MSH3-related adenomatous polyposis in a patient with the negative family history of colorectal polyps.

Recently, biallelic MSH3 germline pathogenic/likely pathogenic variants have been recognized as a rare cause of adenomatous polyposis. We present a 49-year-old woman who was admitted to our high-risk colorectal cancer clinic after incidental detection of a biallelic MSH3 (likely) pathogenic variant when tested for the germline (likely) pathogenic variants in hereditary breast and ovarian cancer related genes. The focus of this case report is to describe the genotype and phenotype of our patient with MSH3-related adenomatous polyposis. More than half of the polyps (13/19) were located in the right colon. In addition, benign and malignant extraintestinal lesions may be common as our patient had simple liver and kidney cysts and two basal cell skin carcinomas.

Complete mesocolic excision in comparison with conventional surgery for right colon cancer: a nationwide multicenter study of the Italian Society of Surgical Oncology colorectal cancer network (CoME-in trial). Study protocol for a randomized controlled trial.

Complete mesocolic excision with central vascular ligation, or simply CME, includes the sharp dissection along the mesocolic visceral and parietal layers, with the ligation of the main vessels at their origins. To date, there is low evidence on its safety and efficacy. This is a study-protocol of a multicenter, randomized, superiority trial in patients with right-sided colon cancer. It aims to investigate whether the complete mesocolic excision improves the oncological outcomes as compared with conventional right hemicolectomy, without worsening early outcomes. Data on efficacy and safety of complete mesocolic excision are available only from a large trial recruiting eastern patients and from a low-volume single-center western study. No results on survival are still available. For this reason, complete mesocolic excision continues to be a controversial topic in daily practice, particularly in western world. This new nationwide multicenter large-volume trial aims to provide further data on western patients, concerning both postoperative and survival outcomes.

Increased Risk of Advanced Colonic Adenomas and Timing of Surveillance Colonoscopy Following Solid Organ Transplantation.

BACKGROUND: Detection and removal of colonic adenomatous polyps (CAP) decreases colorectal cancer (CRC) development, particularly with more or larger polyps or polyps with advanced villous/dysplastic histology. Immunosuppression following solid organ transplantation (SOT) may accelerate CAP development and progression compared to average-risk population but the benefit of earlier colonoscopic surveillance is unclear. AIMS: Study the impact of maintenance immunosuppression post-SOT on developmental timing, multiplicity and pathological features of CAP, by measuring incidence of advanced CAP (villous histology, size ≥ 10 mm, ≥ 3 polyps, presence of dysplasia) post-SOT and the incidence of newly diagnosed CRC compared to average-risk age-matched population. METHODS: Single-center retrospective cohort study of SOT recipients. RESULTS: 295 SOT recipients were included and were compared with 291 age-matched average-risk controls. The mean interval between screening and surveillance colonoscopies between SOT and control groups was 6.3 years vs 5.9 years (p = 0.13). Post-SOT maintenance immunosuppression mean duration averaged 59.9 months at surveillance colonoscopy. On surveillance examinations, SOT recipients exhibited more advanced (≥ 10 mm) adenomas compared to matched controls (9.2% vs. 3.8%, p = 0.034; adjusted OR 2.38; 95% CI 1.07-5.30). CONCLUSION: SOT recipients appear at higher risk for developing advanced CAP, suggesting that earlier surveillance should be considered.

Colorectal paragangliomas with immunohistochemical deficiency of succinate dehydrogenase subunit B.

Recent progress in paraganglioma (PGL) revealed genotype-phenotype relationship, especially succinate dehydrogenase complex subunit B (SDHB) gene mutation-related to the extra-adrenal origin and metastasis. SDHB-immunohistochemistry can detect all types of SDH-subunit mutations, and is a useful tool to detect SDH-mutation tumors. PGLs usually occur along with sympathetic, and parasympathetic chains, however, colorectal paraganglioma is extremely rare. We have experienced one sigmoid colon PGL and one rectal PGL. These colorectal PGLs: a sigmoid colon PGL measuring 25 mm associated with a gastrointestinal stromal tumor (GIST) of the stomach, and a rectal PGL measuring 75 × 45 mm with elevated norepinephrine level were analyzed by immunohistochemistry for INSM1, chromogranin A, synaptophysin, tyrosine hydroxylase, dopamine-beta-hydroxylase, and SDHB and SDHA. The tumors were strongly positive for above markers, however, negative for SDHB. Both PGLs negative for SDHB immunohistochemistry were defined SDHB-deficient PGLs. Histologic grading of the PGLs by GAPP was well differentiated in sigmoid PGL versus poorly differentiated in rectal PGL. Although these PGLs were the same Stage II of TNM classification, the patient with sigmoid colon PGL had neither recurrence nor metastasis for 5 years after the operation, however, the patient with rectal PGL suffered the recurrent multiple metastases and expired 5 years after the operation. Herein, we compared these colorectal PGLs in regard to the patients' prognostic factors. Patient prognosis with these colorectal PGLs was mostly related to the tumor size and histologic grade under the same situation of SDH-deficiency.

Toward Elucidating the Physiological Impacts of Residual Stresses in the Colorectum.

Irritable bowel syndrome afflicts 10-20% of the global population, causing visceral pain with increased sensitivity to colorectal distension and normal bowel movements. Understanding and predicting these biomechanics will further advance our understanding of visceral pain and complement the existing literature on visceral neurophysiology. We recently performed a series of experiments at three longitudinal segments (colonic, intermediate, and rectal) of the distal 30 mm of colorectums of mice. We also established and fitted constitutive models addressing mechanical heterogeneity in both the through-thickness and longitudinal directions of the colorectum. Afferent nerve endings, strategically located within the submucosa, are likely nociceptors that detect concentrations of mechanical stresses to evoke the perception of pain from the viscera. In this study, we aim to: (1) establish and validate a method for incorporating residual stresses into models of colorectums, (2) predict the effects of residual stresses on the intratissue mechanics within the colorectum, and (3) establish intratissue distributions of stretches and stresses within the colorectum in vivo. To these ends we developed two-layered, composite finite element models of the colorectum based on our experimental evidence and validated our approaches against independent experimental data. We included layer- and segment-specific residual stretches/stresses in our simulations via the prestrain algorithm built into the finite element software febio. Our models and modeling approaches allow researchers to predict both organ and intratissue biomechanics of the colorectum and may facilitate better understanding of the underlying mechanical mechanisms of visceral pain.

Optical clearing reveals TNBS-induced morphological changes of VGLUT2-positive nerve fibers in mouse colorectum.

Colorectal hypersensitivity and sensitization of both mechanosensitive and mechanically insensitive afferents develop after intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) in the mouse, a model of postinfectious irritable bowel syndrome. In mice in which ∼80% of extrinsic colorectal afferents were labeled genetically using the promotor for vesicular glutamate transporter type 2 (VGLUT2), we systematically quantified the morphology of VGLUT2-positive axons in mouse colorectum 7-28 days following intracolonic TNBS treatment. After removal, the colorectum was distended (20 mmHg), fixed with paraformaldehyde, and optically cleared to image VGLUT2-positive axons throughout the colorectal wall thickness. We conducted vector path tracing of individual axons to allow systematic quantification of nerve fiber density and shape. Abundant VGLUT2-positive nerve fibers were present in most layers of the colorectum, except the serosal and longitudinal muscular layers. A small percentage of VGLUT2-positive myenteric plexus neurons was also detected. Intracolonic TNBS treatment significantly reduced the number of VGLUT2-positive nerve fibers in submucosal, myenteric plexus, and mucosal layers at day 7 post-TNBS, which mostly recovered by day 28. We also found that almost all fibers in the submucosa were meandering and curvy, with ∼10% showing pronounced curviness (quantified by the linearity index). TNBS treatment resulted in a significant reduction of the proportions of pronounced curvy fibers in the rectal region at 28 days post-TNBS. Altogether, the present morphological study reveals profound changes in the distribution of VGLUT2-positive fibers in mouse colorectum undergoing TNBS-induced colitis and draws attention to curvy fibers in the submucosa with potential roles in visceral nociception.NEW & NOTEWORTHY We conducted genetic labeling and optical clearing to visualize extrinsic sensory nerve fibers in whole-mount colorectum, which revealed widespread presence of axons in the submucosal layer. Remarkably, axons in the submucosa were meandering and curvy, in contrast to axons in other layers generally aligned with the basal tissues. Intracolonic TNBS treatment led to pronounced changes of nerve fiber density and curviness, suggesting nerve fiber morphologies as potentially contributing factors to sensory sensitization.

Autocrine and paracrine purinergic signaling in the most lethal types of cancer.

Cancer comprises a collection of diseases that occur in almost any tissue and it is characterized by an abnormal and uncontrolled cell growth that results in tumor formation and propagation to other tissues, causing tissue and organ malfunction and death. Despite the undeniable improvement in cancer diagnostics and therapy, there is an urgent need for new therapeutic and preventive strategies with improved efficacy and fewer side effects. In this context, purinergic signaling emerges as an interesting candidate as a cancer biomarker or therapeutic target. There is abundant evidence that tumor cells have significant changes in the expression of purinergic receptors, which comprise the G-protein coupled P2Y and AdoR families of receptors and the ligand-gated ion channel P2X receptors. Tumor cells also exhibit changes in the expression of nucleotidases and other enzymes involved in nucleotide metabolism, and the concentrations of extracellular nucleotides are significantly higher than those observed in normal cells. In this review, we will focus on the potential role of purinergic signaling in the ten most lethal cancers (lung, breast, colorectal, liver, stomach, prostate, cervical, esophagus, pancreas, and ovary), which together are responsible for more than 5 million annual deaths.

Opioid-induced constipation in patients with cancer pain in Japan (OIC-J study): a post hoc subgroup analysis of patients with lung cancer.

OBJECTIVE: To evaluate the opioid-induced constipation burden in the subgroup of patients with lung cancer who participated in the observational Opioid-Induced Constipation in Patients with Cancer Pain in Japan (OIC-J) study. METHODS: The prospective, observational study, OIC-J, included 212 patients with various tumour types, 33% of whom had lung cancer. The incidence of opioid-induced constipation was evaluated using several diagnostic criteria, as well as the physician's diagnosis and patient's subjective assessment. Following initiation of opioids, patients recorded details of bowel movements (i.e. date/time, Bristol Stool Scale form, sensations of incomplete evacuation or anorectal obstruction/blockage and degree of straining) in a diary for 2 weeks. Relationships between patient characteristics and opioid-induced constipation onset and effects of opioid-induced constipation on quality of life were explored. RESULTS: In total, 69 patients were included in this post hoc analysis. The incidence of opioid-induced constipation varied (39.1-59.1%) depending on which diagnostic criteria was used. Diagnostic criteria that included a quality component or a patient's feeling of bowel movement as an evaluation item (i.e. Rome IV, physician's diagnosis, Bowel Function Index, patient's assessment) showed higher incidences of opioid-induced constipation than recording the number of spontaneous bowel movements alone. Opioid-induced constipation occurred rapidly after initiating opioids and had a significant impact on Patient Assessment of Constipation Symptoms total score (P = 0.0031). Patient baseline characteristics did not appear to be predictive of opioid-induced constipation onset. CONCLUSIONS: In patients with lung cancer, opioid-induced constipation can occur quickly after initiating opioids and can negatively impact quality of life. Early management of opioid-induced constipation, with a focus on quality-of-life improvement and patient's assessments of bowel movements, is important for these patients.

Physiological and pathophysiological role of ion channels and transporters in the colorectum and colorectal cancer.

The incidence of colorectal cancer has increased annually, and the pathogenesis of this disease requires further investigation. In normal colorectal tissues, ion channels and transporters maintain the water-electrolyte balance and acid/base homeostasis. However, dysfunction of these ion channels and transporters leads to the development and progression of colorectal cancer. Therefore, this review focuses on the progress in understanding the roles of ion channels and transporters in the colorectum and in colorectal cancer, including aquaporins (AQPs), Cl- channels, Cl- / HCO3- exchangers, Na+ / HCO3- transporters and Na+ /H+ exchangers. The goal of this review is to promote the identification of new targets for the treatment and prognosis of colorectal cancer.

Nomograms that predict the survival of patients with adenocarcinoma in villous adenoma of the colorectum: a SEER-based study.

BACKGROUND: Considering that the knowledge of adenocarcinoma in villous adenoma of the colorectum is limited to several case reports, we designed a study to investigate independent prognostic factors and developed nomograms for predicting the survival of patients. METHODS: Univariate and multivariate Cox regression analyses were used to evaluate prognostic factors. A nomogram predicting cancer-specific survival (CSS) was performed; internally and externally validated; evaluated by receiver operating characteristic (ROC) curve, C-index, and decision curve analyses; and compared to the 7th TNM stage. RESULTS: Patients with adenocarcinoma in villous adenoma of the colorectum had a 1-year overall survival (OS) rate of 88.3% (95% CI: 87.1-89.5%), a 3-year OS rate of 75.1% (95% CI: 73.3-77%) and a 5-year OS rate of 64.5% (95% CI: 62-67.1%). Nomograms for 1-, 3- and 5-year CSS predictions were constructed and performed better with a higher C-index than the 7th TNM staging (internal: 0.716 vs 0.663; P < 0.001; external: 0.713 vs 0.647; P < 0.001). Additionally, the nomogram showed good agreement between internal and external validation. According to DCA analysis, compared to the 7th TNM stage, the nomogram showed a greater benefit across the period of follow-up regardless of the internal cohort or external cohort. CONCLUSION: Age, race, T stage, pathologic grade, N stage, tumor size and M stage were prognostic factors for both OS and CSS. The constructed nomograms were more effective and accurate for predicting the 1-, 3- and 5-year CSS of patients with adenocarcinoma in villous adenoma than 7th TNM staging.

Visceral pain from colon and rectum: the mechanotransduction and biomechanics.

Visceral pain is the cardinal symptom of functional gastrointestinal (GI) disorders such as the irritable bowel syndrome (IBS) and the leading cause of patients' visit to gastroenterologists. IBS-related visceral pain usually arises from the distal colon and rectum (colorectum), an intraluminal environment that differs greatly from environment outside the body in chemical, biological, thermal, and mechanical conditions. Accordingly, visceral pain is different from cutaneous pain in several key psychophysical characteristics, which likely underlies the unsatisfactory management of visceral pain by drugs developed for other types of pain. Colorectal visceral pain is usually elicited from mechanical distension/stretch, rather than from heating, cutting, pinching, or piercing that usually evoke pain from the skin. Thus, mechanotransduction, i.e., the encoding of colorectal mechanical stimuli by sensory afferents, is crucial to the underlying mechanisms of GI-related visceral pain. This review will focus on colorectal mechanotransduction, the process of converting colorectal mechanical stimuli into trains of action potentials by the sensory afferents to inform the central nervous system (CNS). We will summarize neurophysiological studies on afferent encoding of colorectal mechanical stimuli, highlight recent advances in our understanding of colorectal biomechanics that plays critical roles in mechanotransduction, and review studies on mechano-sensitive ion channels in colorectal afferents. This review calls for focused attention on targeting colorectal mechanotransduction as a new strategy for managing visceral pain, which can also have an added benefit of limited CNS side effects, because mechanotransduction arises from peripheral organs.

Adequacy evaluation of the annual colonoscopic surveillance and individual difference of disease phenotypes in Lynch syndrome.

BACKGROUND: Regular endoscopic surveillance for Lynch syndrome is reported to reduce colorectal cancer (CRC)-related mortality. However, the appropriate surveillance intervals are still unclear. We evaluated the adequacy of annual colonoscopy and investigated the differences in tumor occurrence rates between individual patients. METHODS: In total, 25 patients with Lynch syndrome who underwent colonoscopic surveillance between 2007 and 2016 at the Iwakuni Clinical Center were included. We retrospectively investigated the surveillance frequency and the clinical features associated with tumor development. RESULTS: Colonoscopic surveillance was performed every 397 days on average. A total of 101 tumors, including 8 intramucosal carcinomas and 15 carcinomas, were observed within the study period. Annual colonoscopy detected six malignancies, including a carcinoma requiring surgery. Tumor incidence was associated with tumor existence in the initial colonoscopies (P = 0.018). Patients with a tumor occurrence rate of 0.4 tumors per year during our observation period were significantly more likely to have malignancies detected during regular surveillance than patients who had a lower occurrence rate (P < 0.001). Malignancy occurrence rate was strongly associated with tumor occurrence rate (P < 0.001, R2 = 0.44). CONCLUSIONS: Annual colonoscopic surveillance for Lynch syndrome patients was effective in reducing the risk of CRC progression, but was insufficient to completely avoid surgery. Because the tumor occurrence rate differed substantially between individuals, more intensive surveillance was required for high-risk patients.

Mucosal Schwann cell hamartoma of the gastroesophageal junction: A series of 6 cases and comparison with colorectal counterpart.

Mucosal Schwann cell hamartoma (MSCH) is an uncommon neural lesion characterized by an ill-defined proliferation of S100-positive Schwann cells in the lamina propria, with reported cases exclusively occurring in the colorectum. Here we describe the first series of MSCHs arising in the gastroesophageal junction (GEJ) and discuss their clinicopathologic features in comparison with their colorectal counterparts. We searched the UCLA pathology database from 01/2014 to 12/2018 to identify cases carrying the diagnosis of MSCH. A total of 48 cases (45 in-house, 3 consults) of colorectal MSCHs and 6 cases (1 in-house, 5 consults) of GEJ MSCHs were identified. For GEJ MSCHs, there were 4 males and 2 females with an average age of 70.2 years (range: 57-76 years). Clinical indications for endoscopy included history of gastroesophageal reflux disease (n = 2), heartburn (n = 2), dysphagia (n = 1), and iron deficiency anemia (n = 1). Endoscopic findings at the GEJ were available for 5 patients including irregular Z-line (n = 3), mild nodular carditis (n = 1), and normal (n = 1). None of them showed a polyp or nodule. The mean size of the lesion was 2.8 mm (range: 2-4 mm) microscopically. None of the colorectal or GEJ MSCH cases had an association with inherited syndromes. In conclusion, MSCH of the gastrointestinal tract is predominantly seen in the colorectum, but also infrequently seen in the GEJ. GEJ MSCH shares histologic and immunohistochemical features with its colorectal counterpart, but is usually an incidental finding with no endoscopically visible lesion. As there is no syndromic association with MSCH, additional treatment, work-up and follow-up are unnecessary.

Load-bearing function of the colorectal submucosa and its relevance to visceral nociception elicited by mechanical stretch.

Mechanical distension beyond a particular threshold evokes visceral pain from distal colon and rectum (colorectum), and thus biomechanics plays a central role in visceral nociception. In this study we focused on the layered structure of the colorectum through the wall thickness and determined the biomechanical properties of layer-separated colorectal tissue. We harvested the distal 30 mm of mouse colorectum and dissected this tissue into inner and outer composite layers. The inner composite consists of the mucosa and submucosa, whereas the outer composite includes the muscular layers and serosa. We divided each composite axially into three 10-mm-long segments and conducted biaxial mechanical extension tests and opening-angle measurements for each tissue segment. In addition, we quantified the thickness of the rich collagen network in the submucosa by nonlinear imaging via second-harmonic generation (SHG). Our results reveal that the inner composite is slightly stiffer in the axial direction, whereas the outer composite is stiffer circumferentially. The stiffness of the inner composite in the axial direction is about twice that in the circumferential direction, consistent with the orientations of collagen fibers in the submucosa approximately ±30° to the axial direction. Submucosal thickness measured by SHG showed no difference from proximal to distal colorectum under the load-free condition, which likely contributes to the comparable tension stiffness of the inner composite along the colorectum. This, in turn, strongly indicates the submucosa as the load-bearing structure of the colorectum. This further implies nociceptive roles for the colorectal afferent endings in the submucosa, which likely encode tissue-injurious mechanical distension.NEW & NOTEWORTHY Visceral pain from distal colon and rectum (colorectum) is usually elicited from mechanical distension/stretch, rather than from heating, cutting, or pinching, which usually evoke pain from the skin. We conducted layer-separated biomechanical tests on mouse colorectum and identified an unexpected role of submucosa as the load-bearing structure of the colorectum. Outcomes of this study will focus attention on sensory nerve endings in the submucosa that likely encode tissue-injurious distension/stretch to cause visceral pain.

EIF3E-RSPO2 and PIEZO1-RSPO2 fusions in colorectal traditional serrated adenoma.

AIMS: Traditional serrated adenoma (TSA) is an uncommon type of colorectal serrated polyp. RSPO fusions, which potentiate WNT signalling, are common and characteristic genetic alterations in TSA. The aim of this study was to further characterise the prevalence and variation of RSPO fusions in TSA. METHODS AND RESULTS: Quantitative polymerase chain reaction (PCR) analysis of 99 TSAs revealed overexpression of RSPO2 and RSPO3 in six and 29 lesions, respectively. Reverse transcription PCR identified previously reported PTPRK-RSPO3 fusion transcripts in all 29 TSAs with RSPO3 overexpression, confirming that PTPRK-RSPO3 is the predominant RSPO fusion in TSAs. Among the six lesions with RSPO2 overexpression, two overexpressed full-length RSPO2. An EIF3E-RSPO2 fusion, which is a known recurrent RSPO fusion in colorectal cancer, was detected in three lesions. In addition, rapid amplification of cDNA ends identified a novel PIEZO1-RSPO2 fusion in one TSA. All of the four TSAs with RSPO2 fusions concurrently had KRAS mutations and showed the classic histological features. CONCLUSIONS: The present study identified EIF3E-RSPO2 and PIEZO1-RSPO2 in TSAs. Our observations expand the spectrum of RSPO fusions in TSAs, and suggest that TSAs are precursors of colorectal cancers with these RSPO2 fusions.

Colorectal large-cell neuroendocrine carcinoma with lymphoid stroma: further evidence confirming a unique subtype associated with MLH1/PMS2 loss, BRAF mutation, Epstein-Barr virus negativity, and the possibility of a better prognosis.

AIMS: Pure large-cell neuroendocrine carcinoma (LCNEC) is an uncommon but well-recognised primary tumour of the colorectum. It is characterised by large cells organised in a discernible neuroendocrine pattern with >20 mitoses per 10 high-power fields (HPFs), and/or a Ki67 index of >20%, and coagulative tumour necrosis is invariably present. These features are supplemented by positivity for neuroendocrine immunohistochemical markers. The aim of this study was to highlight three primary LCNECs of the colorectum. METHODS AND RESULTS: All three patients were elderly females, aged 79, 85 and 89 years, who presented with ascending colon (two) tumours and a rectal tumour. All three tumours were large, ulcerated, polypoid masses (85, 76 and 55 mm; average size 72 mm) and were pT3N2. Histologically, the tumours were composed of packets and nests of cells with rosettes; other areas were in sheets composed of large cells. The mitotic counts were 23/10 HPFs, 27/10 HPFs and 24/10 HPFs, respectively. There was no mucosal dysplasia, precursor adenoma or associated adenocarcinoma component. All cases contained mainly peritumoral lymphoid aggregates, with smaller numbers of intratumoral lymphocytes. Synaptophysin, chromogranin (less intensely) and epithelial markers were expressed in all cases in the majority of the tumour cells. The Ki67 proliferative indices were 95%, 100%, and 80%, respectively. Two patients survived for 48 and 72 months, whereas the third is alive after 12 months without evidence of recurrence. CONCLUSIONS: These unusual primary colorectal LCNECs with an accompanying lymphoid component are characterised by loss of MLH1/PMS2, BRAF mutation, microsatellite instability, and Epstein-Barr virus negativity. The patients also have better overall survival than those with LCNECs lacking an accompanying lymphoid component.

Location of colorectal adenomas and serrated polyps in patients under age 50.

BACKGROUND: The incidence of colorectal cancer, especially located in distal colorectum, is rising markedly in young patients. Conventional adenomas and serrated polyps have been widely recognized as precursors of colorectal cancer. AIM: To investigate the correlation of polyp feature with polyp location in patients under age 50. METHOD: Patients under age 50 who had received colonoscopy were included from 2010 to 2018. Clinical data including number, location, size, and histopathology of polyps were collected. Odd ratios and 95% confidence interval of adenomas with their location were calculated. RESULT: In total, 25,636 patients aged 18-49 were enrolled, among which 4485 patients had polyps, with polyp detection rate of 17.5%. A total of 2484 and 2387 patients had conventional adenomas and serrated polyps, respectively. 76.0% advanced adenomas and 69.5% ≥ 10-mm serrated polyps were located in the distal colorectum. The detection rate of advanced adenomas was higher in patients aged 45-49. Patients with adenomas especially advanced adenomas in the distal colorectum were more likely to have advanced adenoma in the proximal colon. CONCLUSION: Among patients under age 50, advanced adenomas and ≥ 10-mm serrated polyps were predominantly in the distal colorectum. Advanced adenomas tended to be found in patients aged 45-49. Our results might explain the rising trend of distal colorectal cancer and emphasize the necessity for colonoscopy screening among these populations.

Second-harmonic imaging microscopy for identifying colorectal intraepithelial neoplasia.

In this study, second-harmonic imaging microscopy was used to monitor precancerous colorectal lesions at different stages. It was found that the morphology of glands and lamina propria in mucosa changes with the progression of colorectal diseases from normal to low-grade intraepithelial neoplasia to high-grade intraepithelial neoplasia and this microscopy has the ability of direct visualization of these warning symptoms. Furthermore, two morphologic variables were quantified to determine the changes of glands and collagen in lamina propria during the development of colorectal intraepithelial neoplasia. These results suggest that second-harmonic imaging microscopy has the potential in label-freely and effectively distinguishing between normal and precancerous colorectal tissues, and will be helpful for early diagnosis and treatment of colorectal diseases.

Assessing global transitions in human development and colorectal cancer incidence.

Colorectal cancer incidence has paralleled increases in human development across most countries. Yet, marked decreases in incidence are now observed in countries that have attained very high human development. Thus, in this study, we explored the relationship between human development and colorectal cancer incidence, and in particular assessed whether national transitions to very high human development are linked to temporal patterns in colorectal cancer incidence. For these analyses, we utilized the Human Development Index (HDI) and annual incidence data from regional and national cancer registries. Truncated (30-74 years) age-standardized incidence rates were calculated. Yearly incidence rate ratios and HDI ratios, before and after transitioning to very high human development, were also estimated. Among the 29 countries investigated, colorectal cancer incidence was observed to decrease after reaching the very high human development threshold for 12 countries; decreases were also observed in a further five countries, but the age-standardized incidence rates remained higher than that observed at the threshold. Such declines or stabilizations are likely due to colorectal cancer screening in some populations, as well as varying levels of exposure to protective factors. In summary, it appears that there is a threshold at which human development predicts a stabilization or decline in colorectal cancer incidence, though this pattern was not observed for all countries assessed. Future cancer planning must consider the increasing colorectal cancer burden expected in countries transitioning towards higher levels of human development, as well as possible declines in incidence among countries reaching the highest development level.

Increased expression of interleukin-21 along colorectal adenoma-carcinoma sequence and its predicating significance in patients with sporadic colorectal cancer.

The role and significance of interleukin (IL)-21 in the development of sporadic CRC have not been well defined. The aim of this study is therefore to investigate the dynamics of the IL-21 along colorectal adenoma-carcinoma sequence and to evaluate the impact of IL-21 on clinicopathological parameters and CRC prognosis. The real-time PCR results showed that the level of IL-21 in adenomas (n=50) and sporadic CRC (n=50) were significantly higher than that in normal controls (n=18), which were predominately observed in the adenoma/CRC stroma. Analysis revealed that IL-21 level was correlated with the overall survival time in CRC patients. Double immunofluorescence observations confirmed that IL-21 positive cells were mostly natural killer cells and T lymphocytes in the tumor stroma. These results indicate that significant increased IL-21 expression present within the adenoma/CRC microenvironment might have a potential predicating significance for survival time in patients with CRC.