patients without acid suppression therapy (135 men, mean age: 59.8 years), who lived in the Japanese community, took a QUEST questionnaire (a self-administered questionnaire for the screening of GERD) in 1998. Blood samples were taken for the measurement of an anti-Helicobacter pylori antibody and pepsinogen (PG) I/II to assess the grade of gastric atrophy. Of these patients, 289 scored less than six points and were diagnosed as non-GERD. Two-hundred-and-forty-one patients (95 men, mean age: 67.0 years) took the QUEST questionnaire again in 2004 (after 6 years). The incidence of newly-developed GERD was analyzed. These patients were categorized into three groups based on their initial PG I/II (group A: less than three, group B: three to six, and group C: more than six). The risk factors of GERD occurrence were evaluated. RESULTS: Of the 241 non-GERD patients, 37 patients (15.4%) developed GERD after 6 years. The incidence of newly-developed GERD in group C was significantly higher than both groups A and B (group A: 3.8% [three of 79], group B: 11.8% (11/93), group C: 33.3% (26/69), P < 0.01, respectively). The prevalence of H. pylori negativity, constipation, and medication of Ca antagonists in newly-developed GERD were significantly higher than in those who did not develop GERD. [Correction added after online publication on 1 July 2007: the preceding sentence has replaced one that read 'The prevalence of H. pylori negativity, constipation, and medication of Ca antagonists in newly-developed GERD were significantly higher than in those who did develop GERD.'] CONCLUSION: The incidence of newly-developed GERD in the Japanese community was 16.5% for 6 years. The incidence of newly-developed GERD patients who scored a PG I/II over six was significantly higher than those who scored lower. H. pylori negativity, constipation, and medication of Ca antagonists might be risk factors of GERD occurrence.

Activation of CDCA1-KNTC2, members of centromere protein complex, involved in pulmonary carcinogenesis.

We found cotransactivation of cell division associated 1 (CDCA1) and kinetochore associated 2 (KNTC2), members of the evolutionarily conserved centromere protein complex, in non-small cell lung carcinomas (NSCLC). Immunohistochemical analysis using lung cancer tissue microarray confirmed high levels of CDCA1 and KNTC2 proteins in the great majority of lung cancers of various histologic types. Their elevated expressions were associated with poorer prognosis of NSCLC patients. Knockdown of either CDCA1 or KNTC2 expression with small interfering RNA significantly suppressed growth of NSCLC cells. Furthermore, inhibition of their binding by a cell-permeable peptide carrying the CDCA1-derived 19-amino-acid peptide (11R-CDCA1(398-416)) that correspond to the binding domain to KNTC2 effectively suppressed growth of NSCLC cells. As our data imply that human CDCA1 and KNTC2 seem to fall in the category of cancer-testis antigens, and that their simultaneous up-regulation is a frequent and important feature of cell growth/survival of lung cancer, selective suppression of CDCA1 or KNTC2 activity and/or inhibition of the CDCA1-KNTC2 complex formation could be a promising therapeutic target for treatment of lung cancers.