Search

In recent years there has been undoubted progress in the evaluation and development of targeted agents for non-small cell lung cancer (NSCLC). A major contributor has been the discovery of molecular subtypes harbouring a critical oncogenic driver mutation, specifically sensitizing mutations in the epidermal growth factor receptor (EGFR) gene and the EML4-ALK gene translocation. Radiotherapy is a cornerstone of therapy for the curative intent treatment of early stage, localized disease; and for the palliation of symptoms in advanced, metastatic disease. In this molecular targeted era there is limited understanding of how best to combine targeted agents with radiotherapy and in general clinical studies with radiotherapy have lagged behind studies of targeted agents with chemotherapy. Here we summarise the progress made to date and highlight future directions. [ABSTRACT FROM AUTHOR]

The underutilization of e-learning among university lecturers is an important issue that needs to be resolved. This study aimed to formulate an e-learning postadoption model for Malaysian universities. Data were collected using self-administered questionnaires involving 36 e-learning experts who from lecturers in public and private universities in Malaysia. The data collected was then analyzed using the extent analysis method proposed by Chang ( European Journal of Operational Research, 95 (3), 649-655, 1996) to examine the weights and rankings of the factors and subfactors. This study showed that for e-learning postadoption, the most important factor is institution service quality, followed by system quality, content quality, instructors' characteristics, and learners' characteristics. This study extends the information systems success model into the e-learning postadoption context. In particular, this study offered insights concerning the dependencies among the factors in the model within the Malaysian university context. The findings are useful for the long-range strategic management of university administrators, and the model can be adopted as a reference to form a rating system to analyze e-learning postadoption. University administrators can analyze critical factors that increase e-learning's post adoption and lead to more efficient resource allocation and management of e-learning., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Importance: Return to work after stroke is an important rehabilitation outcome. Vocational rehabilitation may support people with stroke to return to work., Objective: To report the return-to-work rate of people with stroke who completed a local community-based vocational rehabilitation program and to describe the program's impact on their community reintegration., Design: Retrospective database study., Setting: Community-based voluntary welfare organization., Participants: Fifty-eight men and women ages 21 to 55 yr, formally diagnosed with stroke, with no significant cognitive impairment, and fit to undergo rehabilitation., Intervention: A pilot community-based interdisciplinary vocational rehabilitation program implemented between 2014 and 2017. The program included physical rehabilitation, psychosocial support, employment support, and caregiver support services., Outcomes and Measures: Return-to-work rate and community reintegration as measured by the Community Integration Questionnaire (CIQ)., Results: Fifty participants completed the program. Their median age was 44 yr, and most were male (n = 37; 74%). Forty-four participants (88%) returned to work after completing the program. Statistically significant differences (p < .001) were found between their CIQ scores at program enrollment and at completion., Conclusions and Relevance: The program appeared to benefit people with stroke in their return-to-work process. Future studies are recommended to determine the effectiveness of such programs and identify features contributing to their success. Potential implications for occupational therapy practice are that vocational rehabilitation interventions can be initiated earlier, comprehensive return-to-work programs can better address the unique needs of people with stroke, and interdisciplinary evaluations are needed to assess suitability for return to work., What This Article Adds: One of occupational therapy's unique goals is to facilitate performance and participation in valued activities such as work. Occupational therapists can play a pivotal role across the continuum of care to support their clients to explore and achieve their vocational goals after stroke., (Copyright © 2020 by the American Occupational Therapy Association, Inc.)

Background: Many individuals leave costly inpatient detoxification programs prematurely because of the severity of withdrawal symptoms experienced. In the absence of opioid-assisted detoxification in Singapore, diazepam is used to manage withdrawal. However since diazepam is addictive, there is a need to explore the effectiveness of alternative medications., Design and Procedures: The study aimed to examine the safety and efficacy of lofexidine, a non-opiate, non-addictive, alpha 2-adrenergic agonist in assisting opioid detoxification in Singapore, using a randomized, double-blind, investigator-initiated placebo-controlled trial comparing lofexidine against diazepam. Opioid dependent patients (n = 111) were randomized to receive a 10-day course of lofexidine (n = 56) or diazepam (n = 55). The primary endpoint was the Objective Opioid Withdrawal Scale (OOWS) score on days 3 and 4 and secondary outcomes were the Short Opioid Withdrawal Scale (SOWS) score, program retention rate, and ratings of opiate craving., Main Findings: The OOWS, SOWS and opiate craving scores were consistently lower in the lofexidine group relative to the diazepam group over the 14-day study period; however no statistically significant differences were found on days 3 and 4 (peak withdrawal). Changes in mean pupil size during peak withdrawal were significantly smaller in the lofexidine group and more participants in the lofexidine group remained in treatment and completed detoxification., Conclusions: Lofexidine was at least as effective as diazepam in reducing the opioid withdrawal syndrome and increased treatment retention. In addition to its non-addictive and non-abuse properties, lofexidine has several clinical advantages over diazepam. The use of lofexidine is recommended when opioid-assisted medications are not available., (Copyright © 2018 Elsevier Inc. All rights reserved.)

There is increasing preclinical evidence suggesting that metformin, an antidiabetic drug, has anticancer properties against various malignancies, including colorectal cancer. However, the majority of evidence, which was derived from cancer cell lines and xenografts, was likely to overestimate the benefit of metformin because these models are inadequate and require supraphysiologic levels of metformin. Here, we generated patient-derived xenograft (PDX) lines from 2 colorectal cancer patients to assess the properties of metformin and 5-fluorouracil (5-FU), the first-line drug treatment for colorectal cancer. Metformin (150 mg/kg) as a single agent inhibits the growth of both PDX tumors by at least 50% ( P < 0.05) when administered orally for 24 days. In one of the PDX models, metformin given concurrently with 5-FU (25 mg/kg) leads to an 85% ( P = 0.054) growth inhibition. Ex vivo culture of organoids generated from PDX demonstrates that metformin inhibits growth by executing metabolic changes to decrease oxygen consumption and activating AMPK-mediated pathways. In addition, we also performed genetic characterizations of serial PDX samples with corresponding parental tissues from patients using next-generation sequencing (NGS). Our pilot NGS study demonstrates that PDX represents a useful platform for analysis in cancer research because it demonstrates high fidelity with parental tumor. Furthermore, NGS analysis of PDX may be useful to determine genetic identifiers of drug response. This is the first preclinical study using PDX and PDX-derived organoids to investigate the efficacy of metformin in colorectal cancer. Mol Cancer Ther; 16(9); 2035-44. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Studies on circulating tumor cells (CTCs) have largely focused on platform development and CTC enumeration rather than on the genomic characterization of CTCs. To address this, we performed targeted sequencing of CTCs of colorectal cancer patients and compared the mutations with the matched primary tumors. We collected preoperative blood and matched primary tumor samples from 48 colorectal cancer patients. CTCs were isolated using a label-free microfiltration device on a silicon microsieve. Upon whole genome amplification, we performed amplicon-based targeted sequencing on a panel of 39 druggable and frequently mutated genes on both CTCs and fresh-frozen tumor samples. We developed an analysis pipeline to minimize false-positive detection of somatic mutations in amplified DNA. In 60% of the CTC-enriched blood samples, we detected primary tumor matching mutations. We found a significant positive correlation between the allele frequencies of somatic mutations detected in CTCs and abnormal CEA serum level. Strikingly, we found driver mutations and amplifications in cancer and druggable genes such as APC, KRAS, TP53, ERBB3 , FBXW7 and ERBB2 . In addition, we found that CTCs carried mutation signatures that resembled the signatures of their primary tumors. Cumulatively, our study defined genetic signatures and somatic mutation frequency of colorectal CTCs. The identification of druggable mutations in CTCs of preoperative colorectal cancer patients could lead to more timely and focused therapeutic interventions., Competing Interests: CONFLICTS OF INTEREST Axel M Hillmer is an employee of TRON, a not-for-profit company, and receives research funding from GlaxoSmithKline. Bing Lim is an employee of Merck. Wai Min Phyo, Jess Honganh Vo and Min-Han Tan are the employees of Lucence Diagnostics Pte Ltd. The rest of the authors declare that they have no conflicts of interest.

Clusters of tumor cells are often observed in the blood of cancer patients. These structures have been described as malignant entities for more than 50 years, although their comprehensive characterization is lacking. Contrary to current consensus, we demonstrate that a discrete population of circulating cell clusters isolated from the blood of colorectal cancer patients are not cancerous but consist of tumor-derived endothelial cells. These clusters express both epithelial and mesenchymal markers, consistent with previous reports on circulating tumor cell (CTC) phenotyping. However, unlike CTCs, they do not mirror the genetic variations of matched tumors. Transcriptomic analysis of single clusters revealed that these structures exhibit an endothelial phenotype and can be traced back to the tumor endothelium. Further results show that tumor-derived endothelial clusters do not form by coagulation or by outgrowth of single circulating endothelial cells, supporting a direct release of clusters from the tumor vasculature. The isolation and enumeration of these benign clusters distinguished healthy volunteers from treatment-naïve as well as pathological early-stage (≤IIA) colorectal cancer patients with high accuracy, suggesting that tumor-derived circulating endothelial cell clusters could be used as a means of noninvasive screening for colorectal cancer. In contrast to CTCs, tumor-derived endothelial cell clusters may also provide important information about the underlying tumor vasculature at the time of diagnosis, during treatment, and throughout the course of the disease., (Copyright © 2016, American Association for the Advancement of Science.)

Background: The aim of this retrospective study was to assess our experience of 41 patients with anal fistulae treated with video-assisted anal fistula treatment (VAAFT)., Methods: Forty-one consecutive patients with cryptoglandular anal fistulae were included. Patients with low intersphincteric anal fistulae or those with gross perineal abscess were excluded. Eleven (27 %) patients had undergone prior fistula surgery with 5 (12 %) having had three or more previous operations., Results: All patients underwent the diagnostic phase as well as diathermy and curettage of the fistula tracts during VAAFT. Primary healing rate was 70.7 % at a median follow-up of 34 months. Twelve patients recurred or did not heal and underwent a repeat VAAFT procedure utilising various methods of dealing with the internal opening. There was a secondary healing rate of 83 % with two recurrences. Overall, stapling of the internal opening had a 22 % recurrence rate, while anorectal advancement flap had a 75 % failure rate. There was no recurrence seen in six cases after using the over-the-scope-clip (OTSC(®)) system to secure the internal opening., Conclusions: VAAFT is useful in the identification of fistula tracts and enables closure of the internal opening. Adequate closure is essential with the method used to close large or fibrotic internal openings being the determining factor for success or failure. The OTSC system delivered the most consistent result without leaving a substantial perianal wound. Ensuring thorough curettage and drainage of the tract during VAAFT is also important to facilitate healing. We believe that this understanding will bring about a decrease in the high recurrence rates currently seen in many series of anal fistulae.

Inflammatory bowel disease (IBD) was previously thought to be rare in Asia, but emerging data indicate rising incidence and prevalence of IBD in the region. The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology with the goal of developing best management practices, coordinating research, and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis with specific relevance to the Asia-Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis, and management of Crohn's disease. The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses, and treatment availability. It does not intend to be all comprehensive and future revisions are likely to be required in this ever-changing field., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology (APAGE) with the goal of developing best management practices, coordinating research and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis (UC) with specific relevance to the Asia-Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis and management of Crohn's disease (CD). The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses and treatment availability. It does not intend to be all-comprehensive and future revisions are likely to be required in this ever-changing field., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Mutations in oncogenes along the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the resistance to cetuximab in patients with metastatic colorectal cancer (mCRC). However, the relative significance of these mutations based on their frequencies of occurrence in the Singaporean population remains unclear. In the present study, the prevalence of Kirsten rat sarcoma viral oncogene homolog ( KRAS ), v-Raf murine sarcoma viral oncogene homolog B ( BRAF ), phosphoinositide 3-kinase ( PI3K ) and EGFR somatic mutations were determined among Singaporean patients with mCRC. DNA extracted from 45 pairs of surgically resected tumor and normal mucosa samples was subjected to direct sequencing or restriction fragment length polymorphism. Associations of the genetic mutations with various clinicopathological parameters were further explored. Mutations in either codon 12 or 13 of KRAS were confirmed as prominent phenomena among the included Singaporean mCRC patients, at a prevalence comparable with that of Caucasian and patients of other Asian ethnicities [33.3% (90% confidence interval, 21.8-44.9%)]. KRAS mutation was not associated with clinicopathological features, including age, gender and ethnicity of patients, or the tumor site, differentiation and mucinous status. Conversely, the prevalence of BRAF (0%), PI3K (2.2%) and EGFR (0%) mutations were low. The results of the present study indicate that KRAS mutations are prevalent among the studied population, and confirm the low prevalence of BRAF , PI3K and EGFR mutations. KRAS should be prioritized as an investigational gene for future studies of predictive biomarkers of cetuximab response among Singaporean patients with mCRC.

Characterization of genetic alterations in tumor biopsies serves as useful biomarkers in prognosis and treatment management. Circulating tumor cells (CTCs) obtained non-invasively from peripheral blood could serve as a tumor proxy. Using a label-free CTC enrichment strategy that we have established, we aimed to develop sensitive assays for qualitative assessment of tumor genotype in patients. Blood consecutively obtained from 44 patients with local and advanced colorectal cancer and 18 healthy donors were enriched for CTCs using a size-based microsieve technology. To screen for CTC mutations, we established high-resolution melt (HRM) and allele-specific PCR (ASPCR) KRAS-codon 12/13- and BRAF-codon 600- specific assays, and compared the performance with pyrosequencing and Sanger sequencing. For each patient, the resulting CTC genotypes were compared with matched tumor and normal tissues. Both HRM and ASPCR could detect as low as 1.25% KRAS- or BRAF-mutant alleles. HRM detected 14/44 (31.8%) patients with KRAS mutation in CTCs and 5/44 (11.3%) patients having BRAF mutation in CTCs. ASPCR detected KRAS and BRAF mutations in CTCs of 10/44 (22.7%) and 1/44 (2.3%) patients respectively. There was an increased detection of mutation in blood using these two methods. Comparing tumor tissues and CTCs mutation status using HRM, we observed 84.1% concordance in KRAS genotype (p = 0.000129, Fishers' exact test; OR = 38.7, 95% CI = 4.05-369) and 90.9% (p = 0.174) concordance in BRAF genotype. Our results demonstrate that CTC enrichment, coupled with sensitive mutation detection methods, may allow rapid, sensitive and non-invasive assessment of tumor genotype., (Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Suicidality is more commonly reported among individuals with addictions relative to the general population, though data from Asian countries remain scarce. The medical records of 2187 Singaporean patients with drug (n=879), alcohol (n=754) or gambling (n=554) disorders entering an outpatient treatment service were examined to explore differences in suicidal ideation and lifetime attempts between substance and gambling addictions. The relationship between suicidality, co-morbidity and addiction severity were also examined. 25.0% reported thoughts of suicide in the past month, 11.8% had a suicide plan and 12.2% reported lifetime attempts. Rates of suicidal ideation (thoughts, and plan) but not lifetime attempts were significantly higher among gambling than substance use patients. Co-morbid (DSM-IV axis-1) disorders were found among 32.5%, 38% and 40% of those reporting thoughts, plan and lifetime attempts respectively. Addiction severity was higher and quality of life lower among those reporting suicidal behaviors. Logistic regression revealed co-morbidity, debt, gender (being female) and being a gambling patient as significant predictors of suicidal behaviors. The findings highlight the importance of screening for suicidality, even in the absence of co-morbidity, particularly among gambling disorder patients with debts. Suicide risk should be assessed periodically and referral to suicidal prevention interventions routinely offered to this vulnerable population., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The efficacy of psychological approaches for the treatment of pathological gambling has been established in rigorous, tightly-controlled trials and limited to Western populations. To address the dearth of research on Asian pathological gamblers, we examined outcomes after 3 months of treatment for 389 pathological gamblers in Singapore., Methods: Data generated from a treatment outcome monitoring program at a national outpatient service were examined to identify changes in gambling behaviors, problem severity, and quality of life, as well as demographic, clinical, and treatment process predictors of these outcomes after 3 months of treatment. Baseline measures were administered on patients' first visit and repeated at 3-month follow-up (n = 284) together with assessment of treatment satisfaction., Results: The sample was predominantly male (88.2%), Chinese (90.0%) and averaged 39.0 years of age. At 3-month follow-up, quality of life improved, 57.4% reported abstinence, and significant reductions were also observed in frequency and problem severity (all P < 0.001). Significant predictors of clinically meaningful improvement in frequency and problem severity included being a strategic gambler, exposure to gambling after 21 years of age, gambling on more days and self-reported problem seriousness at baseline, and higher treatment satisfaction. Few predictors of quality of life were found., Conclusions: Pathological gamblers in Singapore seem to respond well to psychological treatment. Clinicians may consider more intensive/adjunct approaches for nonstrategic gambling patients, patients with poor motivation, or those with early exposure to gambling given their poorer prognosis. Patient satisfaction (expectations and experience) should also be assessed and managed, viewing progress toward treatment goals to ensure individual needs are met to optimize treatment responses.

Fecal microRNAs (miRNAs) are increasingly explored as non-invasive markers of colorectal cancer (CRC). However, its holistic profile in Asian CRC patients remains elusive. In the present study, the global human fecal miRNAs in Asian Chinese CRC patients was assayed to elucidate novel diagnostic fecal markers. Additionally, the influence of blood in stool on fecal miRNA levels was investigated for the first time. Microarray analysis was applied to profile the fecal miRNAs extracted from CRC patients and healthy subjects. Concurrently, surgically resected tumor and matched normal mucosae were analyzed. Potential fecal miRNA markers were further confirmed using real-time PCR in 17 CRC patients and 28 healthy subjects. Global miRNA profiling uncovered 17 fecal markers (p<0.05) differentially regulated in CRC. Fecal miR-223 and miR-451 represented robust markers in distinguishing CRC patients from healthy subjects, as evident from areas under the receiver operator characteristic curves of 0.939 and 0.971, respectively. Blood in stool affected fecal miR-451, miR-223 and miR-135b levels to a varying extent and substantially impacted the interpretation of the clinical data. Notably, a discrete set of aberrant miRNAs occurred within the tumor, indicating the presence of contributors beyond the exfoliation of tumor cells to the fecal miRNA profile. In summary, the utility of a global miRNA screening approach was successfully demonstrated in elucidating diagnostic markers of CRC. In particular, fecal miR-223 and miR-451 hold promise in detecting CRC.

Germline mutation in the adenomatous polyposis coli (APC) gene causes the majority (80%) of familial adenomatous polyposis (FAP), an autosomal dominantly inherited form of colorectal cancer (CRC). Mutation in 5'end of exon 9 of APC usually results in an attenuated form of FAP (aFAP), characterized by later age of onset and fewer polyps. The presence of exon 9a, an in-frame isoform with exon 8 spliced to 3'end of exon 9, modulates any deleterious effect of the mutation. A third lowly expressed isoform that completely skips exon 9 is present in both healthy individuals and FAP patients. We report here an interesting case of a proband with an APC mutation in 5'end of exon 9 that presented with six synchronous advanced CRCs at age 37. The novel insertion-deletion (indel) at codon 409, c.1226-1229delTTTTinsAAA, caused upregulation of the 'skip exon 9' isoform, r934-1312del, resulting in a premature stop codon at exon 10 and a truncated protein that removed all of the β-catenin (CTNNB1) binding motifs, thus activating the downstream T-cell transcription factor (Tcf) pathway. Exon 9a isoform was concomitantly downregulated. This finding emphasizes the necessity of examining the various isoforms of exon 9 to avoid clinical mismanagement and counseling based on just the mutation site by genomic DNA sequencing alone.

Background: Germline defects of mismatch repair (MMR) genes underlie Lynch Syndrome (LS). We aimed to gain comprehensive genetic and epigenetic profiles of LS families in Singapore, which will facilitate efficient molecular diagnosis of LS in Singapore and the region., Methods: Fifty nine unrelated families were studied. Mutations in exons, splice-site junctions and promoters of five MMR genes were scanned by high resolution melting assay followed by DNA sequencing, large fragment deletions/duplications and promoter methylation in MLH1, MSH2, MSH6 and PMS2 were evaluated by multiplex ligation-dependent probe amplification. Tumor microsatellite instability (MSI) was assessed with five mononucleotide markers and immunohistochemical staining (IHC) was also performed., Results: Pathogenic defects, all confined to MLH1 and MSH2, were identified in 17 out of 59 (28.8%) families. The mutational spectrum was highly heterogeneous and 28 novel variants were identified. One recurrent mutation in MLH1 (c.793C>T) was also observed. 92.9% sensitivity for indication of germline mutations conferred by IHC surpassed 64.3% sensitivity by MSI. Furthermore, 15.6% patients with MSS tumors harbored pathogenic mutations., Conclusions: Among major ethnic groups in Singapore, all pathogenic germline defects were confined to MLH1 and MSH2. Caution should be applied when the Amsterdam criteria and consensus microsatellite marker panel recommended in the revised Bethesda guidelines are applied to the local context. We recommend a screening strategy for the local LS by starting with tumor IHC and the hotspot mutation testing at MLH1 c.793C>T followed by comprehensive mutation scanning in MLH1 and MSH2 prior to proceeding to other MMR genes.

Colorectal cancer (CRC) is a major cause of mortality in many developed countries. Effective screening strategies were called for to facilitate timely detection and to promote a better clinical outcome. In this study, the role of fecal metabonomics in the non-invasive detection of CRC was investigated. Gas chromatography/time-of-flight mass spectrometry (GC/TOFMS) was utilized for the metabolic profiling of feces obtained from 11 CRC patients and 10 healthy subjects. Concurrently, matched tumor and normal mucosae surgically excised from CRC patients were profiled. CRC patients were differentiated clearly from healthy subjects based on their fecal metabonomic profiles (orthogonal partial least squares discriminant analysis [OPLS-DA], 1 predictive and 3 Y-orthogonal components, R (2)X = 0.373, R (2)Y = 0.995, Q (2) [cumulative] = 0.215). The robustness of the OPLS-DA model was demonstrated by an area of 1 under the receiver operator characteristic curve. OPLS-DA revealed fecal marker metabolites (e.g., fructose, linoleic acid, and nicotinic acid) that provided novel insights into the tumorigenesis of CRC. Interestingly, a disparate set of CRC-related metabolic aberrations occurred at the tissue level, implying the contribution of processes beyond the direct shedding of tumor cells to the fecal metabotype. In summary, this work established proof-of-principle for GC/TOFMS-based fecal metabonomic detection of CRC and offered new perspectives on the underlying mechanisms.

Purpose: Changes in tumour 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) uptake during concurrent chemo-radiotherapy in patients with non-small cell lung cancer (NSCLC) have been reported, at variable time points, in two pilot positron emission tomography (PET) studies. The aim of this study was to assess whether FLT changes occur early in response to radiotherapy (RT) without concurrent chemotherapy and whether such changes exceed test-retest variability., Methods: Sixteen patients with NSCLC, scheduled to have radical RT, underwent FLT PET once/twice at baseline to assess reproducibility and/or after 5-11 RT fractions to evaluate response. Primary and nodal malignant lesions were manually delineated on CT and volume, mean and maximum standardized uptake values (SUV(mean) and SUV(max)) estimated. Analysis included descriptive statistics and parameter fitting to a mixed-effects model accounting for patients having different numbers of evaluable lesions., Results: In all, 35 FLT PET scans from 7 patients with a total of 18 lesions and 12 patients with a total of 30 lesions were evaluated for reproducibility and response, respectively. SUV(mean) reproducibility in primary tumours (SD 8.9%) was better than SUV(max) reproducibility (SD 12.6%). In nodes, SUV(mean) and SUV(max) reproducibilities (SD 18.0 and 17.2%) were comparable but worse than for primary tumours. After 5-11 RT fractions, primary tumour SUV(mean) decreased significantly by 25% (p = 0.0001) in the absence of significant volumetric change, whereas metastatic nodes decreased in volume by 31% (p = 0.020) with a larger SUV(mean) decrease of 40% (p < 0.0001). Similar changes were found for SUV(max)., Conclusion: Across this group of NSCLC patients, RT induced an early, significant decrease in lesion FLT uptake exceeding test-retest variability. This effect is variable between patients, appears distinct between primary and metastatic nodal lesions, and in primary tumours is lower than previously reported for concurrent chemo-RT at a similar time point. These results confirm the potential for FLT PET to report early on radiation response and to enhance the clinical development of novel drug-radiation combinations by providing an interpretable, early pharmacodynamic end point.

Background: Colorectal cancer (CRC) in "young" patients under 50 years of age is uncommon. There have been conflicting reports regarding both the clinicopathological features of CRC in young patients and prognosis. The aim of this study was to review and compare the clinical characteristics, prognostic factors, and overall survival of patients in three different age groups (40 years and under, 41-50 years, over 50 years of age) and the prognosis of these patients., Methods: A total of 2,426 consecutive patients who had undergone surgical resection for sporadic colorectal cancer at Singapore General Hospital in the period from 2000 to 2005 were retrieved from a prospectively collected computer database. There were 73 patients (3.0 %) in Group 1 (40 years old or less), 257 (10.6 %) in Group 2 (41-50 years old), and 2,096 (86.4 %) in Group 3 (>50 years old). Clinicopathological features were assessed using univariate analysis to evaluate significant differences, survival curves were constructed using the Kaplan-Meier method, and multivariate analysis was performed to evaluate the independent prognostic factors., Results: Young CRC patients tend to present with a higher incidence of mucinous and signet ring cell tumors (Group 1-20.5 %, Group 2-8.2 %, Group 3-6.2 %, p < 0.001) and have more poorly differentiated tumors (Group 1-20.0 %, Group 2-9.7 %, Group 3-7.4 %, p = 0.014). Furthermore, young CRC patients tend to present with regional lymph node metastases (Group 1-65.7 %, Group 2-60.8 %, Group 3-51.0 %, p = 0.001) and distant metastases (Group 1-31.5 %, Group 2-24.1 %, Group 3-19.4 %, p = 0.006). Multivariate analysis reveals, however, that young age is not an independent prognostic factor for cancer-specific survival (CSS) (p = 0.392). Five-year CSS for Group 1 was 56.6 % (95 % confidence interval (CI) 44.8-68.4 %), Group 2 53.8 % (95 % CI 47.3-60.3 %), and Group 3 61.1 % (95 % CI 58.9-63.3 %)., Conclusions: Although presenting with advanced tumors and with poorer prognostic factors such as presence of mucin and poor histological differentiation, young CRC patients do not have a worse prognosis.

Gas chromatography mass spectrometry (GC/MS)-based fecal metabonomics represents a powerful systems biology approach for elucidating metabolic biomarkers of lower gastrointestinal tract (GIT) diseases. Unlike metabolic profiling of fecal water, the profiling of complete fecal material remains under-explored. Here, a gas chromatography/time-of-flight mass spectrometry (GC/TOFMS) method was developed and validated for the global metabonomic profiling of human feces. Fecal and fecal water metabotypes were also profiled and compared. Additionally, the unclear influence of blood in stool on the fecal metabotype was investigated unprecedentedly. Eighty milligram of lyophilized feces was ultrasonicated with 1mL of methanol:water (8:2) for 30min, followed by centrifugation, drying of supernatant, oximation and trimethylsilylation for 45min. Lyophilized feces demonstrated a more comprehensive metabolic coverage than fecal water, based on the number of chromatographic peaks. Principal component analysis (PCA) indicated occult blood (1mgHb/g feces) exerted a negligible effect on the fecal metabotype. Conversely, a unique metabotype related to feces spiked with gross blood (100mgHb/g feces) was revealed (PCA, R(2)X=0.837, Q(2)=0.794), confirming the potential confounding effect of gross GIT bleeding on the fecal metabotype. This pertinent finding highlights the importance of prudent interpretation of fecal metabonomic data, particularly in GIT diseases where bleeding is prevalent., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: The incidence of mismatch repair deficiency in colorectal cancer (CRC) in young people remains unknown in Asians. The present study assessed the clinicopathological features and efficacy of immunohistochemistry screening for Lynch syndrome in young Asian CRC patients., Material and Methods: This was a retrospective review conducted in Singapore General Hospital between January 2006 and December 2010 of 240 unrelated patients under the age of 50. All patients had immunohistochemical (IHC) staining for mismatch repair proteins in resected CRC specimen data retrieved from a prospective computerized database., Results: A total of 21 % (n = 51) of the patients had abnormal IHC staining. Loss of staining for MLH1, MSH2, MSH6, and PMS2 proteins was observed in 10, 4, 6, and 13 % of tumors, respectively. Of the 22 patients who had abnormal staining of MLH1, 13 had concomitant abnormal staining for PMS2. One tumor specimen had abnormal staining in all four proteins. If the Amsterdam criteria alone were to be used, 86 % (n = 44) of the cohort would have not been detected for mismatch repair gene defects., Conclusions: The overall burden of germline mismatch repair deficiency in the Singapore population may be as high as 21 %. The Amsterdam criteria alone are inadequate to detect Lynch syndrome patients. The use of IHC staining of at least four mismatch repair proteins is a useful screening strategy for Lynch syndrome diagnosis. Routine screening of mismatch repair deficiency may be recommended for all young Asian CRC patients.

Introduction and Aims: Evidence of treatment effectiveness for alcohol use disorders (AUD) have emerged predominantly from Western studies, using highly controlled trials that may not reflect real-world settings. This paper examines treatment outcome and its predictors among Asian problem drinkers participating in a treatment outcome monitoring program at an addiction treatment centre in Singapore., Design and Methods: Data were collected at intake and 3, 6 and 12 months, although the focus of this paper is on reliable change at 3 months among the 70% who were followed up. Five hundred and forty-one AUD-diagnosed outpatients presenting for treatment, over a 2-year period, were assessed on drinking behaviours and administered the Addiction Severity Index-Lite, Personal Wellbeing Index (PWI) and Treatment Perceptions Questionnaire., Results: At 3 months, drinking days, alcohol units and alcohol use severity had more than halved and 69% were either abstinent or had reliably reduced their drinking days. Baseline drinking days and treatment satisfaction predicted 3-month drinking frequency but not severity. Positive alcohol outcomes observed at 3 months were sustained among those followed up until 12 months. Mean PWI score improved significantly and fell within the 'normal' range. Treatment satisfaction also emerged as the only significant predictor of reliable positive change in both drinking days and PWI score., Discussion and Conclusions: Significant reductions in drinking frequency and severity are possible for Asian problem drinkers after 12 weeks of outpatient treatment. The identified predictors suggest that more frequent drinkers and patients with past/current psychiatric comorbidities may require a more intensive treatment approach to optimise treatment outcomes., (© 2012 Australasian Professional Society on Alcohol and other Drugs.)

Resistance to 5-fluorouracil (5FU) poses a constant challenge to the management of colorectal cancer (CRC). Consistent efforts were called for to identify molecular markers that can effectively predict patients' response. This study investigated the role of nucleoside transporters, particularly human equilibrative nucleoside transporter 1 (hENT1), in predicting clinical treatment outcome with 5FU-based therapy. Expression of a panel of nucleoside transporters in biopsied tumors from 7 CRC patients was measured by real-time PCR prior to 5FU-based chemotherapy. To provide mechanistic support for the role of hENT1 in 5FU resistance, cell viability of Caco-2 cells was measured, following incubation with varying concentrations of 5FU and a hENT1 inhibitor. Biopsied tumors were further subjected to global metabonomic profiling using gas chromatography/mass spectrometry. High hENT1 levels in tumor tissue correlated with poor clinical response to 5FU. Corroborating with the clinical findings, chemical inhibition of hENT1 in Caco-2 cells resulted in an augmentation of 5FU efficacy. Metabonomic profiling revealed that the pretreatment metabotype associated with non-responders to 5FU therapy was distinct from metabotype of responders (partial least-squares discriminant analysis Q(2) (cumulative) = 0.898, R(2)X = 0.513, R(2)Y = 0.996). This is the first clinical report on the relationships of intratumoral expression of nucleoside transporters and tumor metabotype with response to 5FU among CRC patients. Coupled to the in vitro findings, our preliminary data suggested hENT1 to be a potential codeterminant of clinical response to 5FU.

Well-established clinicopathological variables used in the risk stratification of gastrointestinal stromal tumor (GIST) may not completely predict rectal GIST, an uncommon and poorly studied GIST subset. The aim of the present study was to determine the patterns of relapse and morbidities associated with recurrence in rectal GIST. A single-institution retrospective study between 2002 and 2011 was conducted, identifying 9 patients (8%) with localized rectal GIST, while comparing small intestinal (n=37) and gastric (n=63) GIST (median age, 60 years). Rectal GIST tumors were smaller compared to small intestinal/gastric GIST (P=0.044). The number of mitoses per 50 high-power field (HPF) did not differ by primary site. In general, 73% of patients were high-risk, as defined by the National Institutes of Health (NIH) consensus criteria, however, only 25% received adjuvant imatinib. Fewer rectal GIST patients achieved negative surgical margins compared to small intestinal/gastric GIST (67 vs. 92%; P=0.054). Of the 9 patients with localized rectal GIST 6 had peri-operative tumor rupture, anastomotic breakdown or required anal sphincter-compromising surgery. At the time of the first relapse, 83% of the recurrences were local failures for rectal GIST, compared to 21% for small intestinal/gastric GIST (P=0.005). The median relapse-free survival was 51 months for the entire cohort, and 54, 36 and 56 months for rectal, small intestinal and gastric GIST, respectively (P=0.468). Rectal GIST was found to be associated with high rates of local relapse and significant morbidity, despite being significantly smaller compared to GIST of other sites. A multimodality peri-operative therapeutic approach may be required to improve outcomes.

Colorectal cancer (CRC) is the most common cancer in Singapore. We sought to evaluate the long-term cost-effectiveness of targeted genetic testing and surveillance programs in individuals at high risk of hereditary non-polyposis colorectal cancer (HNPCC), as compared to an unselective clinical surveillance program alone in Singapore. A Markov model analysis from the healthcare service provider's perspective was developed to follow over a lifetime a cohort of cancer-free 21-year-old individuals, who were first-degree relatives of HNPCC patients with a known mutation. Genetic testing strategy provided a lifetime saving of Singapore dollars (SGD) 13,588 per person and gained additional life years of 0.01, as compared to clinical surveillance alone, by sparing non-mutation carriers from unnecessary and invasive intensive clinical surveillance (assuming 100% compliance with recommended surveillance programs in both strategies). Sensitivity analyses showed that as long as the compliance rate in mutation carriers was not lower than that for individuals without genetic testing, pursuing a genetic testing strategy would either be a more favorable option with discounted incremental cost-effectiveness ratios ranging from SGD 6,961 to 17,289 per life year gained or a dominant status achieved (more life year gained and less costly). Genetic testing for individuals at high risk of HNPCC allows targeted clinical surveillance to be directed at mutation carriers, ensuring efficient use of healthcare resources and reduces CRC-related mortality. It can be regarded as a cost-effective strategy in Singapore, if an improved compliance with recommended surveillance protocol is achieved in proven mutation carriers.

Colorectal cancer (CRC) is the fourth most common cause of death from cancer in the world. The limitations of the currently available methods and biomarkers for CRC management highlight the necessity of finding novel markers. Metabonomics can be used to search for potential markers that can provide molecular insight into human CRC. The emergence of two-dimensional gas chromatography time of flight mass spectrometry (GC × GC/TOFMS) has comprehensively enhanced the metabolic space coverage of conventional GC/MS. In this study, a GC × GC/TOFMS was developed for the tissue-based global metabonomic profiling of CRC. A Pegasus GC × GC/TOFMS (Leco Corp., St. Joseph, MI, USA) system comprising an Agilent 7890 GC and Pegasus IV TOFMS was used for this purpose. An Agilent DB-1 (30 m × 250 μm × 0.25 μm) fused silica capillary column and a Restek Rxi®-17 (1 m × 100 μm × 0.10 μm) fused silica capillary column were used as the primary and secondary columns, respectively. The method was applied for global metabonomic profiling of matched CRC and normal tissues (n = 63) obtained from 31 CRC patients during surgery. An attempt was also made to compare GC × GC/TOFMS with GC/MS and NMR in similar application. The results showed that the metabotype associated with CRC is distinct from that of normal tissue and led to the identification of chemically diverse marker metabolites. Metabolic pathway mapping suggested deregulation of various biochemical processes such as glycolysis, Krebs cycle, osmoregulation, steroid biosynthesis, eicosanoid biosynthesis, bile acid biosynthesis, lipid, amino acid and nucleotide metabolism.

Introduction: Stage IV colorectal cancer (CRC) is a heterogeneous disease with many treatment options. The optimum management algorithm is yet to be established. The aim of this study was to evaluate the prognostic factors of survival and to determine the operative benefit of resection of the primary tumour followed by chemotherapy., Methods: Seven hundred twenty-eight consecutive patients who presented with stage IV CRC from 1999 to 2007 were identified. The demographics and clinicopathological characteristics of these patients were reviewed. Survival curves were constructed using the Kaplan-Meier method. Multivariate analysis assessed independent prognostic factors., Results: In the surgical management of the primary, 79% (n = 572) were performed electively, 18% (n = 134) as an emergency procedure and 3% (n = 22) did not have any surgery. Twelve percent (n = 78) had a permanent stoma. Major morbidity was 4.3% (n = 31), and 30-day mortality was low at 6% (n = 46). Ten percent (n = 71) had a subsequent metasectomy. Patients who underwent curative resections tended to be female (p = 0.05), of a younger age group (age, ≤ 50; p = 0.005), as well as had better haemoglobin (p = 0.0001) and albumin levels (p = 0.0001). For the study cohort, the cancer-specific survival (CSS) at 1 year was 47.9% [95% confidence interval (CI), 44.2-51.6%], 3-year CSS was 10.8% (95% CI, 3.3-13.3%) and 5-year CSS was 7.0% (95% CI, 4.8-9.2%). CSS was significantly higher in patients that underwent colonic resection. In cases where resection of the primary was possible, multivariate analysis revealed that CEA value >40 ng/ml, low albumin levels ≤ 34 g/l, poorly differentiated tumours, advanced tumour stage (T3/T4), nodal disease (N1/N2) and presence of diffuse metastasis were all significant factors associated with poorer cancer-specific survival., Conclusion: This study has shown a good survival benefit in stage IV CRC when an aggressive policy of primary resection is adopted. Resection of metastases with curative intent should be performed whenever possible.

High macrophage infiltration into tumours often correlates with poor prognoses; in colorectal, stomach and skin cancers, however, the opposite is observed but the mechanisms behind this phenomenon remain unclear. Here, we sought to understand how tumour-associated macrophages (TAMs) in colorectal cancer execute tumour-suppressive roles. We found that TAMs in a colorectal cancer model were pro-inflammatory and inhibited the proliferation of tumour cells. TAMs also produced chemokines that attract T cells, stimulated proliferation of allogeneic T cells and activated type-1 T cells associated with anti-tumour immune responses. Using colorectal tumour tissues, we verified that TAMs in vivo were indeed pro-inflammatory. Furthermore, the number of tumour-infiltrating T cells correlated with the number of TAMs, suggesting that TAMs could attract T cells; and indeed, type-1 T cells were present in the tumour tissues. Patient clinical data suggested that TAMs exerted tumour-suppressive effects with the help of T cells. Hence, the tumour-suppressive mechanisms of TAMs in colorectal cancer involve the inhibition of tumour cell proliferation alongside the production of pro-inflammatory cytokines, chemokines and promoting type-1 T-cell responses. These new findings would contribute to the development of future cancer immunotherapies based on enhancing the tumour-suppressive properties of TAMs to boost anti-tumour immune responses., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Genome-wide association studies (GWAS) in Caucasians have identified fourteen index single nucleotide polymorphisms (iSNPs) that influence colorectal cancer (CRC) risk., Methods: We investigated the role of eleven iSNPs or surrogate SNPs (sSNPs), in high linkage disequilibrium (LD, r(2)≥ 0.8) and within 100 kb vicinity of iSNPs, in 2,000 age- and gender-matched Singapore Chinese (SCH) cases and controls., Results: Only iSNP rs6983267 at 8q24.21 and sSNPs rs6695584, rs11986063, rs3087967, rs2059254, and rs7226855 at 1q41, 8q23.3, 11q23.1, 16q22.1 and 18q21.1 respectively showed evidence of association with CRC risk, with odds ratios (OR) ranging from 1.13 to 1.40. sSNP rs827401 at 10p14 was associated with rectal cancer risk (OR = 0.74, 95% CI 0.63-0.88) but not disease prognosis (OR = 0.91, 95% CI 0.69-1.20). Interestingly, sSNP rs3087967 at 11q23.1 was associated with CRC risk in men (OR = 1.34, 95% CI 1.14-1.58) but not women (OR = 1.07, 95% CI: 0.88-1.29), suggesting a gender-specific role. Half of the Caucasian-identified variants, including the recently fine-mapped BMP pathway loci, BMP4, GREM1, BMP2 and LAMA 5, did not show any evidence for association with CRC in SCH (OR ~1; p-value >0.1). Comparing the results of this study with that of the Northern and Hong Kong Chinese, only variants at chromosomes 8q24.21, 10p14, 11q23.1 and 18q21.1 were replicated in at least two out of the three Chinese studies., Conclusions: The contrasting results between Caucasians and Chinese could be due to different LD patterns and allelic frequencies or genetic heterogeneity. The results suggest that additional common variants contributing to CRC predisposition remained to be identified.

Background: Patients fulfilling Amsterdam-1 criteria without mismatch repair deficiency (termed familial colorectal cancer type X (FCC type X)) were reported to have lower cancer risks than classic Lynch syndrome. This study investigates the polyp and cancer burden of this population and demonstrates relationships with a family history score (FHS)., Methods: The Jagelman Registry was queried for patients meeting Amsterdam criteria with microsatellite stable/low colorectal cancers. The risk of colorectal neoplasia was ascertained using a published FHS. Polyp distribution, histology and cumulative counts as well as extra-colonic tumours in the pedigree were reviewed., Results: Twenty-one patients (9 males, 12 females) met study criteria. The median lifetime polyp count was 3 (range 1–36). FHS 8 (80%) was significantly associated with an increased risk of colorectal cancer compared with those with scores <8 who are more likely to develop polyps (P < 0.01). Twelve patients (57%) had predominantly left-sided polyps. Ten colorectal cancers (7 left-sided, 3 right-sided) were diagnosed at a median age of 48 (range 30–74) years. Only three tumours were mucinous or demonstrated tumour-infiltrating lymphocytes, typical of high microsatellite instability tumours. All patients had family history of colorectal cancers (CRCs) and at least 10 patients had a family history of uterine or breast cancer. One patient was found to have hyperplastic polyposis syndrome., Conclusions: FCC type X likely represents a heterogenous group of as yet undefined CRC predispositions. The polyp burden and cancer risk are variable and can be somewhat delineated according to an FHS.

Cumulative evidence shows that eicosanoids such as prostaglandins, leukotrienes, thromboxanes and hydroxy eicosatetraenoic acids play an important role in associating inflammation with human colorectal cancer (CRC). In this study an ultra-pressure liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) method was developed and validated for the targeted profiling of eight relevant eicosanoids and the major metabolic precursor, arachidonic acid (AA), in human colon. Multiple reaction monitoring (MRM) experiments were performed in negative electrospray ionization mode. The metabolites were separated using a C(18) column consisting of 1.7 µm ethylene-bridged hybrid particles (100 × 2.1 mm i.d.) and gradient elution (50 to 95% of solvent B) with a mobile phase comprising water (0.1% formic acid) [solvent A] and acetonitrile (0.1% formic acid) [solvent B] at a flow rate of 0.4 mL/min. The analysis time for each sample was 5.5 min. Our UPLC/MS/MS method demonstrated satisfactory validation results in terms of selectivity, sensitivity, matrix effect, linearity, extraction efficiency, intra- and inter-day precision, accuracy and autosampler stability. The method was applied for the clinical profiling of matched pairs of cancerous and normal colon mucosae obtained from eight colorectal cancer patients. Endogenous levels of AA and selected eicosanoids such as prostaglandin E(2) (PGE(2)), prostacyclin (PGI(2)) [assayed as its stable hydrolytic product 6-keto-prostaglandin(1α) (6-k PGF(1α))] and 12-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-HETE) were found to be significantly different (p <0.05; paired t-test) between cancerous and normal mucosae., (Copyright © 2011 John Wiley & Sons, Ltd.)

Background: Maternal postpartum health is a neglected area both in research and practice. This aspect warrants more attention as the health of postpartum mothers has a considerable influence on her infant and also other family members. Social support provided by family and friends has been identified as a buffer against the many stressors faced by the women. Outcomes such as self-esteem, stress, postnatal depression, breastfeeding levels, infant care, and maternal adaptation have been studied and found to be significantly related to social support. The need to understand the role of social support provided by family and friends provide the impetus for conducting this review., Objectives: The objective of this systematic review was to appraise and synthesise the best available evidence which discusses the impact of social support from family and friends on enhancing the wellbeing of postpartum women., Inclusion Criteria: This review includes women who were within their first year postpartum period, with any number of children, and had given birth to healthy infants. Mothers who had co-existing morbidities such as depression were excluded. Mothers from low socio-economic groups were excluded.This review considered any study that involved the provision of social support by family and/or friends. Interventions provided by peer counsellors were also considered.The six outcomes were stress, self esteem, breastfeeding levels, mental health in relation to postnatal depression, infant care and maternal adaptation.Quantitative This review considered any randomised controlled trials that examined the effectiveness of social support from family and friends on the well being of the postpartum women. As it was not likely to find RCTs on this topic, this review also considered observational studies (cohort, case control, quantitative descriptive studies such as surveys).Qualitative This review considered any interpretive studies that drew on the experiences of social support from family and friends in postpartum women including, but not limited to, designs such as phenomenology, grounded theory and ethnography.The search was conducted only in published literature in English. A search was conducted in the following databases: PsycINFO, MEDLINE, CINAHL, SCOPUS, THE COCHRANE LIBRARY, BMJ Clinical Evidence, Wiley Interscience, ScienceDirect and MEDNAR.Each paper was assessed independently by two reviewers prior to critical appraisal using Joanna Briggs Institute-System for the Unified Management, Assessment and Review of Information (JBI-SUMARI) developed by Joanna Briggs Institute (JBI)., Data Collection/extraction: Qualitative and quantitative data were extracted using the tools from the JBI-SUMARI DATA SYNTHESIS: Qualitative data was synthesised using QARI (Qualitative Assessment and Review Instrument). Quantitative data could not be pooled due to the lack of comparable RCTs or cohort studies and was thus presented in a narrative form., Results: This review included 24 quantitative articles, comprising of two RCTs and 22 descriptive studies. From these studies, social support was shown to have a significant positive correlation with outcomes such as breastfeeding, infant care, maternal adaptation, and self esteem. In addition, social support was shown to have a negative correlation with the levels of stress and postnatal depression. This indicated that increasing the social support of postpartum women will promote breastfeeding, infant care, maternal adaptation and self esteem. Rendering social support also aids in buffering their levels of stress and postnatal depression.Three qualitative articles were included in this review. Meta-synthesis of the qualitative findings yielded 17 findings which were grouped into seven categories and then further categorised into one synthesised finding which was, "Motherhood as a period of learning, adjustment, seeking positive social support whilst buffering against stressors'. This synthesised finding suggested that social support offered by family and friends has both positive and negative effects with which the postpartum mothers have to learn to cope., Conclusions: Family members such as the partners and grandmothers should be involved in the provision of care towards the postpartum women. The support from peer volunteers may also contribute to the desired health outcomes. Healthcare professionals ought to be equipped with the knowledge on social support so that they can better assess the needs of the postpartum women and develop a support plan.Further research is necessary to better understand the negative effects of social support and to test interventions to buffer them. The effectiveness of the various types of social support interventions should be subject to further testing in future research. Further research may help to identify which support provider is more effective in enhancing a particular health outcome.

Introduction: Conflicting data on the clinicopathological characteristics as well as prognosis and survival of signet ring cell (SRC) and mucinous adenocarcinomas (MA) of the colorectum persist., Methods: Consecutive patients (2,764) with sporadic colorectal cancer from 1999 to 2005 were evaluated. The clinicopathological characteristics of these patients were reviewed. Univariate analysis was performed, and survival curves were constructed using the Kaplan-Meier method. Multivariate analysis assessed independent prognostic factors., Results: The incidence of MA and SRC is 6% and 1.1%, respectively. MA and SRC tend to occur in patients aged

Metastasis is the major cause of cancer mortality. We aimed to find a metastasis-prone signature for early stage mismatch-repair proficient sporadic colorectal cancer (CRC) patients for better prognosis and informed use of adjuvant chemotherapy. The genome-wide expression profiles of 82 age-, ethnicity- and tissue-matched patients and healthy controls were analyzed using the Affymetrix U133 Plus 2 array. Metastasis-negative patients have 5 years or more of follow-up. A 10 x 10 two-level nested cross-validation design was used with several families of classification models to identify the optimal predictor for metastasis. The best classification model yielded a 54 gene-set (74 probe sets) with an estimated prediction accuracy of 71%. The specificity, sensitivity, negative and positive predictive values of the signature are 0.88, 0.58, 0.84 and 0.65, respectively, indicating that the gene-set can improve prognosis for early stage sporadic CRC patients. These 54 genes, including node molecules YWHAB, MAP3K5, LMNA, APP, GNAQ, F3, NFATC2, and TGM2, integrate multiple bio-functions in various compartments into an intricate molecular network, suggesting that cell-wide perturbations are involved in metastasis transformation. Further, querying the ;Connectivity Map' with a subset (70%) of these genes shows that Gly-His-Lys and securinine could reverse the differential expressions of these genes significantly, suggesting that they have combinatorial therapeutic effect on the metastasis-prone patients. These two perturbagens promote wound-healing, extracellular matrix remodeling and macrophage activation thus highlighting the importance of these pathways in metastasis suppression for early-stage CRC.

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited form of colorectal cancer (CRC) caused by mutation in the adenomatous polyposis coli (APC) gene. However, APC mutations are not detected in 10-50% of FAP patients. We searched for a new cancer gene by performing genome-wide genotyping on members of an APC mutation-negative FAP variant family and ethnicity-matched healthy controls. No common copy number change was found in all affected members using the unaffected members and healthy controls as baseline. A 111 kb copy number variable (CNV) region at 3q26.1 was shown to have copy number loss in all eight polyps compared to matched lymphocytes of two affected members. A common region of loss in all polyps, which are precursors to CRC, is likely to harbor disease-causing gene in accordance to Knudsen's "two-hit" hypothesis. There is, however, no gene within the deleted region. A 2-Mb scan of the genomic region encompassing the deleted region identified PPM1L, coding for a novel serine-threonine phosphatase in the TGF-beta and BMP signaling pathways. Real-time PCR analyses indicate that the 3'UTR of PPM1L transcript was down-regulated more than two-folds in all six polyps and tumors compared to matched mucosa of the affected member. This down-regulation was not observed in APC mutation-positive FAP patients. Our results suggest that the CNV region at 3q26 harbors an element that regulates the expression of an upstream candidate tumor suppressor, PPM1L, thus providing a novel mechanism for colorectal tumorigenesis in APC mutation-negative familial CRC patients.

The combination of treosulfan and gemcitabine (TG) has been shown to have activity in ovarian cancer. These two agents are thought to be synergistic, with gemcitabine causing the persistence of treosulfan-induced DNA crosslinks. This study aimed to investigate the response rates, survival and toxicity in patients with platinum-resistant ovarian cancer treated with TG. A retrospective case note review of the patients treated with TG was performed in one cancer centre between May 1st, 2000 and November 1st, 2005. Estimates of cumulative survival were obtained using the Kaplan-Meier method. Forty-nine patients were identified; median age at diagnosis was 55 years (range, 31-72) and the median follow-up was 45.1 months (range, 12.2-118.3). TG was used as second-, third-, fourth- and fifth-line chemotherapy in 15, 19, 13 and 2 patients, respectively. Fifteen patients (30.6%) had stable disease; 25 (51%), a partial response; 1 (2%), a complete response and 8 (16.3%) had progressive disease. Median survival following diagnosis was 45.1 months and the median relapse-free survival was 12 months. The median survival time from the start of TG was 13.7 months with a relapse-free survival of 6.3 months. The median number of cycles given was 7. The most common toxicity recorded was myelosuppression. There were no treatment-related deaths. TG chemotherapy produced favourable response rates in a heavily pre-treated group of patients with platinum-resistant epithelial ovarian cancer. This doublet warrants further investigation in a phase III trial setting.

Introduction: Peutz-Jeghers Syndrome (PJS) is an uncommon autosomal dominant hamartomatous polyposis syndrome. Morbidity arises from polyp-related complications and increased risks of malignancy. We report on PJS patients registered in the Singapore Polyposis Registry, identified principal causes of morbidity and appraised current management strategies. A followup protocol based on recent literature has been proposed., Materials and Methods: A search of a prospectively collected database in the Singapore Polyposis Registry was made. Only patients who fulfilled the diagnostic criteria of PJS were included. The clinical records were retrieved for review. Information on affected family members was obtained from the Registry's pedigree records., Results: Seven unrelated patients fulfilled the criteria of having PJS. Principal causes of morbidity include recurrent bouts of abdominal colic, episodes of intestinal obstruction, gastrointestinal bleeding and the need for repeated laparotomies. Six out of 7 patients had initial presentation with acute intestinal obstruction requiring emergency laparotomy. Management was mostly problem-oriented and marked inter-surgeon variation with regard to cancer screening and genetic counselling was observed., Conclusion: Patients with PJS suffer gastrointestinal complications from polyposis and are at increased risks for developing cancers. A move towards surveillance and planned comprehensive care may reduce the morbidity of the condition. A protocol driven approach conducted in the setting of a Polyposis Registry is ideally suited to facilitate such care.

Objectives: Hereditary mixed polyposis syndrome (HMPS) is characterized by polyps of mixed adenomatous/hyperplastic/atypical juvenile histology that are autosomal dominantly inherited and that eventually lead to colorectal cancer (CRC). Although CRC with adenomatous polyps is initiated by inactivating adenomatous polyposis coli (APC), the initiating event of CRC with mixed polyps remains unclear. We aimed to identify the underlying germline defect in HMPS., Methods: We screened for bone morphogenesis protein receptor 1A (BMPR1A) mutation by exonic sequencing, reverse-transcriptase polymerase chain reaction (PCR) followed by cDNA sequencing, and multiplex ligation-dependent probe amplification (MLPA) analysis in eight Singapore Chinese HMPS families., Results: Germline BMPR1A defects were found in four (50%) families. In two families, it is shown to co-segregate with the disease phenotype in all affected members over three generations, indicating that it is the disease-causing mutation. CRC incidence is 75%. The most defining characteristic is the presence of mixed hyperplastic-adenomatous polyps. Juvenile polyps are rarely reported, and if present, are usually of mixed components. Detailed histology of the polyps from one patient over 11 years distinguishes HMPS from juvenile polyposis syndrome (JPS). We report further the first cases of Wilms' tumor and papillary thyroid carcinoma associated with BMPR1A germline defect., Conclusions: Germline BMPR1A defect is the disease-causing mutation in 50% of the HMPS families. If patients present with mixed morphology polyps in the large bowel that are autosomal dominantly inherited and corresponding absence of upper gastrointestinal abnormalities, the gene to begin mutation screening should be BMPR1A rather than APC.

Background: Colorectal cancer (CRC) in the young is rare. Outcomes remain varied compared to older populations. The study reviews characteristics and overall survival (OS) of CRC in patients < or =50 years old., Materials and Methods: Five hundred and twenty-three (14%) of 3,796 sporadic CRCs were identified. Patients were compared for demographics, tumour characteristics, treatment, and 5-year overall specific survival. Independent prognostic factors were evaluated., Results: The majority were males (54%) with a median age of 45 years (range 19-50 years). Sixty-three percent of the patients presented with advanced stage disease (stage III and IV), and tumours were predominantly left-sided (83%). A higher frequency of mucinous or signet ring cell histological subtypes (16% vs 9%, p = 0.028) as well as poorly differentiated tumours (30% vs 12%, p = 0.0001) were present in younger patients < or =40 years. With a median follow-up of 41 months, the 5-year OS is 58% (95% confidence interval 53-64%). Younger patients < or =40 years had significantly superior 5-year OS of 62% vs 58% in the age group 41-50 years old (p = 0.004). Multivariate analysis identified five independent prognostic features: age group of 41-50 years, poorly differentiated tumour grade, presence of perineural infiltration, high tumour stage, and carcinoembryonic antigen values > or =5 ng/ml., Conclusion: This study has revealed significantly improved 5-year survival in young CRC compared to those reported in the literature.

In this study, a gas chromatography/mass spectrometry (GC/MS) method was developed and validated for the metabolic profiling of human colon tissue. Each colon tissue sample (20 mg) was ultra-sonicated with 1 mL of a mixture of chloroform/methanol/water in the ratio of 20:50:20 (v/v/v), followed by centrifugation, collection of supernatant, drying, removal of moisture using anhydrous toluene and finally derivatization using N-methyl-N-trifluoroacetamide (MSTFA) with 1% trimethylchlorosilane (TMCS). A volume of 1 microL of the derivatized mixture was injected into the GC/MS system. A total of 53 endogenous metabolites were separated and identified in the GC/MS chromatogram, all of which were selected to evaluate the sample stability and precision of the method. Of the identified endogenous metabolites 19 belonging to diverse chemical classes and covering a wide range of the GC retention times (Rt) were selected to investigate the quantitative linearity of the method. The developed GC/MS method demonstrated good reproducibility with intra- and inter-day precision within relative standard deviation (RSD) of +/-15%. The metabolic profiles of the intact tissue were determined to be stable (100 +/- 15%) for up to 90 days at -80 degrees C. Satisfactory results were also obtained in the case of other stability-indicating studies such as freeze/thaw cycle stability, bench-top stability and autosampler stability. The developed method showed a good linear response for each of the 19 analytes tested (r(2) > 0.99). Our GC/MS metabolic profiling method was successfully applied to discriminate biopsied colorectal cancer (CRC) tissue from their matched normal tissue obtained from six CRC patients using orthogonal partial least-squares discriminant analysis [two latent variables, R(2)Y = 0.977 and Q(2) (cumulative) = 0.877]., (Copyright 2009 John Wiley & Sons, Ltd.)

Current clinical strategy for staging and prognostication of colorectal cancer (CRC) relies mainly upon the TNM or Duke system. This clinicopathological stage is a crude prognostic guide because it reflects in part the delay in diagnosis in the case of an advanced cancer and gives little insight into the biological characteristics of the tumor. We hypothesized that global metabolic profiling (metabonomics/metabolomics) of colon mucosae would define metabolic signatures that not only discriminate malignant from normal mucosae, but also could distinguish the anatomical and clinicopathological characteristics of CRC. We applied both high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) and gas chromatography mass spectrometry (GC/MS) to analyze metabolites in biopsied colorectal tumors and their matched normal mucosae obtained from 31 CRC patients. Orthogonal partial least-squares discriminant analysis (OPLS-DA) models generated from metabolic profiles obtained by both analytical approaches could robustly discriminate normal from malignant samples (Q(2) > 0.50, Receiver Operator Characteristic (ROC) AUC >0.95, using 7-fold cross validation). A total of 31 marker metabolites were identified using the two analytical platforms. The majority of these metabolites were associated with expected metabolic perturbations in CRC including elevated tissue hypoxia, glycolysis, nucleotide biosynthesis, lipid metabolism, inflammation and steroid metabolism. OPLS-DA models showed that the metabolite profiles obtained via HR-MAS NMR could further differentiate colon from rectal cancers (Q(2)> 0.60, ROC AUC = 1.00, using 7-fold cross validation). These data suggest that metabolic profiling of CRC mucosae could provide new phenotypic biomarkers for CRC management.

Restorative proctocolectomy with ileal pouchanal anastomosis (IPAA) is the surgical treatment of choice for complicated ulcerative colitis. Development of ileal pouch-related cancer is a rare event and usually occurs in association with backwash ileitis or chronic pouchitis. We report a case of adenocarcinoma at the inlet of an ileal pouch in a 68-year-old Caucasian male, 14 years after restorative proctocolectomy for ulcerative colitis in the absence of severe chronic pouchitis or backwash ileitis. The operative technique is described, with a review of the literature on ileal pouch cancer.