Superficial small cerebellar infarcts in cerebral amyloid angiopathy on 3 T MRI: A preliminary study.

BACKGROUND: Strictly superficial cerebellar microbleeds and cerebellar superficial siderosis have been considered markers of advanced cerebral amyloid angiopathy (CAA), but there are few studies on cerebellar ischemic lesions in CAA. We investigated the presence of superficial small cerebellar infarct (SCI) ≤15 mm and its relation to magnetic resonance imaging (MRI) markers in patients with probable CAA. METHODS: Eighty patients with probable CAA were retrospectively evaluated. The presence of superficial SCIs was examined, along with cerebellar microbleeds and cerebellar superficial siderosis, using 3-T MRI. Lobar cerebral microbleeds, cortical superficial siderosis (cSS), enlargement of the perivascular space in the centrum semiovale, and white matter hyperintensity were assessed and the total CAA-small vessel disease (SVD) score was calculated. RESULTS: Nine of the 80 patients (11.3%) had a total of 16 superficial SCIs. By tentatively defining SCI <4 mm as cerebellar microinfarcts, 8 out of 16 (50%) superficial SCIs corresponded to cerebellar microinfarcts. The total CAA-SVD score was significantly higher in patients with superficial SCIs (p = 0.01). The prevalence of cSS (p = 0.018), cortical cerebral microinfarct (p = 0.034), and superficial cerebellar microbleeds (p = 0.006) was significantly higher in patients with superficial SCIs. The number of superficial cerebellar microbleeds was also significantly higher in patients with superficial SCIs (p = 0.001). CONCLUSIONS: Our results suggest that in patients with CAA, superficial SCIs (including microinfarcts) on MRI may indicate more severe, advanced-stage CAA. These preliminary findings should be verified by larger prospective studies in the future.

Magnetic resonance imaging and neuropsychological findings for predicting of cognitive deterioration in memory clinic patients.

Objective: The severity of cerebral small vessel disease (SVD) on magnetic resonance imaging (MRI) has been assessed using hypertensive arteriopathy SVD and cerebral amyloid angiopathy (CAA)-SVD scores. In addition, we reported the modified CAA-SVD score including cortical microinfarcts and posterior dominant white matter hyperintensity. Each SVD score has been associated with cognitive function, but the longitudinal changes remain unclear. Therefore, this study prospectively examined the prognostic value of each SVD score, imaging findings of cerebral SVD, and neuropsychological assessment. Methods: This study included 29 patients diagnosed with mild cognitive impairment or mild dementia at memory clinic in our hospital, who underwent clinical dementia rating (CDR) and brain MRI (3D-fluid attenuated inversion recovery, 3D-double inversion recovery, and susceptibility-weighted imaging) at baseline and 1 year later. Each SVD score and neuropsychological tests including the Mini-Mental State Examination, Japanese Raven's Colored Progressive Matrices, Trail Making Test -A/-B, and the Rivermead Behavioral Memory Test were evaluated at baseline and 1 year later. Results: Twenty patients had unchanged CDR (group A), while nine patients had worsened CDR (group B) after 1 year. At baseline, there was no significant difference in each SVD score; after 1 year, group B had significantly increased CAA-SVD and modified CAA-SVD scores. Group B also showed a significantly higher number of lobar microbleeds than group A at baseline. Furthermore, group B had significantly longer Japanese Raven's Colored Progressive Matrices and Trail Making test-A times at baseline. After 1 year, group B had significantly lower Mini-Mental State Examination, Japanese Raven's Colored Progressive Matrices, and Rivermead Behavioral Memory Test scores and significantly fewer word fluency (letters). Conclusion: Patients with worsened CDR 1 year after had a higher number of lobar microbleeds and prolonged psychomotor speed at baseline. These findings may become predictors of cognitive deterioration in patients who visit memory clinics.

Association between behavioral and psychological symptoms and cerebral small vessel disease MRI findings in memory clinic patients.

Objectives: Cerebral small vessel disease (SVD) is commonly observed among elderly individuals with cognitive impairment and has been recognized as a vascular contributor to dementia and behavioral and psychological symptoms (BPS), however, the relationship between BPS and SVD burden remains unclear. Methods: We prospectively recruited 42 patients with mild cognitive impairment (MCI) or mild dementia from the memory clinic in our hospital, who were assigned to either a clinical dementia rating (CDR) of 0.5 or 1.0, respectively. The presence of BPS was determined through interviews with caregivers. The patients underwent brain MRI and three types of SVD scores, total, cerebral amyloid angiopathy (CAA), and modified CAA, were assigned. Patients were also evaluated through various neuropsychological assessments. Results: The CDR was significantly higher in patients with BPS (p = 0.001). The use of antihypertensive agents was significantly higher in patients without BPS (p = 0.038). The time taken to complete trail making test set-A was also significantly longer in patients with BPS (p = 0.037). There was no significant difference in total SVD and CAA-SVD score (p = 0.745, and 0.096) and the modified CAA-SVD score was significantly higher in patients with BPS (p = 0.046). In addition, the number of total CMBs and lobar CMBs was significantly higher in patients with BPS (p = 0.001 and 0.001). Receiver operating characteristic curves for BPS showed that for modified CAA-SVD, a cutoff score of 3.5 showed 46.7% sensitivity and 81.5% specificity. Meanwhile, for the total number of cerebral microbleeds (CMBs), a cut-off score of 2.5 showed 80.0% sensitivity and 77.8% specificity and for the number of lobar CMBs, a cut-off score of 2.5 showed 73.3% sensitivity and 77.8% specificity. Conclusion: Overall, patients with BPS showed worse CDRs, reduced psychomotor speed, higher modified CAA-SVD scores, larger numbers of total and lobar CMBs. We propose that severe modified CAA scores and higher numbers of total and lobar CMBs are potential risk factors for BPS in patients with mild dementia or MCI. Therefore, by preventing these MRI lesions, the risk of BPS may be mitigated.

Sofosbuvir-velpatasvir in adults with hepatitis C virus infection and compensated cirrhosis in Japan.

BACKGROUND & PURPOSE: Protease-free regimens for chronic hepatitis C virus (HCV) infection are safe and effective for persons with either compensated or decompensated cirrhosis. We examined the efficacy and safety of sofosbuvir-velpatasvir in participants with HCV and compensated cirrhosis in Japan. METHODS: This was a Phase 3, multi-center, open-label study. At 20 sites, 37 individuals with chronic HCV infection of any genotype and compensated cirrhosis received sofosbuvir-velpatasvir (400 mg/100 mg) daily for 12 weeks. Participants were treatment-naïve or treatment-experienced with interferon-based treatments with or without HCV NS3/4A protease inhibitors. Prior exposure with HCV NS5A or NS5B inhibitors was prohibited. The primary study endpoint was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: Among participants, 62% had HCV genotype 1 infection, and 38% had HCV genotype 2. More than three quarters (29/37, 78%) were HCV treatment naïve. All participants (37/37, 100%) achieved SVR12. Seventeen participants (46%) and three participants (8%) had pretreatment resistance-associated substitutions to HCV NS5A and NS5B nucleoside inhibitors respectively, yet no on-treatment breakthrough or relapse occurred. Sofosbuvir-velpatasvir for 12 weeks treatment was safe and well tolerated. The most commonly reported adverse events were headache (8%, 3/37) and diarrhea (5%, 2/37). One serious adverse event, patella fracture, occurred and was considered not treatment related. No participants discontinued study treatment due to an adverse event. Three participants (8%) had a Grade 3 laboratory abnormality; all were hyperglycemia. CONCLUSION: Sofosbuvir-velpatasvir resulted in high SVR rates and was well tolerated among Japanese patients with HCV and compensated cirrhosis. This single-tablet regimen offers a highly effective, protease-inhibitor free regimen for treating HCV. CLINICALTRIALS: gov Identifier: NCT04112303.

Severe spruelike enteropathy and collagenous colitis caused by olmesartan.

BACKGROUND: Olmesartan, which is an angiotensin II receptor blocker, reportedly causes spruelike enteropathy, with intestinal villous atrophy as its typical histopathological finding. Interestingly, collagenous and/or lymphocytic gastritis and colitis occur in some patients. We report the case of a 73-year-old Japanese man with a 2-month clinical history of severe diarrhea and weight loss. There were few reports in which spruelike enteropathy and collagenous colitis were both observed and could be followed up. CASE PRESENTATION: We report a case of a 73-year-old man with a 2-month clinical history of severe diarrhea and weight loss. He had taken olmesartan for hypertension treatment for 5 years. Endoscopic examination with biopsies revealed intestinal villous atrophy and collagenous colitis. Suspecting enteropathy caused by olmesartan, which was discontinued on admission because of hypotension, we continued to stop the drug. Within 3 weeks after olmesartan discontinuation, his clinical symptoms improved. After 3 months, follow-up endoscopy showed improvement of villous atrophy but not of the thickened collagen band of the colon. However, the mucosa normalized after 6 months, histologically confirming that the preexistent pathology was finally resolved. CONCLUSIONS: This report presents a case in which spruelike enteropathy and collagenous colitis were both observed and could be followed up. In unexplained cases of diarrhea, medication history should be reconfirmed and this disease should be considered a differential diagnosis.

Role of Rho GTPase Interacting Proteins in Subcellular Compartments of Podocytes.

The first step of urine formation is the selective filtration of the plasma into the urinary space at the kidney structure called the glomerulus. The filtration barrier of the glomerulus allows blood cells and large proteins such as albumin to be retained while eliminating the waste products of the body. The filtration barrier consists of three layers: fenestrated endothelial cells, glomerular basement membrane, and podocytes. Podocytes are specialized epithelial cells featured by numerous, actin-based projections called foot processes. Proteins on the foot process membrane are connected to the well-organized intracellular actin network. The Rho family of small GTPases (Rho GTPases) act as intracellular molecular switches. They tightly regulate actin dynamics and subsequent diverse cellular functions such as adhesion, migration, and spreading. Previous studies using podocyte-specific transgenic or knockout animal models have established that Rho GTPases are crucial for the podocyte health and barrier function. However, little attention has been paid regarding subcellular locations where distinct Rho GTPases contribute to specific functions. In the current review, we discuss cellular events involving the prototypical Rho GTPases (RhoA, Rac1, and Cdc42) in podocytes, with particular focus on the subcellular compartments where the signaling events occur. We also provide our synthesized views of the current understanding and propose future research directions.

Association between cortical microinfarcts and total small vessel disease burden in cerebral amyloid angiopathy on 3-Tesla magnetic resonance imaging.

BACKGROUND AND PURPOSE: Cortical microinfarcts (CMIs) are frequently found in the brains of patients with advanced cerebral amyloid angiopathy (CAA) at autopsy. The small vessel disease (SVD) score for CAA (i.e., the CAA-SVD score) has been proposed to evaluate the severity of CAA-associated vasculopathic changes by a combination of magnetic resonance imaging (MRI) markers. The aim of this study was to examine the association between total CAA-SVD score and features of CMIs on in vivo 3-Tesla MRI. METHODS: Eighty patients with probable CAA were retrospectively analyzed. Lobar cerebral microbleeds, cortical superficial siderosis, enlargement of perivascular space in the centrum semiovale and white matter hyperintensity were collectively assessed, and the total CAA-SVD score was calculated. The presence of CMI was also examined. RESULTS: Of the 80 patients, 13 (16.25%) had CMIs. CMIs were detected more frequently in the parietal and occipital lobes. A positive correlation was found between total CAA-SVD score and prevalence of CMI (ρ = 0.943; p = 0.005). Total CAA-SVD score was significantly higher in patients with CMIs than in those without (p = 0.009). In a multivariable logistic regression analysis, the presence of CMIs was significantly associated with total CAA-SVD score (odds ratio 2.318 [95% confidence interval 1.228-4.376]; p = 0.01, per each additional point). CONCLUSIONS: The presence of CMIs with a high CAA-SVD score could be an indicator of more severe amyloid-associated vasculopathic changes in patients with probable CAA.

Rho GTPase regulatory proteins in podocytes.

The Rho family of small GTPases (Rho GTPases) are the master regulators of the actin cytoskeleton and consist of 22 members. Previous studies implicated dysregulation of Rho GTPases in podocytes in the pathogenesis of proteinuric glomerular diseases. Rho GTPases are primarily regulated by the three families of proteins; guanine nucleotide exchange factors (GEFs; 82 members), GTPase-activating proteins (GAPs; 69 members), and GDP dissociation inhibitors (GDIs; 3 members). Since the regulatory proteins far outnumber their substrate Rho GTPases and act in concert in a cell/context-dependent manner, the upstream regulatory mechanism directing Rho GTPases in podocytes is largely unknown. In this review, we summarize recent advances in the understanding of the role of Rho GTPase regulatory proteins in podocytes, including the known mutations of these proteins that cause proteinuria in humans. We also provide critical appraisal of the in vivo and in vitro studies and identify the knowledge gap in the field that will require further studies.

Hypertensive Arteriopathy and Cerebral Amyloid Angiopathy in Patients with Cognitive Decline and Mixed Cerebral Microbleeds.

BACKGROUND: Hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA) may contribute to the development of mixed cerebral microbleeds (CMBs). Recently, the total small vessel disease (SVD) scores for HA and CAA were proposed, which are determined by a combination of MRI markers to reflect overall severity of these microangiopathies. OBJECTIVE: We investigated whether or not total HA-SVD and CAA-SVD scores could be used to predict overlap of HA and CAA in patients with mixed CMBs. METHODS: Fifty-three subjects with mixed CMBs were retrospectively analyzed. MRI markers (CMBs, lacunes, perivascular space, white matter hyperintensity [WMH] and cortical superficial siderosis [cSS]) were assessed. The HA-SVD score and CAA-SVD score were obtained for each subject. Anterior or posterior WMH was also assessed using the age-related white matter changes scale. RESULTS: The two scores were positively correlated (ρ= 0.449, p < 0.001). The prevalence of lobar dominant CMB distribution (p < 0.001) and lacunes in the centrum semiovale (p < 0.001) and the severity of WMH in the parieto-occipital lobes (p = 0.004) were significantly higher in the high CAA-SVD score group. cSS was found in four patients with high CAA-SVD score who showed lobar-dominant CMB distribution and severe posterior WMH. CONCLUSION: Mixed CMBs are mainly due to HA. Assessing both two scores may predict the overlap of HA and CAA in individuals with mixed CMBs. Patients with a high CAA-SVD score may have some degree of advanced CAA, especially when lobar predominant CMBs, severe posterior WMH, lobar lacunes, or cSS are observed.

In vivo optical cellular diagnosis for uterine cervical or vaginal intraepithelial neoplasia using flexible gastrointestinal endocytoscopy -a prospective pilot study.

BACKGROUUND: For patients with any kind of atypical squamous intraepithelial lesion of the uterine cervix or vagina, colposcopy and punch biopsy are common procedures for histological determination following cytology. However, colposcopy-guided biopsy does not provide a high level of diagnostic accuracy. The aim of this study was to determine the usefulness of optical biopsy in vivo using endocytoscopy compared with conventional procedures using colposcopy. METHODS: Between May 2018 and March 2019, patients who were scheduled for cervical conization or mapping biopsies of the vagina were prospectively enrolled. Endocytoscopy was performed by senior endoscopists prior to scheduled procedures, and endocytoscopic images and biopsy samples were taken from the most prominent site and surrounding area of the cervical or vaginal lesions. The collection process of images was randomized and anonymous, and three doctors separately evaluated the images according to the ECA classification. ECA 4 and 5 are indicative of endoscopic malignancy. The primary endpoint was diagnostic accuracy (benign or malignant: cervical intraepithelial neoplasia (CIN) 3 or vaginal intraepithelial neoplasia (VAIN) 3 or worse) of cell images at the most prominent site in each patient. RESULTS: A total of 28 consecutive patients were enrolled. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of endocytoscopic images were 95.0% (84.8-98.6%), 87.5% (61.9-96.5%), 95.0% (84.8-98.6%), 87.5% (61.9-96.5%) and 92.9% (78.2-98.0%), respectively. Inter-observer agreement among three reviewers was 0.78 (0.08-9.88, P < 0.01). On the other hand, the accuracy of colposcopy-guided biopsy was 74.1% (64.0-84.0%). CONCLUSIONS: Optical cell diagnosis of cervical or vaginal intraepithelial neoplasia using endocytoscopy provides a high level of diagnostic accuracy. TRIAL REGISTRATION: The study was registered with the UMIN database (ID: 000031712 ). UMIN000031712 . Registered 16 March 2017.

Intestinal goblet cells protect against GVHD after allogeneic stem cell transplantation via Lypd8.

Graft-versus-host disease (GVHD) and infection are major obstacles to successful allogeneic hematopoietic stem cell transplantation (HSCT). Intestinal goblet cells form the mucus layers, which spatially segregate gut microbiota from host tissues. Although it is well known that goblet cell loss is one of the histologic features of GVHD, effects of their loss in pathophysiology of GVHD remain to be elucidated. In mouse models of allogeneic HSCT, goblet cells in the colon were significantly reduced, resulting in disruption of the inner mucus layer of the colon and increased bacterial translocation into colonic mucosa. Pretransplant administration of interleukin-25 (IL-25), a growth factor for goblet cells, protected goblet cells against GVHD, prevented bacterial translocation, reduced plasma concentrations of interferon-γ (IFN-γ) and IL-6, and ameliorated GVHD. The protective role of IL-25 was dependent on Lypd8, an antimicrobial molecule produced by enterocytes in the colon that suppresses motility of flagellated bacteria. In clinical colon biopsies, low numbers of goblet cells were significantly associated with severe intestinal GVHD, increased transplant-related mortality, and poor survival after HSCT. Goblet cell loss is associated with poor transplant outcome, and administration of IL-25 represents an adjunct therapeutic strategy for GVHD by protecting goblet cells.

Impairment of intermediate somatosensory function in corticobasal syndrome.

Corticobasal syndrome (CBS) is characterized by unilateral atrophy of the brain. New diagnostic criteria for CBS include intermediate somatosensory dysfunction. Here, we aimed to carefully examine intermediate somatosensory function to identify tests which can assess impairment in CBS patients. Using voxel-based morphometry (VBM), we also aimed to show the anatomical bases of these impairments. Subjects included 14 patients diagnosed with CBS and 14 patients with Parkinson's disease (PD). Patients were evaluated using intermediate somatosensory tests and neuropsychological assessments. VBM was used to analyze differences in gray matter volumes between CBS and PD patients. In the PD group, no tests showed a significant difference between the dominant-side onset and the non-dominant-side onset. In the CBS group, all tests showed worse scores on the affected side. For detecting intermediate somatosensory dysfunction in CBS, two tests are recommended: tactile object naming and 2-point discrimination. VBM analysis showed that the volume of the left post- and pre-central gyrus, and both sides of the supplementary motor area were significantly decreased in the CBS group compared to the PD group. Although CBS remains untreatable, early and correct diagnosis is possible by performing close examination of intermediate somatosensory function.

Developmental Evaluation of Infants Who Have Received Tadalafil in Utero for Fetal Growth Restriction.

To assess the long-term effects of tadalafil, a therapeutic agent for fetal growth restriction (FGR), we evaluated the developmental progress of 1.5-year-old infants whose mothers had taken tadalafil during pregnancy. Twenty-four infants were assessed. We evaluated infant body weight, height, and head circumference, and performed the Kyoto Scale of Psychological Development (KSPD) test, a standardized developmental assessment covering Postural-Motor (P-M), Cognitive-Adaptive (C-A), and Language-Social (L-S) functions. The sum score was converted to a developmental quotient (DQ). The mean gestational week of the included cases was 36.1 (29-39) weeks, and the mean birth weight was 1841 (874-2646) g. Twenty-one and 20 out of the 24 cases, respectively, attained body weight and height similar to those of age-matched normal infants (within the 3rd percentile); all cases caught up in head circumference. KSPD was performed for 18 cases at 1.5 years of corrected age. The mean DQ scores were 87 (in total): 82 in P-M, 90 in C-A, and 88 in L-S. The total DQ score in one case (5.6%) was less than 70, and ranged from 70 to 85 in five cases (27.7%), and was more than 85 in 11 cases (61.1%). The growth and development of infants born of tadalafil-treated mothers seem to show good progress at a corrected age of 1.5 years.

Histological and magnified endoscopic evaluation of villous atrophy in gastrointestinal graft-versus-host disease.

AIM:  To measure histological villous atrophy and to clarify the diagnostic accuracy of endoscopic villous atrophy in gastrointestinal graft-versus-host disease. METHODS:  Data for patients who underwent upper and/or lower endoscopic examinations after hematopoietic stem cell transplantation were retrospectively collected. In study 1, group A included 56 patients in whom GI-GVHD was histologically confirmed and group B included 60 patients in whom GI-GVHD was not histologically confirmed. Group C included 59 patients before HSCT. The lengths of villi and crypts in the duodenum and terminal ileum were histologically measured. In study 2, the diagnostic accuracies of villous atrophy of the duodenum and of the terminal ileum using magnifying endoscopy were evaluated. RESULTS:  In study 1, the lengths of villi and the villi/crypt (V/C) ratios of the duodenum and terminal ileum in group A were significantly smaller than those in the other groups (p < 0.05). V/C ratio was moderately correlated with clinical severity, histological grades, and endoscopic grades in the terminal ileum. In study 2, the diagnostic accuracies of magnified images for villous atrophy were 83.8% in the duodenum and 94.9% in the terminal ileum. CONCLUSION:  Magnifying endoscopy enables evaluation of villous atrophy and is useful for optical biopsy of GVHD.

Changes of Dyspeptic Symptom after Successful Eradication in Helicobacter pylori-Associated Dyspepsia.

BACKGROUND: Helicobacter pylori (H. pylori) gastritis could cause dyspepsia, and eradication is recommended as the first-line treatment. Patients who continuously have their symptoms under control > 6 months after eradication are defined as having H. pylori-associated dyspepsia (HPD), whereas patients who do not benefit from successful eradication are defined as having functional dyspepsia. OBJECTIVES: We assessed changes in dyspeptic symptoms after successful eradication of H. pylori by using a questionnaire. METHODS: We studied H. pylori-infected dyspeptic participants with abdominal symptom scores > 4 points on the Global Overall Symptom (GOS) scoring items and received eradication therapy. We evaluated their symptoms using the GOS questionnaire before their eradications, at 1-month and at 1-year check-ups after eradication therapy. RESULTS: Thirty dyspeptic participants (mean age 59.6 ± 15.3 years) answered every questionnaire. Fourteen participants (46.7%) had HPD, whereas 16 participants (53.3%) were non-HPD patients. The questionnaire at 1 month showed sensitivity of 64.3% (9/14) and specificity of 56.3% (9/16) for HPD. Approximately 60% of H. pylori-infected dyspepsia participants were identified as having HPD or non-HPD within 1 month after their eradications. CONCLUSIONS: Approximately 60% of HPD participants improved at 1 month after eradication. The questionnaire at 1 month helped diagnose HPD in advance and guided next treatment choice.

Clinical impact of the perioperative management of oral anticoagulants in bleeding after colonic endoscopic mucosal resection.

BACKGROUND: Heparin bridging therapy (HBT) is indeed related to a high frequency of bleeding after endoscopic mucosal resection (EMR). In this study, our aim was to investigate clinical impact of management of oral anticoagulants without HBT in bleeding after colonic EMR. METHODS: From data for patients who underwent consecutive colonic EMR, the relationships of patient factors and procedural factors with the risk of bleeding were analysed. Our management of antithrombotic agents was based on the shortest cessation as follows: the administration of warfarin was generally continued within the therapeutic range, and direct oral anticoagulants (DOACs) were not administered on the day of the procedure. We calculated bleeding risks after EMR in patients who used antithrombotic agents and evaluated whether perioperative management of anticoagulants without HBT was beneficial for bleeding. RESULTS: A total of 1734 polyps in 825 EMRs were analysed. Bleeding occurred in 4.0% of the patients and 1.9% of the polyps. The odds ratios for bleeding using multivariate logistic regression analysis were 3.67 in patients who used anticoagulants and 4.95 in patients who used both anticoagulants and antiplatelet agents. In patients with one-day skip of DOACs, bleeding occurred in 6.5% of the polyps, and there were no significant differences in bleeding risk between HBT and continuous warfarin or one-day skip DOACs. CONCLUSIONS: The use of oral anticoagulants was related to bleeding after colonic EMR, and perioperative management of oral anticoagulants based on the shortest cessation without HBT would be clinically acceptable.

Metal Template Assisted Proximal Arrangement of a Nucleophile and an Electrophile: Site-Selective Acylation of α-Hydroxyamides in Polyols.

Site-selective acylation of α-hydroxyl groups in amides has been achieved in the presence of other primary hydroxyl groups with intrinsic high reactivity. In this methodology, a relatively stable pyridine aldoxime ester was exploited as an acyl donor to suppress undesired acylation. The catalytic activation of a pyridine aldoxime ester with a Lewis acid produced a cationic complex, which preferentially attracted the Lewis basic α-hydroxyamide via a template effect, to thus facilitate o-acylation.

Risk assessment of metachronous squamous cell carcinoma after endoscopic resection for esophageal carcinoma based on the genetic polymorphisms of alcoholdehydrogense-1B aldehyde dehydrogenase-2: temperance reduces the risk.

BACKGROUND: Metachronous multiple squamous cell carcinoma (SCC) of the esophagus and the head and neck is commonly observed in patients who have previously undergone endoscopic resection (ER) for SCC of the esophagus (ESCC). We evaluated the risk for developing metachronous SCC following ER for ESCC based on the genetic polymorphisms for alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) as well as the alcohol consumption and smoking habits. METHODS: We studied 158 patients who underwent ER for ESCC (median follow-up 80 months). Genotyping of ADH1B/ALDH2 was performed using saliva sampling. The alcohol consumption and smoking histories of the patients before and after the ER were documented. RESULTS: Multivariate analyses revealed that inactive heterozygous ALDH2 [hazard ratio (HR) 2.25] and alcohol consumption after ER (HR 1.94) were independently associated with the risk of developing secondary SCC. Moreover, inactive heterozygous ALDH2 (HR 4.39) and alcohol consumption after the ER (HR 2.82) were independently associated with the risk of a third SCC. We analyzed 110 patients who had a history of moderate or heavy alcohol consumption before the ER. The 3-year cumulative incidence rates of secondary SCC in the temperance (n = 65) and non-temperance groups (n = 45) were 14.0 and 42.1% (p = 0.0002). Further, the 5-year cumulative incidence rates of a third SCC in the temperance and non-temperance groups were 0 and 15.6% (p = 0.0011), respectively. In addition, the 7-year cumulative incidence rates of a fourth SCC in the temperance and non-temperance groups were 0 and 15.3% (p = 0.0015), respectively. CONCLUSIONS: Continued alcohol consumption is an important risk factor for the onset of metachronous SCC and is a risk factor for the third and subsequent SCCs. Strict advice in favor of temperance is crucial.