Immunohistochemical molecular markers as predictors of curability of endoscopically resected submucosal colorectal cancer

AIM: To clarify the usefulness of immunohistochemical molecular markers in predicting lymph node metastasis of submucosal colorectal cancer. METHODS: We examined microvessel density, lymphatic vessel density, the Ki-67 labeling index, expression of MUC1 and Matrix metalloproteinase-7 (MMP-7) in tumor cells, and expression of cathepsin D in stromal cells at the invasive front by immunostaining of samples resected from 214 patients with submucosal colorectal cancer. Pathologic features were assessed on hematoxylin-eosin- stained samples. We evaluated the relations between clinicopathologic/immunohistochemical features and lymph node metastasis. RESULTS: Lesions of the superficial type, with an unfavorable histologic grade, budding, lymphatic involvement, high microvessel density (≥ 40), high lymphatic vessel density (≥ 9), high Ki-67 labeling index (≥ 42), and positivity of MUC1, cathepsin D, and MMP-7 showed a significantly high incidence of lymph node metastasis. Multivariate analysis revealed that high microvessel density, unfavorable histologic grade, cathepsin D positivity, high lymphatic vessel density, superficial type, budding, and MUC1 positivity were independent risk factors for lymph node metastasis.A combined examination with four independent immunohistochemical markers (microvessel density, cathepsin D, lymphatic vessel density, and MUC1) revealed that all lesions that were negative for all markers or positive for only one marker were negative for lymph node metastasis. CONCLUSION: Analysis of a combination of immuno- histochemical molecular markers in endoscopically resected specimens of submucosal colorectal cancer allows prediction of curability regardless of the pathologic features visible of hematoxylin-eosin-stained sections.

Clinical significance of type V_I pit pattern subclassification in determining the depth of invasion of colorectal neoplasms

AIM: To clarify whether subclassification of the type VI pit pattern on the basis of magnifying colonoscopy findings is useful in determining the type and depth of invasion of colorectal neoplasms.METHODS: We retrospectively analyzed 272 colorectal neoplasms (117 dysplasias and 155 submucosal invasive carcinomas; 228 patients) with a type V pit pattern [type VI, n = 202; type VN, n = 70 (Kudo and Tsuruta classification system)]. We divided lesions with a type VI pit pattern into two subclasses, mildly irregular lesions and severely irregular lesions, according to the prominent and detailed magnifying colonoscopy findings. We examined the relation between these two subclasses and histology/invasion depth.RESULTS: One hundred and four lesions (51.5%) were judged to be mildly irregular, and 98 lesions (48.5%) were judged to be severely irregular. Ninety-seven (93.3%) mildly irregular lesions showed dysplasias or submucosal invasion of less than 1000 μm (SM < 1000 μm). Fifty-five (56.1%) severely irregular lesions showed submucosal invasion equal to or deeper than 1000 μm (SM ≥ 1000 μm). Mild irregularity was found significantly more often in dysplasias or lesions with SM < 1000 μm than in lesions with SM ≥ 1000 μm (P < 0.01).CONCLUSION: Subclassification of the type VI pit pattern is useful for identifying dysplasias or lesions with SM < 1000 μm.

Defensive medicine practices among gastroenterologists in Japan

AIM： To clarify the prevalence of defensive medicine and the specific defensive medicine practices among gastroenterologists in Japan. METHODS： A survey of gastroenterologists in Hiroshima, Japan, was conducted by mail in March 2006. The number of gastroenterologists reporting defensive medicine behaviors or changes in their scope of practice and the reported defensive medicine practices, i.e., assurance and avoidance behaviors, were examined. RESULTS： A total of 131 （77%） out of 171 gastroenterologists completed the survey. Three （2%） respondents were sued, and most respondents （96%） had liability insurance. Nearly all respondents （98%） reported practicing defensive medicine. Avoidance behaviors, such as avoiding certain procedures or interventions and avoiding caring for high-risk patients, were very common （96%）. Seventy-five percent of respondents reported often avoiding certain procedures or interventions. However, seasoned gastroenterologists （those in practice for more than 20 years） adopted avoidance behaviors significantly less often than those in practice for less than 10 years. Assurance behaviors, i.e., supplying additional services of marginal or no medical value, were also widespread （91%）. Sixty-eight percent of respondents reported that they sometimes or often referred patients to other specialists unnecessarily. CONCLUSION： Defensive medicine may be highly prevalent among gastroenterologists throughout 3apan, with potentially serious implications regarding costs, access, and both technical and interpersonal quality of care.

Strategy for treatment of nonerosive reflux disease in Asia

The paper is to review the clinical and pathophysiologic differences between of nonerosive reflux disease (NERD) and reflux esophagitis (RE), and to propose a treatment strategy for NERD, especially for patients in Asia. A Medline search was performed regarding the clinical and pathophysiologic differences between NERD and RE, and treatment of NERD and RE. The characteristics of NERD patients in Asia are as follows: (1) high proportion of female patients, (2) low frequency of hiatal hernia, (3) high frequency of H pylori infection, (4) severe glandular atrophy of the gastric mucosa, and (5) frequent resistance to proton pump inhibitor (PPI) therapy. In Asian NERD patients, exposure of the esophagus to acid is not increased, and esophageal motility is normal. These characteristics are similar to those of patients in Western countries. Our recommended first-choice treatment is administration of PPI in combination with a prokinetic agent. However, at present, because there is limited evidence regarding effective treatments for NERD, it is best to try several different treatment strategies to find the best treatment for each patient.

Causal role of Helicobacter pylori infection and eradication therapy in gastric carcinogenesis

Many epidemiological reports indicate that Helicobacter pylori （H pylori） infection plays an important role in gastric carcinogenesis. Several genetic and epigenetic alterations contribute to the initiation, promotion, and progression of the cancer cells in a multi-step manner. H pylori is known to induce chronic inflammation in the gastric mucosa. Its products, including superoxides, participate in the DNA damage followed by initiation, and the inflammation-derived cytokines and growth factors contribute to the promotion of gastric carcinogenesis. By eradicating H pylori, gastric inflammation can be cured; the therapy diminishes the levels not only of inflammatory cell infiltration, but also atrophy/ intestinal metaplasia in part. A randomized controlled trial revealed that the eradication therapy diminished the gastric cancer prevalence in cases without precancerous conditions. In addition, recent epidemiological studies from Japanese groups demonstrated that the development of gastric cancer, especially of the intestinal type, was decreased by successful eradication therapy, although these were designed in a non- randomized manner. However, it should be mentioned that endoscopic detection is the only way to evaluate the degree of gastric carcinogenesis. We have reported that the endoscopic and histological morphologies could be modified by eradication therapy and it might contribute to the prevalence of gastric cancer development. Considering the biological nature of cancer cell proliferation, it is considered that a sufficiently long-term follow-up would be essential to discuss the anticancer effect of eradication therapy.

Usefulness of positron emission tomography in primary intestinal follicular lymphoma

Double-balloon enteroscopy (DBE) and video capsule endoscopy are useful for the diagnosis of lymphoma in the small intestine. However, DBE cannot be safely performed in cases with passage disturbance due to wall thickening and stenosis. Additionally, video capsule endoscopy cannot be performed in such cases because of the risk of retention. Here, we report 4 cases of primary follicular lymphoma of the gastrointestinal tract that could be detected using 18F-fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET-CT). The endoscopic findings of these 4 cases included lesions with wall thickening, which comprised macroscopically clusters of nodules, dense clusters of whitish granules or small nodules, fold thickening and ulcers with irregular margins that occupied the whole lumen with edematous mucosa. All patients fulfilled the World Health Organization grade 1 criteria. 18 F-fluorodeoxyglucose PET-CT can help predict the risks that may result from certain endoscopic examinations, such as DBE and video capsule endoscopy.

Selective decrease in colonic CD56^+ T and CD161^+ T cells in the inflamed mucosa of patients with ulcerative colitis

AIM： To investigate the role of local colonic mucosal NK receptor-positive T （NKR＋ T） cells in the regulation of intestinal inflammation, we analyzed the population and function of these cells in ulcerative colitis （UC）. METHODS： Colonic mucosal tissues were obtained from colonoscopic biopsies of the descending colon from 96 patients with UC （51 endoscopically uninflamed, 45 inflamed） and 18 normal controls. Endoscopic appearance and histologic score at the biopsied site were determined by MaLts＇ classification. A single cell suspension was prepared from each biopsy by collagenase digestion. Two NKR^＋ T cell subsets, CD56^＋ （CD56^＋CD3^＋） T cells and CD161＋ （CD161^＋CD3^＋） T cells, were detected by flow cytometric analysis. Intracellular cytokine analysis for anti-inflammatory cytokine interleukin-10 （IL-10） was performed by in vitro stimulation with phorbol-myristateacetate （PMA） and ionomycin. RESULTS： CD56^＋ T cells and CD161^＋ T cells are present in the normal human colon and account for 6.7% and 21.3% of all mononuclear cells, respectively. The populations of both CD56＋ T cells and CD161^＋ T cells were decreased significantly in the inflamed mucosa of UC. In contrast, the frequency of conventional T cells （CD56 CD3^＋ cells and CD161CD3^＋ cells） was similar among the patient and control groups. The populations of NKR^＋ T cells were correlated inversely with the severity of inflammation, which was classified according to the endoscopic and histologic Marts＇ criteria. Interestingly, approximately 4% of mucosal NKR＋ T cells expressing IL-10 were detected by in vitro stimulation with PMA and ionomycin.CONCLUSION： Selective reduction in the population of colonic mucosal NKR＋T cells may contribute to the development of intestinal inflammation in UC.

Outcome of patients who have undergone total enteroscopy for obscure gastrointestinal bleeding

AIM： To assess the diagnostic success and outcome among patients with obscure gastrointestinal bleeding who underwent total enteroscopy with double-balloon endoscopy.

Quest for the best endoscopic imaging modality for computer-assisted colonic polyp staging

BACKGROUND It was shown in previous studies that high definition endoscopy, high magnification endoscopy and image enhancement technologies, such as chromoendoscopy and digital chromoendoscopy [narrow-band imaging(NBI), iScan] facilitate the detection and classification of colonic polyps during endoscopic sessions. However, there are no comprehensive studies so far that analyze which endoscopic imaging modalities facilitate the automated classification of colonic polyps. In this work, we investigate the impact of endoscopic imaging modalities on the results of computer-assisted diagnosis systems for colonic polyp staging.AIM To assess which endoscopic imaging modalities are best suited for the computerassisted staging of colonic polyps.METHODS In our experiments, we apply twelve state-of-the-art feature extraction methods for the classification of colonic polyps to five endoscopic image databases of colonic lesions. For this purpose, we employ a specifically designed experimental setup to avoid biases in the outcomes caused by differing numbers of images per image database. The image databases were obtained using different imaging modalities. Two databases were obtained by high-definition endoscopy in combination with i-Scan technology(one with chromoendoscopy and one without chromoendoscopy). Three databases were obtained by highmagnification endoscopy(two databases using narrow band imaging and one using chromoendoscopy). The lesions are categorized into non-neoplastic and neoplastic according to the histological diagnosis.RESULTS Generally, it is feature-dependent which imaging modalities achieve high results and which do not. For the high-definition image databases, we achieved overall classification rates of up to 79.2% with chromoendoscopy and 88.9% without chromoendoscopy. In the case of the database obtained by high-magnification chromoendoscopy, the classification rates were up to 81.4%. For the combination of high-magnification endoscopy with NBI, results of up to 97.4% for one database and up to 84% for the other were achieved. Non-neoplastic lesions were classified more accurately in general than non-neoplastic lesions. It was shown that the image recording conditions highly affect the performance of automated diagnosis systems and partly contribute to a stronger effect on the staging results than the used imaging modality.CONCLUSION Chromoendoscopy has a negative impact on the results of the methods. NBI is better suited than chromoendoscopy. High-definition and high-magnification endoscopy are equally suited.

Randomized study of lafutidine vs lansoprazole in patients with mild gastroesophageal reflux disease

AIM: To compare the clinical efficacy of the secondgeneration H2 RA lafutidine with that of lansoprazole in Japanese patients with mild gastroesophageal reflux disease(GERD). METHODS: Patients with symptoms of GERD and a diagnosis of grade A reflux esophagitis(according to the Los Angeles classification) were randomized to receive lafutidine(10 mg, twice daily) or lansoprazole(30 mg, once daily) for an initial 8 wk, followed by maintenance treatment comprising half-doses of the assigned drug for 24 wk. The primary endpoint was the frequency and severity of heartburn during initial and maintenance treatment. The secondary endpoints were the sum score of questions 2 and 3 in the Gastrointestinal Symptom Rating Scale(GSRS), and the satisfaction score.RESULTS: Between April 2012 and March 2013, a total of 53 patients were enrolled, of whom 24 and 29 received lafutidine and lansoprazole, respectively. After 8 wk, the frequency and severity of heartburn was significantly reduced in both groups. However, lafutidine was significantly inferior to lansoprazole with regard to the severity of heartburn during initial and maintenance treatment(P = 0.016). The sum score of questions 2 and 3 in the GSRS, and satisfaction scores were also significantly worse in the lafutidine group than the lansoprazole group(P = 0.0068 and P = 0.0048, respectively).CONCLUSION: The clinical efficacy of lafutidine was inferior to that of lansoprazole, even in Japanese patients with mild GERD.

BRIEF ARTICLE New reduced volume preparation regimen in colon capsule endoscopy

AIM:To evaluate the effectiveness of our proposed bowel preparation method for colon capsule endoscopy.METHODS:A pilot,multicenter,randomized controlled trial compared our proposed "reduced volume method"(group A) with the "conventional volume method"(group B) preparation regimens.Group A did not drink polyethylene glycol electrolyte lavage solution(PEGELS) the day before the capsule procedure,while group B drank 2 L.During the procedure day,groups A and B drank 2 L and 1 L of PEG-ELS,respectively,and swallowed the colon capsule(PillCam COLON capsule).Two hours later the first booster of 100 g magnesium citrate mixed with 900 mL water was administered to both groups,and the second booster was administered six hours post capsule ingestion as long as the capsule had not been excreted by that time.Capsule videos were reviewed for grading of cleansing level,RESULTS:Sixty-four subjects were enrolled,with results from 60 analyzed.Groups A and B included 31 and 29 subjects,respectively.Twenty-nine(94%) subjects in group A and 25(86%) subjects in group B had adequate bowel preparation(ns).Twenty-two(71%) of the 31 subjects in group A excreted the capsule within its battery life compared to 16(55%) of the 29 subjects in group B(ns).Of the remaining 22 subjects whose capsules were not excreted within the battery life,all of the capsules reached the left side colon before they stopped functioning.A single adverse event was reported in one subject who had mild symptoms of nausea and vomiting one hour after starting to drink PEG-ELS,due to ingesting the PEG-ELS faster than recommended.CONCLUSION:Our proposed reduced volume bowel preparation method for colon capsule without PEG-ELS during the days before the procedure was as effective as the conventional volume method.

Clinical significance of mucosal suppressors of cytokine signaling 3 expression in ulcerative colitis

AIM:To investigate the clinical significance of mucosal expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3 in human ulcerative colitis (UC). METHODS:Biopsy specimens for histological analysis and mRNA detection were obtained endoscopically from the rectum of 62 patients with UC (36 men; age 13-76 years). The patients were classified endoscopically according to Matts' grade (grade 1 to 4). Expression of SOCS1 and SOCS3 mRNAs was quantified in samples by competitive reverse transcription-polymerase chain reaction (RT-PCR). GAPDH was used as an internal control for efficiency of RT-PCR and amount of RNA. RESULTS:SOCS3 mRNA expression was significantly higher in inflamed mucosa of UC than in inactive mucosa. The level of expression was well correlated with the degree of both endoscopic and histologic inflammation. Interestingly,among the patients in remission,the group with relatively low expression of SOCS3 showed a higher rate of remission maintenance over a 12-mo period. In contrast,SOCS1 mRNA was expressed in both inflamed and non-inflamed colonic mucosa and was not correlated with the activity of colonic mucosa or prognosis. CONCLUSION:These observations suggest that increased expression of mucosal SOCS3,but not of SOCS1,may play a critical role in the development of the colonic inflammation of UC.

Medical malpractice litigation related to gastrointestinal endoscopy in Japan:A two-decade review of civil court cases

AIM: To examine the allegations in malpractice litigations related to gastrointestinal endoscopy in Japan. METHODS: A retrospective review of cases tried in the civil court system during the 21-year period from 1985 to 2005, identified in a computerized legal database, was undertaken. RESULTS: Eighteen malpractice litigations and a total of 30 allegations were identified. Of the 18 (44%) malpractice litigations, 8 (44%) were related to eso- phagogastroduodenoscopy, 4 (22%) to colonoscopy, 4 (22%) to endoscopic sphincterotomy, and 2 (11%) to endoscopic retrograde cholangiopancreatography. Seventeen (94%) cases pertained to complications, and the remaining (6%) case pertained to misdiagnosis. In 10 cases, the patient died of the complications. Allegations were categorized as: (1) performance error during the endoscopic procedure (n = 12, 40%); (2) lack of informed consent (n = 9, 30%); (3) performance error during the treatment after the endoscopic procedure (n = 4, 13%); (4) premedication error (n = 3, 10%); (5) diagnostic error (n = 1, 3%); and (6) indication error for the endoscopic procedure (n = 1, 3%). CONCLUSION: These data may aid in the design of risk prevention strategies to be used by gastrointestinal endoscopists.

Clinicopathological features of minute pharyngeal lesions diagnosed by narrow-band imaging endoscopy and biopsy

AIM:To evaluate the utility of magnified narrow-band imaging(NBI) endoscopy for diagnosing and treating minute pharyngeal neoplasia.METHODS:Magnified NBI gastrointestinal examinations were performed by the first author.A magnification hood was attached to the tip of the endoscope for quick focusing.Most of the examinations were performed under sedation.Magnified NBI examinations were performed for all of the pharyngeal lesions that had noticeable brownish areas under unmagnified NBI observation,and an intrapapillary capillary loop(IPCL) classification was made.A total of 93 consecutive pharyngeal lesions were diagnosed as IPCL type Ⅳ and were suspected to represent dysplasia.Sixty-two lesions of approximately 1 mm in diameter were biopsied in the clinic,and 17 lesions with larger diameters were resected by endoscopic submucosal dissection(ESD) at the Hiroshima University Hospital.In addition to the histological diagnoses,the lesion diameters were microscopically measured in 45 of the 62 biopsies.Thirtyfour of the 62 biopsied patients received endoscopic follow up.RESULTS:Minute pharyngeal lesions were diagnosed in 93 of approximately 3000 patients receiving magnified NBI examinations at the clinic.Of the 93 patients with IPCL type Ⅳ lesions,80 were men,and 13 were women.Fifty-six were drinkers,and 57 were smokers.Two had esophageal cancer.Twenty-one lesions were located on the posterior hypopharyngeal wall,and 72 lesions were located on the posterior oropharyngeal wall.All 93 lesions were flat and showed similar findings in the magnified and unmagnified NBI examinations.Although almost all of the IPCL type Ⅳ lesions showed faint redness when examined under white light,it was difficult to diagnose the lesions using only this technique because the contrast was weaker than that achieved in the NBI examinations.Of the 93 lesions,only 3 had diameters greater than 2.1 mm.Sixty-two lesions of approximately 1 mm were biopsied in the clinic,whereas 17 larger lesions were treated by ESD at the Hiroshima University Hospital.Of the 79 pharyngeal lesions that were biopsied or resected by ESD,5 were histologically diagnosed as high-grade dysplasia,39 were diagnosed as low-grade dysplasia,and 39 were determined to be non-dysplastic lesions.There were no cancerous lesions.Histologically,abnormal cell size variations and increased nuclear size were observed in all of the high-grade dysplasia lesions,while the incidence of these findings in the low-grade dysplasia lesions was low.Of the 62 biopsied lesions,45 were microscopically measurable.The measured diameters ranged from 0.1 to 2.0 mm.The dysplasia ratios increased with the diameters.A follow-up endoscopic examination of the 34 biopsied patients found the rate of complete resection by biopsy to be 79%.The largest lesion in which complete resection was expected was a low-grade dysplasia of 1.9 mm in diameter.CONCLUSION:Minute pharyngeal lesions suspected to be dysplasia that are identified by NBI magnifying endoscopy should be biopsied to determine the diagnosis and further treatment.

Prevalence and impact of musculoskeletal pain in Japanese gastrointestinal endoscopists:A controlled study

AIM:To examine the frequency and prevention of musculoskeletal pain in Japanese gastrointestinal endoscopists and non-endoscopist physicians.METHODS:Questionnaires were sent to 275 endoscopists and 173 non-endoscopists working in Hiroshima University Hospital and its affiliated hospitals.RESULTS:The completed questionnaires were returned by 190(69%)endoscopists and 120(69%)non-endoscopists.The frequency of pain in the hand and wrist,and especially the left thumb,was significantly higher in endoscopists than in non-endoscopists(17%vs 6%,P=0.004).Using multivariate analysis,the only significant factor associated with this pain was the age of the endoscopist(odds ratio 2.77,95%confidence interval,1.23-6.71,P=0.018).Interestingly,endoscopists had made significantly fewer modifications to their endoscopic practices than non-endoscopists(12%vs 33%,P <0.0001)to prevent pain.CONCLUSION:Pain in the hand and wrist may be endoscopy-related.However,endoscopists made little modifications in practice to prevent such pain.More attention to prevention appears necessary.

Deep learning-based magnetic resonance imaging reconstruction for improving the image quality of reduced-field-of-view diffusionweighted imaging of the pancreas

BACKGROUND It has been reported that deep learning-based reconstruction(DLR)can reduce image noise and artifacts,thereby improving the signal-to-noise ratio and image sharpness.However,no previous studies have evaluated the efficacy of DLR in improving image quality in reduced-field-of-view(reduced-FOV)diffusionweighted imaging(DWI)[field-of-view optimized and constrained undistorted single-shot(FOCUS)]of the pancreas.We hypothesized that a combination of these techniques would improve DWI image quality without prolonging the scan time but would influence the apparent diffusion coefficient calculation.AIM To evaluate the efficacy of DLR for image quality improvement of FOCUS of the pancreas.METHODS This was a retrospective study evaluated 37 patients with pancreatic cystic lesions who underwent magnetic resonance imaging between August 2021 and October 2021.We evaluated three types of FOCUS examinations:FOCUS with DLR(FOCUS-DLR+),FOCUS without DLR(FOCUS-DLR−),and conventional FOCUS(FOCUS-conv).The three types of FOCUS and their apparent diffusion coefficient(ADC)maps were compared qualitatively and quantitatively.RESULTS FOCUS-DLR+(3.62,average score of two radiologists)showed significantly better qualitative scores for image noise than FOCUS-DLR−(2.62)and FOCUS-conv(2.88)(P<0.05).Furthermore,FOCUS-DLR+showed the highest contrast ratio and 600 s/mm^(2)(0.72±0.08 and 0.68±0.08)and FOCUS-DLR−showed the highest CR between cystic lesions and the pancreatic parenchyma for the b-values of 0 and 600 s/mm2(0.62±0.21 and 0.62±0.21)(P<0.05),respectively.FOCUS-DLR+provided significantly higher ADCs of the pancreas and lesion(1.44±0.24 and 3.00±0.66)compared to FOCUS-DLR−(1.39±0.22 and 2.86±0.61)and significantly lower ADCs compared to FOCUS-conv(1.84±0.45 and 3.32±0.70)(P<0.05),respectively.CONCLUSION This study evaluated the efficacy of DLR for image quality improvement in reduced-FOV DWI of the pancreas.DLR can significantly denoise images without prolonging the scan time or decreasing the spatial resolution.The denoising level of DWI can be controlled to make the images appear more natural to the human eye.However,this study revealed that DLR did not ameliorate pancreatic distortion.Additionally,physicians should pay attention to the interpretation of ADCs after DLR application because ADCs are significantly changed by DLR.

Involvement of Krüppel-like factor 6 (KLF6) mutation in the development of nonpolypoid colorectal carcinoma

AIM： To examine Kruppel-like factor 6 （KLF6） mutations in nonpolypoid-type tumors and alterations of K-ras, p53, and B-raf in relation between mutation and morphologic type, particularly nonpolypoid-type colorectal carcinomas. METHODS： Fifty-five early nonpolypoid colorectal carcinomas were analyzed. Loss of heterozygosity （LOH） of KLF6 and p53 was determined by microsatellite assay. Mutations of KLF6, K-ras, and B-raf were examined by polymerase chain reaction-single-strand conformation polymorphism followed by direct sequencing. In LOH- positive and/or mutation-positive tumors, multiple （4-7） samples in each tumor were microdissected and examined for genetic alterations, p53 expression was evaluated by immunohistochemistry. RESULTS： LOH of KLF6 and p53 was found in 14 of 29 （48.3%） and 14 of 31 （45.2%） tumors, respectively. In tO of the 14 （71.4%） KLF6 LOH-positive tumors and 9 of the 14 （64.3%） p53 LOH-positive tumors, LOH was found in all of the microdissected samples. In 1 of the tO （10.0%） KLF6 LOH-positive tumors, a single missense mutation was identified. K-ras and B-raf mutations were found in 5 of 55 （9.1%） and 6 of 55 （10.9%） tumors, respectively. However, these mutations were detected only in subsets of microdissected tumor samples. CONCLUSION： These data suggest that KLF6 and p53 mutations are involved in the development of nonpolypoid colorectal carcinoma, whereas K-ras and B-raf mutations are not.

Bandwidth Maximization Approach for Displaced Left-Turn Crossovers Coordination under Heterogeneous Traffic Conditions

As one of the UAIDs(unconventional alternative intersection designs),DLTs(displaced left-turn crossovers)have been presented to mitigate traffic congestion.Although,qualitatively and quantitatively isolated UAIDs outperform their conventional counterparts,there is no simplified procedure to consider the DLTs coordination.Hence,this research investigates the coordination of consecutive DLTs under heterogeneous traffic conditions.To achieve the optimal coordination and provide an efficient coordination control,a bandwidth maximization progression approach was used.Seeking the optimal offset for each pair of consecutive intersections to guarantee the green bandwidth waves along the coordinated corridor,a mixed-integer linear program was adopted.The optimization problem was formulated and solved based on the standard branch-and-bound technique.As a real-world study case,data of three typical intersections located in an arterial corridor in Cairo,Egypt was used.PTV-VISSIM as a microsimulation platform was employed to simulate and evaluate the different signal timing plans.However,to represent the heterogeneous traffic characteristics as close as possible to the reality,different simulation parameters were tuned and validated carefully.The results emphasized the undoubted improvement of coordinated DLTs by different operational performance indices.The total travel time,average delay,the number of stops per vehicle were obviously improved.