Synaptotagmin XIII expression and peritoneal metastasis in gastric cancer.

BACKGROUND: Peritoneal metastasis is a frequent cause of death in patients with gastric cancer. The aim of this study was to identify molecules responsible for mediating peritoneal metastasis of gastric cancer. METHODS: Transcriptome and bioinformatics analyses were conducted to identify molecules associated with peritoneal metastasis. The therapeutic effects of intraperitoneally administered small interfering (si) RNA were evaluated using mouse xenograft models. Expression of mRNA and protein was determined in gastric tissues from patients with gastric cancer. RESULTS: Synaptotagmin XIII (SYT13) was expressed at significantly higher levels in patients with peritoneal recurrence, but not in those with hepatic or distant lymph node recurrence. Inhibition of SYT13 expression in a gastric cancer cell line transfected with SYT13-specific siRNA (siSYT13) was associated with decreased invasion and migration ability of the cells, but not with proliferation and apoptosis. Intraperitoneal administration of siSYT13 significantly inhibited the growth of peritoneal nodules and prolonged survival in mice. In an analysis of 200 patients with gastric cancer, SYT13 expression in primary gastric cancer tissues was significantly greater in patients with peritoneal recurrence or metastasis. A high level of SYT13 expression in primary gastric cancer tissues was an independent risk factor for peritoneal recurrence. CONCLUSION: SYT13 expression in gastric cancer is associated with perioneal metatases and is a potential target for treatment.

Comparative evaluation of new and conventional classifications of magnifying endoscopy with narrow band imaging for invasion depth of superficial esophageal squamous cell carcinoma.

A new classification of magnifying endoscopy with narrow band imaging (ME-NBI) for diagnosing and staging superficial esophageal squamous cell carcinoma (SESCC) was proposed by the Japan Esophageal Society in 2011. This study aimed to compare the new classification with the conventional classifications (Inoue's classification and Arima's classification). This was a prospective analysis of data from a single cancer center involving 151 consecutive patients with 156 SESCCs that were endoscopically or surgically resected. Initially, only ME-NBI images were selected and reviewed independently by three experienced endoscopists. White light imaging (WLI) was then evaluated separately after an interval. The diagnostic performance of each classification and interobserver agreement were assessed, and the WLI findings that affect the diagnosis by the new classification were identified. The specificity for classifying invasive depth as epithelium (EP)/lamina propria mucosae (LPM) confined was higher with the new classification than with Inoue's classification (0.512 vs. 0.349; P = 0.02) and Arima's classification (0.512 vs. 0.279; P < 0.01). However, the sensitivity was lower (0.902 vs. 1.000; P < 0.01) compared with Arima's classification. The concordance rates of three evaluators (κ values) were 0.52 for the new classification, 0.50 for Inoue's classification, and 0.23 for Arima's classification. On multivariate analysis, thickness on WLI independently affected the accuracy of diagnosis with the new classification (OR 3.23; 95%CI, 1.30-8.03). The new classification is superior to conventional classifications with respect to specificity for diagnosing SESCC with depth EP/LPM. Thickness on WLI was a factor negatively affecting the diagnostic performance of the new classification.

Salvage pharyngolaryngectomy with total esophagectomy following definitive chemoradiotherapy.

Historically, total pharyngolaryngectomy with total esophagectomy has been the standard radical surgical treatment for synchronous cancer of the thoracoabdominal esophagus and pharyngolaryngeal region, and for cancer of the cervical esophagus that has invaded as far as the thoracic esophagus. Although definitive chemoradiotherapy that enables preservation of the larynx has often been the first choice of treatment for cancers involving the cervical esophagus, total pharyngolaryngectomy with total esophagectomy is required as a salvage therapy for cases involving failure of complete remission or locoregional recurrence after chemoradiotherapy. However, salvage esophageal surgery after definitive high-dose chemoradiotherapy is generally associated with high morbidity and mortality. The aim of this study was to examine the short-term outcome of salvage total pharyngolaryngectomy with total esophagectomy. From 2001 to 2014, nine patients underwent salvage total pharyngolaryngectomy with total esophagectomy at the Department of Gastroenterological Surgery, Nagoya University. The mortality and morbidity rates were high at 22% and 89%, respectively. Four patients (44%) developed tracheal necrosis, which in two patients eventually led to lethal hemorrhage. Salvage total pharyngolaryngectomy with total esophagectomy is an uncommon and highly demanding surgical procedure that should be carefully planned and conducted in selected centers of excellence. Measures must be taken to preserve the tracheal blood supply, thus avoiding fatal complications.

Detection of serum melanoma-associated antigen D4 in patients with squamous cell carcinoma of the esophagus.

Despite improvements in surgical techniques, perioperative management, and multidisciplinary therapy, treatment outcomes of patients with esophageal squamous cell carcinoma (ESCC) remain poor. Therefore, development of novel molecular biomarkers, which either predict patient survival or become therapeutic targets, is urgently required. In the present study, to facilitate early detection of ESCC and predict its clinical course, we investigated the relationship of the serum level of melanoma-associated antigen (MAGE)-D4 to patients' clinicopathological characteristics. Using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assays, we determined the levels of MAGE-D4 mRNA and protein in cell lysates and conditioned medium of cultures, respectively, of nine ESCC cell lines. Further, we determined MAGE-D4 levels in serum samples collected from 44 patients with ESCC who underwent radical esophagectomy without neoadjuvant therapy as well as from 40 healthy volunteers. Samples of conditioned medium and cell lysates contained comparable levels of MAGE-D4 that correlated closely with the levels of MAGE-D4 mRNA. Preoperative MAGE-D4 levels in the sera of 44 patients with ESCC, which varied from 0 to 2,354 pg/mL (314 ± 505 pg/mL, mean ± standard deviation), were significantly higher compared with those of healthy volunteers. By setting the cutoff at the highest value for healthy volunteers (50 pg/mL), the MAGE-D4-positive group of patients was more likely to have shorter disease-specific and disease-free survival compared with those of the MAGE-D4-negative group, although the differences were not statistically significant. Our results indicate that the elevation of preoperative serum MAGE-D4 levels in some patients with ESCC was possibly caused by excess production of MAGE-D4 by tumor cells followed by its release into the circulation. Clinical implications of serum MAGE-D4 levels should be validated in a large population of patients with ESCC.

Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer.

BACKGROUND: We evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC). PATIENTS AND METHODS: In this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80-120 mg/day S-1 for 2 weeks with 100 mg/m(2) oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60 mg/m(2) cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease. RESULTS: Overall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common ≥grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%). CONCLUSION: SOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS. CLINICAL TRIAL NUMBER: JapicCTI-101021.

Overexpression of melanoma-associated antigen D4 is an independent prognostic factor in squamous cell carcinoma of the esophagus.

To pursue an urgently needed treatment target for esophageal cancer (EC), we investigated the function of the recently discovered melanoma-associated antigen (MAGE)-D4 in squamous cell EC. MAGE-D4 messenger RNA (mRNA) expression was analyzed in nine EC cell lines using quantitative reverse transcription polymerase chain reaction. In 65 surgical specimens of squamous cell EC with no prior neoadjuvant therapy, MAGE-D4 mRNA expression in EC tissues and corresponding normal tissues was analyzed and compared, and evaluated in terms of clinicopathological factors. In representative cases, MAGE-D4 protein distribution was analyzed immunohistochemically. The heterogeneity of MAGE-D4 mRNA expression was confirmed in EC cell lines by quantitative reverse transcription polymerase chain reaction. In surgical specimens, MAGE-D4 mRNA expression was significantly higher in EC tissues than in corresponding normal tissues (P < 0.001). Patients with the highest MAGE-D4 mRNA expression in EC tissues (top quartile, n = 17) had significantly shorter overall survival than patients with low expression (2-year survival: 44% and 73%, respectively, P = 0.006). Univariate analysis identified age (≥65 years), lymphatic involvement, and high MAGE-D4 mRNA expression as significant prognostic factors; high MAGE-D4 mRNA expression was also an independent prognostic factor in multivariable analysis (hazard ratio: 2.194; P = 0.039) and was significantly associated with Brinkman index (P = 0.008) and preoperative carcinoembryonic antigen level (P = 0.002). Immunohistochemical MAGE-D4b expression was consistent with MAGE-D4 mRNA profiling. Our results suggest that MAGE-D4 overexpression influences tumor progression, and MADE-D4 can be a prognostic marker and a potential molecular target in squamous cell EC.

Prospective evaluation of a transnasal endoscopy utilizing flexible spectral imaging color enhancement (FICE) with the Valsalva maneuver for detecting pharyngeal and esophageal cancer.

BACKGROUND/AIMS: This study evaluated the efficacy and safety of transnasal endoscopy (TNE) with flexible spectral imaging color enhancement (FICE) for detection of superficial cancer in the pharyngeal and esophageal regions for high-risk populations. METHODOLOGY: Patients who previously had head and neck or esophageal squamous cell carcinoma were enrolled. Screening was conducted using TNE with conventional white-light endoscopy (WLE) followed by FICE chromoendoscopy. For observation of the pharyngeal region, the Valsalva maneuver was employed. RESULTS: 99 patients were eligible. Six esophageal cancers were detected in four patients (4.0%). The sensitivity, specificity, and accuracy for the detection of cancer were 25.0% (95% CI, 3.4- 71.0), 97.8% (95% CI, 92.1-99.8), and 94.9 % (95% CI, 88.4-98.1), respectively for WLE; 100% (95% CI, 45.4%- 100%), 96.8% (95% CI, 90.7%-99.3%), and 96.9% (95% CI, 89.3%-99.1%), respectively for FICE chromoendoscopy. Pain in the nose and nasal hemorrhage were observed in 3 (3.0%) and 2 patients (2.0%), respectively. Following the Valsalva maneuver, endoscopic scores significantly increased from a mean of 1.1 (0.8-1.4) to 2.0 (1.3-2.6) (p<0.05). CONCLUSIONS: TNE with the Valsalva maneuver is a promising screening method for the pharyngeal and esophageal regions. TNE with FICE chromoendoscopy for detecting pharyngeal and esophageal cancer was more sensitive than WLE.

Particle therapy using carbon ions or protons as a definitive therapy for patients with primary sacral chordoma.

OBJECTIVE: This study retrospectively evaluated the efficacy and toxicity of particle therapy using carbon ions or protons for primary sacral chordomas. METHODS: We evaluated 23 patients with primary sacral chordoma treated with carbon ion therapy (CIT) or proton therapy (PT) between July 2005 and June 2011 at the Hyogo Ion Beam Medical Center, Hyogo, Japan. The median patient age was 72 years. 14 patients were treated with 70.4 Gy equivalents (GyE) in 16 fractions and 9 were treated with 70.4 GyE in 32 fractions. CIT was used for 16 patients, and PT was used for 7 patients. RESULTS: The median follow-up period was 38 months. At 3 years, local control (LC), overall survival (OS) and progression-free survival (PFS) for all patients were 94%, 83% and 68%, respectively. The log-rank test revealed that male sex was significantly related to better PFS (p=0.029). No other factors, including dose fractionation and ion type, were significant for LC, OS or PFS. In nine patients, ≥ Grade 3 acute dermatitis was observed, and ≥ Grade 3 late toxicities were observed in nine patients. The 32-fraction protocol reduced severe toxicities in both the acute and late phases compared with the 16-fraction protocol. CONCLUSION: Particle therapy for patients with sacral chordoma showed favourable LC and OS. Severe toxicities were successfully reduced by modifying the dose fractionation and treatment planning in the later treatment era. Thus, this therapeutic modality should be considered useful and safe. ADVANCES IN KNOWLEDGE: This is the first study including both CIT and PT for sacral chordomas.

Particle therapy for mucosal melanoma of the head and neck. A single-institution retrospective comparison of proton and carbon ion therapy.

PURPOSE: To retrospectively analyze treatment outcomes after particle therapy using protons or carbon ions for mucosal melanoma of the head and neck (HNMM) at the Hyogo Ion Beam Medical Center, as well as to compare proton therapy (PT) and carbon ion therapy (CIT). PATIENTS AND METHODS: Data from 62 HNMM patients without metastasis, treated with PT or CIT between October 2003 and April 2011 were analyzed. Median patient age was 70.5 years (range 33-89 years). Of the total patients, 33 (53 %) had received PT and 29 (47 %) had undergone CIT. Protocols for 65 or 70.2 GyE in 26 fractions were used for both ion types. RESULTS: Median follow-up was 18.0 months (range 5.2-82.7 months). The 1-/2-year overall survival (OS) and local control (LC) rates were 93 %/61 % and 93 %/78 % for all patients, 91 %/44 % and 92 %/71 % for the PT patients and 96 %/62 % and 95 %/59 % for the CIT patients, respectively. No significant differences were observed between PT and CIT. Local recurrence was observed in 8 patients (PT: 5, CIT: 3) and 29 (PT: 18, CIT: 11) experienced distant metastases. Acute reactions were acceptable and all patients completed the planned radiotherapy. Regarding late toxicity, grade 3 or greater events were observed in 5 patients (PT: 3, CIT: 2), but no significant difference was observed between PT and CIT. CONCLUSION: Our single-institution retrospective analysis demonstrated that particle therapy for HNMM achieved good LC, but OS was unsatisfactory. There were no significant differences between PT and CIT in terms of either efficacy or toxicity.

Prospective clinical study of endoscopic ultrasound-guided choledochoduodenostomy with direct metallic stent placement using a forward-viewing echoendoscope.

A prospective clinical study was conducted to evaluate the safety, feasibility, and efficacy of endoscopic ultrasound (EUS)-guided choledochoduodenostomy (CDS) with direct metallic stent placement using a prototype forward-viewing echoendoscope. The indication for EUS - CDS in this study was lower biliary obstruction only, and not failed endoscopic biliary drainage, because the aim was to evaluate EUS - CDS for first-line biliary drainage therapy. The technical and functional success rates were 94 % (17 /18) and 94 % (16 /17), respectively. Early complications (focal peritonitis) were encountered in two patients (11 %). No patients developed late complications. EUS - CDS with direct metallic stent placement using a forward-viewing echoendoscope was generally feasible and effective for malignant distal biliary tract obstruction. The forward-viewing echoendoscope was useful, especially for deploying the metallic stent.

Role of endoscopic ultrasound and endoscopic ultrasound-guided fine-needle aspiration in diagnosing metastasis to the pancreas: a tertiary center experience.

BACKGROUND: Metastasis to the pancreas (MP) is a rare entity that is difficult to identify by imaging alone. Few reports have described endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (FNA) findings. Herein, we try to describe the EUS and EUS-FNA characteristics of MP. METHODS: This retrospective study compared 28 patients with MP (13 males; mean age: 60.1 ± 12.6 years) and 60 control patients (30 males; 62.7 ± 11.5 years) with pancreatic ductal adenocarcinoma (PDAC). All lesions were characterized by EUS, and MP was diagnosed by EUS-FNA (n = 16), surgery (n = 6) or both (n = 6). RESULTS: Multivariate logistic regression revealed that the presence of regular borders (p = 0.004; OR: 8.81, 95% CI: 1.97-39.4), the absence of retention cysts (p = 0.045; OR: 12.5, 95% CI: 1.06-147.0), and the absence of main pancreatic duct (MPD) dilation (p = 0.003; OR: 8.18, 95% CI: 2.04-32.8) were predictors of MP rather than PDAC. The EUS-FNA sampling adequacy was 95.4% (21/22), and the correct diagnosis was obtained in 95.2% (20/21) of cases when K-ras mutation analysis and/or immunostaining were added. CONCLUSION: The presence of regular borders, the absence of retention cysts and the presence of nondilated MPD on EUS indicate MP rather than PDAC. This diagnosis can be accurately confirmed by EUS-FNA with immunostaining and/or K-ras analysis.

FcepsilonRIalpha gene (FCER1A) promoter polymorphisms and total serum IgE levels in Japanese atopic dermatitis patients.

Two promoter polymorphisms of the high-affinity IgE receptor alpha-subunit (FcepsilonRIalpha) gene (FCER1A), -66T>C (rs2251746) and -315C>T (rs2427827), were analysed in Japanese atopic dermatitis subjects. Patients with the -315CT/TT genotype tended to have higher total serum IgE levels, while the proportion of -315CT/TT genotype or the -315T allele was significantly higher in those with highly elevated total serum IgE concentrations.

Role of endoscopic ultrasonography in predicting the response to cyclosporin A in ulcerative colitis refractory to steroids.

BACKGROUND AND AIMS: Although cyclosporin A has been reported to be effective in the treatment of severe ulcerative colitis, factors predicting its therapeutic efficacy remain unclear. Technical progress in endoscopic ultrasonography has improved visualisation of the structure of the colon wall. Here, to assess the value of endoscopic ultrasonography in predicting the response to cyclosporin A treatment, we evaluated the therapeutic effect of cyclosporin A by determining the pre- and post-cyclosporin A thickness of the mucosal layer in the rectum using endoscopic ultrasonography with an ultrasonic catheter probe. PATIENTS AND METHODS: Fifteen ulcerative colitis patients who did not respond to high-doses of corticosteroids were treated with cyclosporin A by continuous intravenous infusion at 4mg/kg/day for 20 days. Before and 20 days after cyclosporin A therapy, clinical disease activity was assessed using clinical activity index scores. Colonoscopy and endoscopic ultrasonography were undertaken before and 20 days after cyclosporin A therapy. RESULTS: Following treatment with cyclosporin A, nine patients showed a decrease in clinical activity index score by six points or more and were defined as responders, while the other six were defined as non-responders. Endoscopic ultrasonography measurement using an ultrasonic catheter probe showed that thickness of the rectal mucosal layer before cyclosporin A was significantly greater in responders than in non-responders (p<0.05). Further, thickness after cyclosporin A was statistically decreased (p<0.01) in the responders but not in the non-responders. CONCLUSIONS: The ultrasonic catheter probe may represent a useful means of predicting and evaluating the efficacy of cyclosporin A treatment in severely ill ulcerative colitis patients.

Insulator-metal phase transition of Pr(0.6)Ca(0.4)MnO(3) studied by x-ray absorption spectroscopy in pulsed magnetic fields.

Evolution of the Mn K-edge x-ray absorption near edge structure (XANES) in Pr(0.6)Ca(0.4)MnO(3) at pulsed magnetic fields has been investigated. A small enhancement of XANES spectra is detected across the magnetic-field-induced transition from the charge- and orbital-ordered (COO) insulator to ferromagnetic metal at 20 K. It is found that the magnetic-field dependence of the enhancement shows clear hysteresis, as seen in the magnetization with metamagnetic transition, suggesting a significant correlation between the change in the XANES and the field-induced collapse of the COO state. The enhancement of the absorption can be explained by an increase of the 4p density of states due to a reduction of hybridization between the 4p state of the central Mn ion with the core hole and the neighboring Mn 3d state. Local structural change around Mn ions is expected to modify the strength of the hybridization.