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Aim: To determine the knowledge of certain University of Nigeria Teaching Hospital, (UNTH) staff about ARI case management and the impact of ARI case management training on their knowledge. Materials and Methods: This was done during two three-day training courses, which were based on the National Acute Respiratory Infections Programme (NARIP) adaptation of the WHO standard case management module. Pre- and post- (training) tests were done and were marked by the same person. Results: The general mean±S.D pre- and post-test scores were 38.68± 10.22% and 73.44±18.35% respectively (P

Accurately capturing children's word learning abilities is critical for advancing our understanding of language development. Researchers have demonstrated that utilizing more complex statistical methods, such as mixed-effects regression and hierarchical linear modeling, can lead to a more complete understanding of the variability observed within children's word learning abilities. In the current paper, we demonstrate how a person-centered approach to data analysis can provide additional insights into the heterogeneity of word learning ability among children while also aiding researchers' efforts to draw individual-level conclusions. Using previously published data with 32 typically developing and 32 late-talking infants who completed a novel noun generalization (NNG) task to assess word learning biases (i.e., shape and material biases), we compare this person-centered method to three traditional statistical approaches: (1) a t -test against chance, (2) an analysis of variance (ANOVA), and (3) a mixed-effects regression. With each comparison, we present a novel question raised by the person-centered approach and show how results from the corresponding analyses can lead to greater nuance in our understanding of children's word learning capabilities. Person-centered methods, then, are shown to be valuable tools that should be added to the growing body of sophisticated statistical procedures used by modern researchers.

Background & Aims: Dysbiosis of gut microbiota is linked to the development of colorectal cancer (CRC). However, microbiota-based stratification of CRC tissue and how this relates to clinicomolecular characteristics and prognosis remains to be clarified., Methods: Tumor and normal mucosa from 423 patients with stage I to IV CRC were profiled by bacterial 16S rRNA gene sequencing. Tumors were characterized for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), APC, BRAF, KRAS, PIK3CA, FBXW7, SMAD4, and TP53 mutations, subsets for chromosome instability (CIN), mutation signatures, and consensus molecular subtypes (CMS). Microbial clusters were validated in an independent cohort of 293 stage II/III tumors., Results: Tumors reproducibly stratified into 3 oncomicrobial community subtypes (OCSs) with distinguishing features: OCS1 (Fusobacterium/oral pathogens, proteolytic, 21%), right-sided, high-grade, MSI-high, CIMP-positive, CMS1, BRAF V600E, and FBXW7 mutated; OCS2 (Firmicutes/Bacteroidetes, saccharolytic, 44%), and OCS3 (Escherichia/Pseudescherichia/Shigella, fatty acid β-oxidation, 35%) both left-sided and exhibiting CIN. OCS1 was associated with MSI-related mutation signatures (SBS15, SBS20, ID2, and ID7) and OCS2 and OCS3 with SBS18 related to damage by reactive oxygen species. Among stage II/III patients, OCS1 and OCS3 both had poorer overall survival compared with OCS2 for microsatellite stable tumors (multivariate hazard ratio [HR], 1.85; 95% confidence interval [CI], 1.15-2.99; P = .012; and HR, 1.52; 95% CI 1.01-2.29; P = .044, respectively) and left-sided tumors (multivariate HR, 2.66; 95% CI, 1.45-4.86; P = .002; and HR, 1.76; 95% CI, 1.03-3.02; P = .039, respectively)., Conclusions: OCS classification stratified CRCs into 3 distinct subgroups with different clinicomolecular features and outcomes. Our findings provide a framework for a microbiota-based stratification of CRC to refine prognostication and to inform the development of microbiota-targeted interventions., (Copyright © 2023 AGA Institute. All rights reserved.)

Coral reef soundscapes are increasingly studied for their ecological uses by invertebrates and fishes, for monitoring habitat quality, and to investigate effects of anthropogenic noise pollution. Few examinations of aquatic soundscapes have reported particle motion levels and variability, despite their relevance to invertebrates and fishes. In this study, ambient particle acceleration was quantified from orthogonal hydrophone arrays over several months at four coral reef sites, which varied in benthic habitat and fish communities. Time-averaged particle acceleration magnitudes were similar across axes, within 3 dB. Temporal trends of particle acceleration corresponded with those of sound pressure, and the strength of diel trends in both metrics significantly correlated with percent coral cover. Higher magnitude particle accelerations diverged further from pressure values, potentially representing sounds recorded in the near field. Particle acceleration levels were also reported for boat and example fish sounds. Comparisons with particle acceleration derived audiograms suggest the greatest capacity of invertebrates and fishes to detect soundscape components below 100 Hz, and poorer detectability of soundscapes by invertebrates compared to fishes. Based on these results, research foci are discussed for which reporting of particle motion is essential, versus those for which sound pressure may suffice.

Although many crustaceans produce sounds, their hearing abilities and mechanisms are poorly understood, leaving uncertainties regarding whether or how these animals use sound for acoustic communication. Marine invertebrates lack gas-filled organs required for sound pressure detection, but some of them are known to be sensitive to particle motion. Here, we examined whether the American lobster ( Homarus americanus ) could detect sound and subsequently sought to discern the auditory mechanisms. Acoustic stimuli responses were measured using auditory evoked potential (AEP) methods. Neurophysiological responses were obtained from the brain using tone pips between 80 and 250 Hz, with best sensitivity at 80-120 Hz. There were no significant differences between the auditory thresholds of males and females. Repeated controls (recordings from deceased lobsters, moving electrodes away from the brain and reducing seawater temperature) indicated the evoked potentials' neuronal origin. In addition, AEP responses were similar before and after antennules (including statocysts) were ablated, demonstrating that the statocysts, a long-proposed auditory structure in crustaceans, are not the sensory organs responsible for lobster sound detection. However, AEPs could be eliminated (or highly reduced) after immobilizing hairfans, which cover much of lobster bodies. These results suggest that these external cuticular hairs are likely to be responsible for sound detection, and imply that hearing is mechanistically possible in a wider array of invertebrates than previously considered. Because the lobsters' hearing range encompasses the fundamental frequency of their buzzing sounds, it is likely that they use sound for intraspecific communication, broadening our understanding of the sensory ecology of this commercially vital species. The lobsters' low-frequency acoustic sensitivity also underscores clear concerns about the potential impacts of anthropogenic noise., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

TP53 mutations drive colorectal cancer development, with missense mutations frequently leading to accumulation of abnormal TP53 protein. TP53 alterations have been associated with poor prognosis and chemotherapy resistance, but data remain controversial. Here, we examined the predictive utility of TP53 overexpression in the context of current adjuvant treatment practice for patients with stage III colorectal cancer. A prospective cohort of 264 stage III patients was tested for association of TP53 expression with 5-year disease-free survival, grouped by adjuvant treatment. Findings were validated in an independent retrospective cohort of 274 stage III patients. Overexpression of TP53 protein (TP53+) was found in 53% and 52% of cases from the prospective and retrospective cohorts, respectively. Among patients receiving adjuvant chemotherapy, TP53+ status was associated with shorter disease-free survival (p ≤ 0.026 for both cohorts), while no difference in outcomes between TP53+ and TP53- cases was observed for patients treated with surgery alone. Considering patients with TP53- tumors, those receiving adjuvant treatment had better outcomes compared with those treated with surgery alone (p ≤ 0.018 for both cohorts), while no treatment benefit was apparent for patients with TP53+ tumors. Combined cohort-stratified analysis adjusted for clinicopathological variables and DNA mismatch repair status confirmed a significant interaction between TP53 expression and adjuvant treatment for disease-free survival (p interaction  = 0.030). For the combined cohort, the multivariate hazard ratio for TP53 overexpression among patients receiving adjuvant chemotherapy was 2.03 (95% confidence interval 1.41-2.95, p < 0.001), while the hazard ratio for adjuvant treatment among patients with TP53- tumors was 0.42 (95% confidence interval 0.24-0.71, p = 0.001). Findings were maintained irrespective of tumor location or when restricted to mismatch repair-proficient tumors. Our data suggest that adjuvant chemotherapy benefit in stage III colorectal cancer is restricted to cases with low-level TP53 protein expression. Identifying TP53+ tumors could highlight patients that may benefit from more aggressive treatment or follow-up.

Benthic marine suspension feeders provide an important link between benthic and pelagic ecosystems. The strength of this link is determined by suspension-feeding rates. Many studies have measured suspension-feeding rates using indirect clearance-rate methods, which are based on the depletion of suspended particles. Direct methods that measure the flow of water itself are less common, but they can be more broadly applied because, unlike indirect methods, direct methods are not affected by properties of the cleared particles. We present pumping rates for three species of suspension feeders, the clams Mya arenaria and Mercenaria mercenaria and the tunicate Ciona intestinalis , measured using a direct method based on particle image velocimetry (PIV). Past uses of PIV in suspension-feeding studies have been limited by strong laser reflections that interfere with velocity measurements proximate to the siphon. We used a new approach based on fitting PIV-based velocity profile measurements to theoretical profiles from computational fluid dynamic (CFD) models, which allowed us to calculate inhalant siphon Reynolds numbers ( Re ). We used these inhalant Re and measurements of siphon diameters to calculate exhalant Re , pumping rates, and mean inlet and outlet velocities. For the three species studied, inhalant Re ranged from 8 to 520, and exhalant Re ranged from 15 to 1073. Volumetric pumping rates ranged from 1.7 to 7.4 l h -1 for M . arenaria , 0.3 to 3.6 l h -1 for M . m ercenaria and 0.07 to 0.97 l h -1 for C . intestinalis We also used CFD models based on measured pumping rates to calculate capture regions, which reveal the spatial extent of pumped water. Combining PIV data with CFD models may be a valuable approach for future suspension-feeding studies., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

Purpose: Mutation of BRAF at the valine 600 residue occurs in approximately 10% of colorectal cancers, a group with particularly poor prognosis. The response of BRAF mutant colorectal cancer to recent targeted strategies such as anti-BRAF or combinations with MEK and EGFR inhibitors remains limited and highly heterogeneous within BRAF V600E cohorts. There is clearly an unmet need in understanding the biology of BRAF V600E colorectal cancers and potential subgroups within this population., Experimental Design: In the biggest yet reported cohort of 218 BRAF V600E with gene expression data, we performed unsupervised clustering using non-negative matrix factorization to identify gene expression-based subgroups and characterized pathway activation., Results: We found strong support for a split into two distinct groups, called BM1 and BM2. These subtypes are independent of MSI status, PI3K mutation, gender, and sidedness. Pathway analyses revealed that BM1 is characterized by KRAS/AKT pathway activation, mTOR/4EBP deregulation, and EMT whereas BM2 displays important deregulation of the cell cycle. Proteomics data validated these observations as BM1 is characterized by high phosphorylation levels of AKT and 4EBP1, and BM2 patients display high CDK1 and low cyclin D1 levels. We provide a global assessment of gene expression motifs that differentiate BRAF V600E subtypes from other colorectal cancers., Conclusions: We suggest that BRAF mutant patients should not be considered as having a unique biology and provide an in depth characterization of heterogeneous motifs that may be exploited for drug targeting. Clin Cancer Res; 23(1); 104-15. ©2016 AACR., (©2016 American Association for Cancer Research.)

Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles., Competing Interests: No conflicts of interest to disclose.

Purpose: Resource limitations are a concern in most modern public hospital systems. The aim of this study is to prospectively quantify the total caseload of a tertiary colorectal surgery unit to identify areas of redundancy., Methods: Data was collected prospectively at all points of clinical care (outpatient clinic, inpatient referrals, operating theatre and endoscopy) between March 2014 and March 2015 using specifically designed templates. The final data was analysed using descriptive statistics., Results: During the study period, 4012 patient episodes were recorded: 2871 in outpatient clinic, 186 as emergency patient referrals, 541 at colonoscopy and 414 at surgery. The largest component of the caseload was made up primarily of colonoscopy results follow-up, protocol review for previous cancer or polyps and post-operative review. Sixty-eight percent of these episodes did not result in any active intervention such as further tests or surgery. Most new outpatient referrals were undifferentiated, with the most common indications being minor rectal bleeding, non-specific gastrointestinal symptoms, and minor non-bleeding anorectal problems. Of the new referrals, 56 % were booked for a colonoscopy, and only 13.3 % were booked directly for elective surgery., Conclusion: A large component of the caseload of a tertiary colorectal surgery unit is made up of post-colonoscopy, post-operative, and surveillance protocol follow-up, with a significant proportion of patients not requiring any active intervention. The majority of new referrals are undifferentiated and result in a low rate of direct booking for operative intervention. Rationalisation of this resource using evidence-based methods could reduce redundancy, workload, and cost.

In bilaterian animals, the circadian clock is intimately involved in regulating energetic metabolism. Although cnidarians exhibit diel behavioral rhythms including cycles in locomotor activity, tentacle extension and spawning, daily cycles in cnidarian metabolism have not been described. To explore a possible circadian metabolic cycle, we maintained the anemone Nematostella vectensis in a 12 h light/dark cycle, a reversed light cycle, or in constant darkness. Oxygen consumption rates were measured at intervals using an optical oxygen meter. Respiration rates responded to entrainment with higher rates during light periods. During a second experiment with higher temporal resolution, respiration rates peaked late in the light period. The diel pattern could be detected after six days in constant darkness. Together, our results suggest that respiration rates in Nematostella exhibit a daily cycle that may be under circadian control and that the cycle in respiration rate is not driven by the previously described nocturnal increase in locomotor activity in this species., (© 2016. Published by The Company of Biologists Ltd.)

Aim: To determine the frequency of identification of the triradiate fold during colonoscopy and evaluate its reliability as a marker of caecal intubation., Methods: One hundred consecutive patients undergoing colonoscopy in a tertiary hospital colorectal unit from May to September 2013 were studied. Video documentation of the caecum was recorded and shown to consultant colorectal surgeons on the unit. Each reviewer was asked through a series of questions to independently identify the triradiate fold. The main outcome was the frequency of visualisation of the triradiate fold in the caecum., Results: The triradiate fold was seen on average in 18% of cases, but inter-observer agreement was poor. There were only four patients (4%) in which all reviewers agreed on the presence of a triradiate fold. In patients who had undergone previous appendicectomy, the appendiceal orifice was less frequently seen compared with patients who had not undergone appendicectomy., Conclusion: The triradiate fold is infrequently seen during colonoscopy and is therefore an unreliable landmark of caecal intubation.

Background: APC mutations (APC-mt) occur in ∼70% of colorectal cancers (CRCs), but their relationship to prognosis is unclear., Methods: APC prognostic value was evaluated in 746 stage I-IV CRC patients, stratifying for tumour location and microsatellite instability (MSI). Microarrays were used to identify a gene signature that could classify APC mutation status, and classifier ability to predict prognosis was examined in an independent cohort., Results: Wild-type APC microsatellite stable (APC-wt/MSS) tumours from the proximal colon showed poorer overall and recurrence-free survival (OS, RFS) than APC-mt/MSS proximal, APC-wt/MSS distal and APC-mt/MSS distal tumours (OS HR⩾1.79, P⩽0.015; RFS HR⩾1.88, P⩽0.026). APC was a stronger prognostic indicator than BRAF, KRAS, PIK3CA, TP53, CpG island methylator phenotype or chromosomal instability status (P⩽0.036). Microarray analysis similarly revealed poorer survival in MSS proximal cancers with an APC-wt-like signature (P=0.019). APC status did not affect outcomes in MSI tumours. In a validation on 206 patients with proximal colon cancer, APC-wt-like signature MSS cases showed poorer survival than APC-mt-like signature MSS or MSI cases (OS HR⩾2.50, P⩽0.010; RFS HR⩾2.14, P⩽0.025). Poor prognosis APC-wt/MSS proximal tumours exhibited features of the sessile serrated neoplasia pathway (P⩽0.016)., Conclusions: APC-wt status is a marker of poor prognosis in MSS proximal colon cancer.

Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/β-catenin signalling levels 'just-right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282-1581) leaving 1-3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5' to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2-3 intact 20AARs were associated with 5' mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over-representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3' to the MCR. Microsatellite unstable cancers showed hyper-mutation at MCR mono- and di-nucleotide repeats, leaving 2-3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate 'fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/β-catenin signalling, with different 'optimal' thresholds for proximal and distal cancers.

Purpose: PIK3CA and PTEN mutations are prevalent in colorectal cancer and potential markers of response to mitogen-activated protein/extracellular signal-regulated kinase inhibitors and anti-EGF receptor antibody therapy. Relationships between phosphoinositide 3-kinase (PI3K) pathway mutation, clinicopathologic characteristics, molecular features, and prognosis remain controversial., Experimental Design: A total of 1,093 stage I-IV colorectal cancers were screened for PIK3CA (exons 9 and 20), KRAS (codons 12-13), BRAF (codon 600) mutations, and microsatellite instability (MSI). PTEN (exons 3-8) and CpG island methylator phenotype (CIMP) status were determined in 744 and 489 cases. PIK3CA data were integrated with 17 previous reports (n = 5,594)., Results: PIK3CA and PTEN mutations were identified in 11.9% and 5.8% of colorectal cancers. PTEN mutation was associated with proximal tumors, mucinous histology, MSI-high (MSI-H), CIMP-high (CIMP-H), and BRAF mutation (P < 0.02). PIK3CA mutation was related to older age, proximal tumors, mucinous histology, and KRAS mutation (P < 0.04). In integrated cohort analysis, PIK3CA exon 9 and 20 mutations were overrepresented in proximal, CIMP-low (CIMP-L), and KRAS-mutated cancers (P ≤ 0.011). Comparing PIK3CA exonic mutants, exon 20 mutation was associated with MSI-H, CIMP-H, and BRAF mutation, and exon 9 mutation was associated with KRAS mutation (P ≤ 0.027). Disease-free survival for stage II/III colorectal cancers did not differ by PI3K pathway status., Conclusion: PI3K pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile-serrated pathway (MSI-H/CIMP-H/BRAF(mut)), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-L/KRAS(mut)) of tumorigenesis. Our data highlight the PI3K pathway as a therapeutic target in distinct colorectal cancer subtypes.

Activation of the canonical TGF-β signaling pathway provides growth inhibitory signals in the normal intestinal epithelium. Colorectal cancers (CRCs) frequently harbor somatic mutations in the pathway members TGFBR2 and SMAD4, but to what extent mutations in SMAD2 or SMAD3 contribute to tumorigenesis is unclear. A cohort of 744 primary CRCs and 36 CRC cell lines were sequenced for SMAD4, SMAD2, and SMAD3 and analyzed for allelic loss by single-nucleotide polymorphism (SNP) microarray analysis. Mutation spectra were compared between the genes, the pathogenicity of mutations was assessed, and relationships with clinicopathologic features were examined. The prevalence of SMAD4, SMAD2, and SMAD3 mutations in sporadic CRCs was 8.6% (64 of 744), 3.4% (25 of 744), and 4.3% (32 of 744), respectively. A significant overrepresentation of two genetic hits was detected for SMAD4 and SMAD3, consistent with these genes acting as tumor suppressors. SMAD4 mutations were associated with mucinous histology. The mutation spectra of SMAD2 and SMAD3 were highly similar to that of SMAD4, both in mutation type and location within the encoded proteins. In silico analyses suggested the majority of the mutations were pathogenic, with most missense changes predicted to reduce protein stability or hinder SMAD complex formation. The latter altered interface residues or disrupted the phosphorylation-regulated Ser-Ser-X-Ser motifs within SMAD2 and SMAD3. Functional analyses of selected mutations showed reductions in SMAD3 transcriptional activity and SMAD2-SMAD4 complex formation. Joint biallelic hits in SMAD2 and SMAD3 were overrepresented and mutually exclusive to SMAD4 mutation, underlining the critical roles of these three proteins within the TGF-β signaling pathway.

Background: Familial adenomatous polyposis (FAP) is a hereditary disorder characterized by polyposis along the gastrointestinal tract. Information on adenoma status below the duodenum has previously been restricted due to its inaccessibility in vivo. Capsule Endoscopy (CE) may provide a useful adjunct in screening for polyposis in the small bowel in FAP patients. This study aims to evaluate the effectiveness of CE in the assessment of patients with FAP, compared to other imaging modalities for the detection of small bowel polyps., Method: 20 consecutive patients with previously diagnosed FAP and duodenal polyps, presenting for routine surveillance of polyps at The Royal Melbourne Hospital were recruited. Each fasted patient initially underwent a magnetic resonance image (MRI) of the abdomen, and a barium small bowel follow-through study. Capsule Endoscopy was performed four weeks later on the fasted patient. An upper gastrointestinal side-viewing endoscopy was done one (1) to two (2) weeks after this. Endoscopists and investigators were blinded to results of other investigations and patient history., Results: Within the stomach, upper gastrointestinal endoscopy found more polyps than other forms of imaging. SBFT and MRI generally performed poorly, identifying fewer polyps than both upper gastrointestinal and capsule endoscopy. CE was the only form of imaging that identified polyps in all segments of the small bowel as well as the only form of imaging able to provide multiple findings outside the stomach/duodenum., Conclusion: CE provides important information on possible polyp development distal to the duodenum, which may lead to surgical intervention. The place of CE as an adjunct in surveillance of FAP for a specific subset needs consideration and confirmation in replication studies., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12608000616370.

Purpose: About 15% of colorectal cancers harbor microsatellite instability (MSI). MSI-associated gene expression changes have been identified in colorectal cancers, but little overlap exists between signatures hindering an assessment of overall consistency. Little is known about the causes and downstream effects of differential gene expression., Experimental Design: DNA microarray data on 89 MSI and 140 microsatellite-stable (MSS) colorectal cancers from this study and 58 MSI and 77 MSS cases from three published reports were randomly divided into test and training sets. MSI-associated gene expression changes were assessed for cross-study consistency using training samples and validated as MSI classifier using test samples. Differences in biological pathways were identified by functional category analysis. Causation of differential gene expression was investigated by comparison to DNA copy-number data., Results: MSI-associated gene expression changes in colorectal cancers were found to be highly consistent across multiple studies of primary tumors and cancer cell lines from patients of different ethnicities (P < 0.001). Clustering based on consistent changes separated additional test cases by MSI status, and classification of individual samples predicted MSI status with a sensitivity of 96% and specificity of 85%. Genes associated with immune response were up-regulated in MSI cancers, whereas genes associated with cell-cell adhesion, ion binding, and regulation of metabolism were down-regulated. Differential gene expression was shown to reflect systematic differences in DNA copy-number aberrations between MSI and MSS tumors (P < 0.001)., Conclusions: Our results show cross-study consistency of MSI-associated gene expression changes in colorectal cancers. DNA copy-number alterations partly cause the differences in gene expression between MSI and MSS cancers.

Desmoid tumors are locally invasive, nonmetastasizing fibrous tumors most frequently seen in patients with familial polyposis coli (FPC). Of 325 patients with FPC treated at the Cleveland Clinic, 29 (8.9%) were found to have a total of 36 desmoid tumors. These tumors occur in young patients (mean age: 29.8 years), particularly women (ratio 3:1), and most appeared after previous colectomy (86%). The majority (72% of all desmoids, 90% of patients) were located within the abdomen, specifically within the mesentery of the small intestine. In most cases, attempts at surgical resection were followed by recurrence, and other previous treatments were similarly ineffective. Six of the 29 patients (21%) died from the desmoid and three died from other causes. The recent use of sulindac (Clinoril) has produced some early encouraging results in four patients with these tumors that have proven so difficult to treat in the past.