Masakazu Miyake

Reduced levels of hydroxylated, polyunsaturated ultra long-chain fatty acids in the serum of colorectal cancer patients: implications for early screening and detection

BackgroundThere are currently no accurate serum markers for detecting early risk of colorectal cancer (CRC). We therefore developed a non-targeted metabolomics technology to analyse the serum of pre-treatment CRC patients in order to discover putative metabolic markers associated with CRC. Using tandem-mass spectrometry (MS/MS) high throughput MS technology we evaluated the utility of selected markers and this technology for discriminating between CRC and healthy subjects.MethodsBiomarker discovery was performed using Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). Comprehensive metabolic profiles of CRC patients and controls from three independent populations from different continents (USA and Japan; total n = 222) were obtained and the best inter-study biomarkers determined. The structural characterization of these and related markers was performed using liquid chromatography (LC) MS/MS and nuclear magnetic resonance technologies. Clinical utility evaluations were performed using a targeted high-throughput triple-quadrupole multiple reaction monitoring (TQ-MRM) method for three biomarkers in two further independent populations from the USA and Japan (total n = 220).ResultsComprehensive metabolomic analyses revealed significantly reduced levels of 28-36 carbon-containing hydroxylated polyunsaturated ultra long-chain fatty-acids in all three independent cohorts of CRC patient samples relative to controls. Structure elucidation studies on the C28 molecules revealed two families harbouring specifically two or three hydroxyl substitutions and varying degrees of unsaturation. The TQ-MRM method successfully validated the FTICR-MS results in two further independent studies. In total, biomarkers in five independent populations across two continental regions were evaluated (three populations by FTICR-MS and two by TQ-MRM). The resultant receiver-operator characteristic curve AUCs ranged from 0.85 to 0.98 (average = 0.91 ± 0.04).ConclusionsA novel comprehensive metabolomics technology was used to identify a systemic metabolic dysregulation comprising previously unknown hydroxylated polyunsaturated ultra-long chain fatty acid metabolites in CRC patients. These metabolites are easily measurable in serum and a decrease in their concentration appears to be highly sensitive and specific for the presence of CRC, regardless of ethnic or geographic background. The measurement of these metabolites may represent an additional tool for the early detection and screening of CRC.

An application of the 2-nitrobenzenesulfenyl method to proteomic profiling of human colorectal carcinoma: A novel approach for biomarker discovery.

In the development of novel biomarkers, the proteomic approach is advantageous because using it the cancer‐associated proteins can be directly identified. We previously developed a 2‐nitrobenzenesulfenyl (NBS) method to improve quantitative proteome analysis. Here, we applied this method to proteomic profiling of colorectal carcinoma (CRC) to identify novel proteins with altered expression in CRC. Each pair of tumor and normal tissue specimens from 12 CRC patients was analyzed, and approximately 5000 NBS‐labeled paired peaks were quantified. Peaks with altered signal intensities (>1.5‐fold) and occurring frequently in the samples (>70%) were selected, and 128 proteins were identified by MS/MS analyses as differentially expressed proteins in CRC tissues. Many proteins were newly revealed to be CRC related; 30 were reported in earlier studies of CRC. Six proteins that were up‐regulated in CRC (ZYX, RAN, RCN1, AHCY, LGALS1, and VIM) were further characterized and validated by Western blot and immunohistochemistry. All six were found to be CRC‐localized, either in cancer cells or in stroma cells near the cancer cells. These results indicate that the proteins identified in this study are novel candidates for CRC markers, and that the NBS method is useful in proteome mining to discover novel biomarkers.

Reduction of novel circulating long-chain fatty acids in colorectal cancer patients is independent of tumor burden and correlates with age

BackgroundSerum levels of novel hydroxy polyunsaturated ultra long-chain fatty acids (hPULCFAs) have been previously shown to be reduced in pre-treatment CRC patients compared to disease-free subjects, independent of disease stage. However, whether reduced levels of hPULCFAs result from the presence of cancer is currently unknown, as is the distribution of hPULCFAs in the general population. The following studies were carried out to assess whether conventional therapy would result in restoration of systemic hPULCFAs in CRC patients, and to investigate the relationship between hPULCFA levels and age.MethodsTandem mass spectrometry was used to determine serum levels of the 28 carbon-containing hPULCFA C28H46O4 (CRC-446) in the following cohorts: two independent Japanese CRC populations following surgical tumor removal (n = 86), a North American Caucasian CRC cohort (n = 150) following post-surgery combination chemo/radiation therapy, 990 randomly selected anonymized serum samples from subjects ranging between 11 and 99 years of age, as well as longitudinally collected serum samples from healthy normals (n = 8, up to 90 weeks) and stage IV CRC subjects on combination therapy (n = 12, up to 63 weeks).ResultsSerum CRC-446 levels in CRC subjects were significantly lower than controls (mean of 0.297 ± 0.07 ug/ml in controls versus 0.092 ± 0.03 in CRCs, p < 0.001), and were unaffected by surgical tumor removal or by chemo/radiation treatment (p > 0.05 between pre vs post surgery). CRC-446 levels showed a strong inverse association with age (p < E-11) across the randomly-selected cohort of 990 subjects, with no correlation observed in the CRC-positive subjects. Longitudinal intra-subject results, however, showed relatively stable CRC-446 levels over the short term of up to 90 weeks in both disease-free subjects and late-stage CRC patients.ConclusionsOur findings show that CRC-446 levels are not affected by conventional CRC treatment and inversely correlate with age, which suggest that reduced serum CRC-446 levels likely exist prior to the development of CRC. Extrapolation of the results to a simple screening scenario showed that, compared to fecal blood testing, pre-colonoscopy screening using serum CRC-446 levels would require 80% fewer colonoscopies, would identify risk in subjects under the age of 50, and would result in increased numbers of early cases detected. The precise role these serum metabolites play in the aetiology of cancer development remains to be determined.

Prognostic impact of preoperative NLR and CA19-9 in pancreatic cancer

BACKGROUND Recently, several preoperative proinflammatory markers and nutritional factors such as neutrophil-to-lymphocyte ratio (NLR) and prognostic nutrition index (PNI) have been reported as significant predictor for poor prognosis of various malignant tumors. In this study, we evaluated the prognostic values of these preoperative parameters in patients with resectable pancreatic head cancer. METHODS We retrospectively reviewed consecutive patients who underwent PD for pancreatic head cancer between 2007 and 2012. A total of 46 patients were enrolled in this analysis. Preoperative parameters such as CRP, CA19-9, NLR and PNI at the time of presentation were recorded as well as overall survival. Cancer specific survival was assessed using Kaplan-Meier method. Univariate and multivariate Cox regression models were applied to evaluate the prognostic relevance of preoperative parameters. The correlations between CA19-9 values, NLR and pathological findings, first recurrence site were respectively reviewed. RESULTS In multivariable analysis preoperative high NLR (≧2.7) and high CA19-9 (≧230) were independent prognostic factors for poor survival (P value: 0.03 and 0.025, respectively). Kaplan-Meier survival analysis demonstrated the overall 2-year survival rate in patients with high NLR or high CA19-9 were 37.5% compared with 89.9% in patients with low NLR and low CA19-9. CONCLUSION Preoperative NLR and serum CA19-9 offer significant prognostic information associated with overall survival following PD in the patients with pancreatic head cancer.

Heterogeneity of colorectal cancers and extraction of discriminator gene signatures for personalized prediction of prognosis.

Dissected specimens of colorectal cancer (CRC) have been intensively studied using molecular sketches (gene signatures) to obtain a set of discriminator gene signatures for accurate prognosis prediction in individual patients. The discriminators obtained so far are not universally applicable, as the gene sets reflect the method and site of the study. In this study, we show that dissected stage II and III CRC samples are significantly heterogeneous in molecular sketches, and are not appropriate sources for discriminator extraction unless handled individually. To search for an accurate discriminator gene set for prediction of metastases, we need to start with less heterogeneous stage II CRC. We examined 198 (92 stage II and 106 stage III) CRC dissected samples for the predictability of discriminator gene signatures by analyzing stage II CRC alone, stage III alone, or in combination. The best predictive power of discriminator genes was obtained only when these genes were extracted and validated with stage II CRC samples. An accurate discriminator gene set for the prediction of CRC metastases can be obtained by focusing on stage II CRC samples.

Safety and Efficacy of Palliative Colorectal Stent Placement Using a Nasal Endoscope Technique

The purpose of this study was to evaluate the safety and efficacy of palliative self-expanding metallic stent (SEMS) placement using a nasal endoscope technique in the context of colorectal malignant obstruction. Eighteen patients with malignant colorectal obstruction who underwent palliative SEMS insertion using a nasal endoscope technique at the Toyonaka Municipal Hospital from August 2005 to August 2011 were enrolled and retrospectively analyzed. In all cases, a guidewire could be inserted on the oral side of the tumor. The placement success rate was 94.4% (17/18), and the complication rate was 23.5% (4 cases). The stent migrated in 3 cases, and perforation occurred in 1 case following bevacizumab chemotherapy. These outcomes indicate that stenting is useful for terminal patients and that nasal endoscopy is useful in cases of difficult guidewire placement.

Safety and Efficacy of Fondaparinux for Prophylaxis of Venous Thromboembolism after Colorectal Cancer Resection: A Propensity Score Matched Analysis

Background/Aims: The aim of this study was to examine the safety and efficacy of fondaparinux (FPX) for venous thromboembolism (VTE) prophylaxis after colorectal cancer surgery. Methods: Records of 953 patients with colorectal cancer who underwent resection between 2006 and 2013 were reviewed. Patients were divided into two groups: the FPX group (n = 362), treated with subcutaneous FPX plus intermittent pneumatic compression (IPC) and the IPC group (n = 591), treated with IPC alone. The incidence of symptomatic VTE, major bleeding, minor bleeding, and other postoperative complications were compared using propensity score matching. Results: Symptomatic VTE occurred only in one patient (0.2%) in the IPC group. In the FPX group, the incidence of major and minor bleeding was 0.55% (2 of 362) and 9.4% (34 of 362), respectively. After propensity score matching, there were no differences between the two groups in the incidence of symptomatic VTE, major bleeding, and other common postoperative complications. Only the incidence of minor bleeding was significantly higher in the FPX group compared to the IPC group. Conclusion: FPX is potentially an effective form of VTE prophylaxis; it is safe in terms of both postoperative bleeding and other common complications after colorectal cancer surgery.

Laparoscopic sigmoidectomy in a case of sigmoid colon cancer with situs inversus totalis: Lap sigmoidectomy with situs inversus

Situs inversus totalis (SIT) is a rare anatomic anomaly in which organs in the chest and abdomen exist in a mirror image reversal of their normal positions. SIT can complicate surgical procedures, and few reports have described laparoscopic surgery for colorectal cancer in patients with SIT. Here, we report a case of successful laparoscopic surgery in a patient with SIT and sigmoid colon cancer. Laparoscopic sigmoidectomy involved colonic mobilization with high ligation of the inferior mesenteric vessels and complete mesocolic excision. The operating surgeon stood on the patients left side, opposite the normal location for sigmoidectomy. By placing a 12‐mm trocar in the left iliac fossa and using an automatic endoscopic linear stapler, the operating surgeon was able to perform left‐handed colon resection without having to change position or move the laparoscopic monitor mid‐procedure. An automatic endoscopic linear stapler is useful for laparoscopic left‐side colon surgery in a patient with SIT.

Risk factors for bleeding in patients receiving fondaparinux after colorectal cancer surgery

Objective: The aim of this study was to identify risk factors for bleeding complications in patients who receive Venous thromboembolism (VTE) prophylaxis with fondaparinux (FPX) after colorectal cancer surgery. Methods: Records of 546 patients who underwent VTE prophylaxis with intermittent pneumatic compression and FPX after colorectal cancer surgery between January 2009 and May 2014 were reviewed. Patient characteristics, surgical procedures, and patient laboratory data were examined to identify risk factors for bleeding complications using univariate and multivariate logistic regression. Results: We reviewed the records of 324 males and 222 females. Median age and BMI were 68.5 years and 22.7 kg/m2, respectively. The number of laparoscopic surgeries was 366. Median operative time and blood loss were 188.5 min and 20 ml, respectively. The incidence (%) of bleeding events was 5.3%. In univariate analysis, age ≥80 years, BMI ≥25.0 kg/m2, hypertension, and antithrombotic therapy were associated with a significantly higher incidence of bleeding events. Multivariate analysis identified age ≥80 years (odds ratio 5.814; 95% confidence interval 2.502-13.278) as an independent risk factor. Conclusion: Age ≥80 is a risk factor for bleeding in patients who receive FPX for VTE prophylaxis after colorectal cancer surgery.

Randomized phase II study of mixing steroid to reduce venous pain in patients with colorectal cancer receiving oxaliplatin through peripheral vein (APOLLO study).

474 Background: Although theCapeOX (capecitabine+oxaliplatin) regimen obviates the need for a central venous port, administration of oxaliplatin through peripheral vein can cause venous pain. One of the reasons is pH. The pH level of oxaliplatin solution is about 4.8 and that of buffered by steroid is approximately 7.0. To test the hypothesis that adjusting the pH of oxaliplatin solution by mixing steroid can reduce venous pain, we have conducted the randomized control study to compare pH-adjusted oxaliplatin solution with unadjusted oxaliplatin solution. Methods: This was a single-blinded multicenter randomized phase II study. Colorectal cancer patients receiving oxaliplatin through peripheral vein were enrolled and randomly assigned to arm A (oxaliplatin 130 mg/m2 with dexamethasone (DEX) 2 mg) or arm B (the same, without DEX) (UMIN000004286. Venous pain was evaluated according to CTCAE criteria (ver. 4.0) and the verbal rating scale (VRS). Assessments were conducted every 3 weeks until cycle 4. Results...