Detection of oral cancer and oral potentially malignant disorders using artificial intelligence-based image analysis.

BACKGROUND: We aimed to construct an artificial intelligence-based model for detecting oral cancer and dysplastic leukoplakia using oral cavity images captured with a single-lens reflex camera. SUBJECTS AND METHODS: We used 1043 images of lesions from 424 patients with oral squamous cell carcinoma (OSCC), leukoplakia, and other oral mucosal diseases. An object detection model was constructed using a Single Shot Multibox Detector to detect oral diseases and their locations using images. The model was trained using 523 images of oral cancer, and its performance was evaluated using images of oral cancer (n = 66), leukoplakia (n = 49), and other oral diseases (n = 405). RESULTS: For the detection of only OSCC versus OSCC and leukoplakia, the model demonstrated a sensitivity of 93.9% versus 83.7%, a negative predictive value of 98.8% versus 94.5%, and a specificity of 81.2% versus 81.2%. CONCLUSIONS: Our proposed model is a potential diagnostic tool for oral diseases.

Non-Pure Intestinal Phenotype as an Indicator of Progression in Sporadic Nonampullary Duodenal Adenomas: A Multicenter Retrospective Cohort Study.

INTRODUCTION: We aimed to evaluate the natural course of sporadic nonampullary duodenal adenomas (SNDAs) and determine the risk factors of progression. METHODS: We retrospectively analyzed the follow-up outcomes of patients with biopsy-diagnosed SNDA between April 2010 and March 2016 at 13 institutions. All initial biopsy specimens were centrally evaluated. Only those diagnosed with adenomas were included. Mucinous phenotypes were classified into pure intestinal and non-pure intestinal phenotypes. Cumulative incidence rates of carcinoma and tumor enlargement were evaluated. Tumor enlargement was defined as a ≥25% or 5-mm increase in tumor size. RESULTS: Overall, 121 lesions were analyzed. Within a median observation period of 32.7 months, 5 lesions were diagnosed as carcinomas; the cumulative 5-year incidence of carcinoma was 9.5%. Male sex ( P = 0.046), initial lesion size ≥10 mm ( P = 0.044), and non-pure intestinal phenotype ( P = 0.019) were significantly associated with progression to carcinoma. Tumor enlargement was observed in 22 lesions, with a cumulative 5-year incidence of 33.9%. Initial lesion size ≥10 mm ( P < 0.001), erythematous lesion ( P = 0.002), high-grade adenoma ( P = 0.002), Ki67 negative ( P = 0.007), and non-pure intestinal phenotype ( P = 0.001) were risk factors of tumor enlargement. In a multivariate analysis, an initial lesion size ≥10 mm ( P = 0.010) and non-pure intestinal phenotype ( P = 0.046) were independent and significant risk factors of tumor enlargement. DISCUSSION: Lesion size ≥10 mm and non-pure intestinal phenotype on initial biopsy are risk factors of cancer progression and tumor enlargement in cases with SNDA. Thus, management effectiveness may be improved by focusing on lesion size and the mucinous phenotype.

Carbon dioxide insufflation reduces the relapse of ulcerative colitis after colonoscopy: A randomized controlled trial.

BACKGROUND AND AIM: Colonoscopy is necessary for diagnosing and surveilling patients with ulcerative colitis, though it may cause disease flares. Colonoscopy with carbon dioxide (CO2) insufflation decreases abdominal discomfort; however, its effect on exacerbation incidence in ulcerative colitis remains unclear. Therefore, this study aimed to evaluate the colonoscopy effects using CO2 insufflation in patients with ulcerative colitis. METHODS: Overall, 96 remissive patients with ulcerative colitis (partial Mayo score ≤ 2) who underwent total colonoscopy between March 2015 and December 2019 at Osaka University Hospital were enrolled and blindly randomized to the CO2 (n = 45) and air (n = 51) insufflation group (UMIN-CTR, number: UMIN000018801). The post-procedural abdominal discomfort and the clinical relapse (partial Mayo score ≥ 3) rate within 8 weeks were evaluated. RESULTS: Baseline backgrounds did not differ between the groups. The mean abdominal fullness and pain scores were significantly lower in the CO2 group than in the Air group immediately (p = 0.0003, p = 0.0003) and 30 min (p < 0.0001, p < 0.0001) after colonoscopy. While the overall clinical relapse rate remained unchanged between the groups, the clinical relapse rate at 8 weeks after colonoscopy was significantly lower in the CO2 group than in the Air group in patients not in complete remission (Mayo endoscopic subscore ≥ 1, p = 0.049; or partial Mayo score ≥ 1, p = 0.022). CONCLUSIONS: CO2 insufflation can reduce abdominal discomfort in remissive patients with ulcerative colitis and decrease clinical relapse at 8 weeks after colonoscopy for those not in complete remission.

Elderly onset age is associated with low efficacy of first anti-tumor necrosis factor treatment in patients with inflammatory bowel disease.

The outcomes of patients with elderly onset (EO) inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) remains uncertain. The present study evaluated the efficacy and safety of anti-TNF treatment for bio-naïve EO-IBD. Elderly patients were defined as those 60 years and older, and further divided into those with EO (Elderly-EO) and those with non-elderly onset (Elderly-NEO). A total of 432 bio-naïve patients were enrolled in this multicenter observational study, comprising 55 with Elderly-EO (12.7%), 25 with Elderly-NEO (5.8%), and 352 under age 60 (Non-elderly, 81.5%). After 52 weeks of anti-TNF treatment, clinical and steroid-free remission rates were significantly lower in Elderly-EO than in Non-elderly (37.7% and 60.8%; P = 0.001, and 35.9% and 57.8%; P = 0.003, respectively), and comparable between Elderly-NEO and Non-elderly. Multivariate analysis revealed that elderly onset was a significant factor for both clinical remission (OR, 0.49, 95% CI 0.25-0.96) and steroid-free remission (OR, 0.51, 95% CI 0.26-0.99) after 52 weeks of anti-TNF treatment. The rate of cumulative severe adverse events was significantly higher in Elderly-EO than in Non-elderly (P = 0.007), and comparable between Elderly-NEO and Non-elderly. In conclusion, anti-TNF treatment for bio-naïve EO-IBD may be less effective and raise safety concerns.

Passive Way of Measuring QOL/Well-Being Levels Using Smartphone Log.

Research on mental health states involves paying increasing attention to changes in daily life. Researchers have attempted to understand such daily changes by relying on self-reporting through frequent assessment using devices (smartphones); however, they are mostly focused on a single aspect of mental health. Assessing the mental health of a person from various perspectives may help in the primary prevention of mental illness and the comprehensive measurement of mental health. In this study, we used users' smartphone logs to build a model to estimate whether the scores on three types of questionnaires related to quality of life and well-being would increase compared to the previous week (fluctuation model) and whether they would be higher compared to the average for that user (interval model). Sixteen participants completed three questionnaires once per week, and their smartphone logs were recorded over the same period. Based on the results, estimation models were built, and the F-score ranged from 0.739 to 0.818. We also analyzed the features that the estimation model emphasized. Information related to "physical activity," such as acceleration and tilt of the smartphone, and "environment," such as atmospheric pressure and illumination, were given more weight in the estimation than information related to "cyber activity," such as usage of smartphone applications. In particular, in the Positive and Negative Affect Schedule (PANAS), 9 out of 10 top features in the fluctuation model and 7 out of 10 top features in the interval model were related to activities in the physical world, suggesting that short-term mood may be particularly heavily influenced by subjective activities in the human physical world.

Machine learning approaches to predict gestational age in normal and complicated pregnancies via urinary metabolomics analysis.

The elucidation of dynamic metabolomic changes during gestation is particularly important for the development of methods to evaluate pregnancy status or achieve earlier detection of pregnancy-related complications. Some studies have constructed models to evaluate pregnancy status and predict gestational age using omics data from blood biospecimens; however, less invasive methods are desired. Here we propose a model to predict gestational age, using urinary metabolite information. In our prospective cohort study, we collected 2741 urine samples from 187 healthy pregnant women, 23 patients with hypertensive disorders of pregnancy, and 14 patients with spontaneous preterm birth. Using gas chromatography-tandem mass spectrometry, we identified 184 urinary metabolites that showed dynamic systematic changes in healthy pregnant women according to gestational age. A model to predict gestational age during normal pregnancy progression was constructed; the correlation coefficient between actual and predicted weeks of gestation was 0.86. The predicted gestational ages of cases with hypertensive disorders of pregnancy exhibited significant progression, compared with actual gestational ages. This is the first study to predict gestational age in normal and complicated pregnancies by using urinary metabolite information. Minimally invasive urinary metabolomics might facilitate changes in the prediction of gestational age in various clinical settings.

Vascular endothelial growth factor-A is an Immunohistochemical biomarker for the efficacy of bevacizumab-containing chemotherapy for duodenal and jejunal adenocarcinoma.

BACKGROUND: The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. METHODS: This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, ß-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. RESULTS: A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30-0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. CONCLUSION: Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Psychologic stress and disease activity in patients with inflammatory bowel disease: A multicenter cross-sectional study.

BACKGROUND AND AIMS: Psychologic stress can affect the pathogenesis of inflammatory bowel disease (IBD), but the precise contribution of psychologic stress to IBD remains unclear. We investigated the association of psychologic stress with disease activity in patients with IBD, especially in terms of mental state and sleep condition. METHODS: This was a multi-center observational study comprising 20 institutions. Data were collected using survey forms for doctors and questionnaires for patients, and the association of psychologic stress with clinical parameters was investigated. Mental state was evaluated using the Center for Epidemiologic Studies Depression (CES-D) scale, and sleep condition was evaluated by querying patients about the severity of insomnia symptoms. RESULTS: A total of 1078 IBD patients were enrolled, including 303 patients with Crohn's disease and 775 patients with ulcerative colitis. Seventy-five percent of IBD patients believed that psychologic stress triggered an exacerbation of their disease (PSTE group) and 25% did not (non-PSTE group). The CES-D scores were significantly higher for patients with clinically active disease than for those in remission in the PSTE group (median (interquartile range) = 7 (4-9.5) vs. 5 (3-7), p < .0001), but not in the non-PSTE group (5 (2-8) vs. 4 (3-7), p = 0.78). Female sex and disease exacerbation by factors other than psychologic stress were independent factors of psychologic stress-triggered disease exacerbation. Also, patients with insomnia had higher disease activity than those without insomnia, especially in the PSTE group. CONCLUSIONS: A worsened mental state correlates with disease activity in IBD patients, especially those who believe that their disease is exacerbated by psychologic stress.

Endoscopic alterations in Peyer's patches in patients with ulcerative colitis: A prospective, multicenter study.

BACKGROUND AND AIM: Peyer's patches (PPs) play a major role in intestinal mucosal immunity; however, their role in ulcerative colitis (UC) is not well investigated. We evaluated endoscopic features of PPs on narrow-band imaging with magnifying endoscopy (NBI-ME) and investigated their association with clinical factors. METHODS: We prospectively recruited 105 patients with UC, 18 with Crohn's disease, 16 with disease control, and 33 healthy control subjects at three institutions from 2014 to 2017. NBI-ME images of the villi of PPs were evaluated according to the Villi Index, and patients were divided into the Villi Index low (L) and high (H) types. The 1-year sustained clinical remission rate was evaluated between L-type and H-type PPs in patients with UC. RESULTS: The proportions of patients with H-type PPs were significantly higher among UC, Crohn's disease, and disease control patients than among healthy control patients (P = 0.0125, 0.018, 0.0007). In UC, age, gender, endoscopic score, and extent of disease involvement were not significantly different between L-type and H-type PPs, whereas the sustained clinical remission rate was significantly higher in L-type PPs than in H-type PPs (88% [57/65] vs 65% [17/26], P = 0.019). Multivariate analysis revealed that the L type of PPs was a significant factor for sustained clinical remission (odds ratio 3.8, 95% confidence interval 1.1-12.9, P = 0.033). CONCLUSIONS: Patients with UC showed endoscopic alterations in PPs on NBI-ME, and highly altered appearance of PPs can be associated with a high risk of clinical relapse in patients with UC.

Exosomal microRNAs derived from colon cancer cells promote tumor progression by suppressing fibroblast TP53 expression.

The tumor microenvironment offers favorable conditions for tumor progression, and activated fibroblasts, known as cancer-associated fibroblasts, play a pivotal role. TP53-deficient cancer cells are known to induce strong fibroblast activation. We aimed to elucidate the oncogenic role of exosomes derived from TP53-deficient colon cancer cells in fibroblast proliferation and tumor growth. Cancer cell-derived exosomes (CDEs) were isolated from the conditioned media of cancer cells using a sequential ultracentrifugation method. The effects of exosomes on tumor growth were evaluated using human cell lines (TP53-WT colon cancer, HCT116; TP53-mutant colon cancer, HT29; and fibroblasts, CCD-18Co and WI-38) and an immune-deficient nude mouse xenograft model. HCT116 (HCT116sh p53 ) cells deficient in TP53 accelerated cocultured fibroblast proliferation compared to TP53-WT HCT116 (HCT116sh control ) cells in vitro. Exosomes from HCT116sh p53 cells suppressed TP53 expression of fibroblasts and promoted their proliferation. Xenografts of HCT116sh p53 cells grew significantly faster than those of HCT116sh control cells in the presence of co-injected fibroblasts, but this difference was diminished by CDE inhibition. Microarray analysis identified upregulation of several microRNAs (miR-1249-5p, miR-6737-5p, and miR-6819-5p) in TP53-deficient CDEs, which were functionally proven to suppress TP53 expression in fibroblasts. Exosomes derived from TP53-mutant HT29 cells also suppressed TP53 expression in fibroblasts and accelerated their growth. The proliferative effect of HT29 on cocultured fibroblasts was diminished by inhibition of these miRNAs in fibroblasts. Our results suggest that CDEs play a pivotal role in tumor progression by fibroblast modification. Cancer cell-derived exosomes might, therefore, represent a novel therapeutic target in colon cancer.

Usefulness of intestinal real-time virtual sonography in patients with inflammatory bowel disease.

BACKGROUND AND AIM: Transabdominal ultrasonography (US) examination for the intestine is often difficult, and its precedence for intestinal examination depends on accessibility to experienced ultrasonographers. Real-time virtual sonography (RVS) assists examination of US as a fusion method by synchronizing US images with pre-captured computed tomography or magnetic resonance images. We aimed to evaluate the feasibility to use RVS for the examination of the intestine. METHODS: The time to scan three parts of the intestine was compared between conventional US and RVS in seven participants without intestinal diseases. Whether RVS accurately synchronized US images with reference images of intestinal target lesions was judged in 20 patients with inflammatory bowel disease. RESULTS: Examination time to scan the ascending colon and the ileocecum using intestinal RVS was significantly shorter than that using conventional US alone (36.7 vs 50.0 s [P = 0.0313] and 35.4 vs 66.4 s [P = 0.0156], respectively) in participants without intestinal diseases. Well-synchronized US images of the intestinal lesions, such as stenosis, with reference computed tomography/magnetic resonance images were obtained by RVS in all the lesions in the fixed parts of the colon (ascending and descending colon), and images of nine lesions in 12 lesions (75%) were well synchronized in the unfixed part of the intestine in Crohn's disease patients. CONCLUSION: Real-time virtual sonography significantly reduced the examination time of intestinal US. Intestinal RVS can help the ultrasonographer to guide the US probe to detect and monitor intestinal lesions by synchronizing reference images, especially in inflammatory bowel disease patients (UMIN Clinical Trials Registry number: UMIN000011571).

The heart's exposure to radiation increases the risk of cardiac toxicity after chemoradiotherapy for superficial esophageal cancer: a retrospective cohort study.

BACKGROUND: Chemoradiotherapy effectively treats superficial esophageal cancer and is optimal to preserve organs. However, late toxicity, particularly in cardiac diseases, obstructs clinical outcomes. We revealed the risk factors for cardiac event development post-chemoradiotherapy. METHODS: Data from 80 patients who were diagnosed with submucosal invasive esophageal cancer without metastasis (confirmed using multiple modalities) and who underwent chemoradiotherapy between 2006 and 2014 were analyzed. Patients were 11% (9/80) female, and the median age and follow-up were 66.5 y and 73 mo, respectively. We calculated the individual radiation dose to the heart and analyzed relationships between the cardiac event occurrence rate and each clinical factor. RESULTS: The 5-y overall and recurrence-free survival rates were 74.6 and 62.4%, respectively. Among the total number of deaths, 34.6% was caused by esophageal cancer. During the follow-up, 13 patients developed severe cardiac events (ischemic heart diseases, n = 7; pericardial effusion, n = 3, atrial fibrillation, n = 1; and sudden death, n = 2). The significant risk factor for cardiac events post-chemoradiotherapy was the level of the heart's exposure to radiation, with higher exposure associated with greater occurrence. History of smoking, obesity, comorbidity, and history of cardiac disease were unrelated to cardiac event occurrence post-chemoradiotherapy. CONCLUSIONS: Chemoradiotherapy is a favorable intervention for superficial esophageal cancer. Reducing the radiation dose to the heart likely contributes to preventing cardiac toxicity post-chemoradiotherapy.

Maternity Log study: a longitudinal lifelog monitoring and multiomics analysis for the early prediction of complicated pregnancy.

PURPOSE: A prospective cohort study for pregnant women, the Maternity Log study, was designed to construct a time-course high-resolution reference catalogue of bioinformatic data in pregnancy and explore the associations between genomic and environmental factors and the onset of pregnancy complications, such as hypertensive disorders of pregnancy, gestational diabetes mellitus and preterm labour, using continuous lifestyle monitoring combined with multiomics data on the genome, transcriptome, proteome, metabolome and microbiome. PARTICIPANTS: Pregnant women were recruited at the timing of first routine antenatal visits at Tohoku University Hospital, Sendai, Japan, between September 2015 and November 2016. Of the eligible women who were invited, 65.4% agreed to participate, and a total of 302 women were enrolled. The inclusion criteria were age ≥20 years and the ability to access the internet using a smartphone in the Japanese language. FINDINGS TO DATE: Study participants uploaded daily general health information including quality of sleep, condition of bowel movements and the presence of nausea, pain and uterine contractions. Participants also collected physiological data, such as body weight, blood pressure, heart rate and body temperature, using multiple home healthcare devices. The mean upload rate for each lifelog item was ranging from 67.4% (fetal movement) to 85.3% (physical activity), and the total number of data points was over 6 million. Biospecimens, including maternal plasma, serum, urine, saliva, dental plaque and cord blood, were collected for multiomics analysis. FUTURE PLANS: Lifelog and multiomics data will be used to construct a time-course high-resolution reference catalogue of pregnancy. The reference catalogue will allow us to discover relationships among multidimensional phenotypes and novel risk markers in pregnancy for the future personalised early prediction of pregnancy complications.

Adenoma of colorectal laterally spreading tumor nongranular type with biological phenotypic features similar to cancer.

BACKGROUND AND AIM: Colorectal laterally spreading tumors (LSTs) are morphologically subdivided into granular (LST-G) and nongranular (LST-NG) categories. We aimed to elucidate the differences in oncogenic characteristics between the two types. METHODS: Laterally spreading tumors resected by endoscopic submucosal dissection and surgery from March 2009 to May 2017 were examined for p53 positivity, Ki-67 labeling index (LI), microvessel density, degree of fibrosis, intensities of inducible nitric oxide synthase (iNOS) and nitrotyrosine (NT), and expression of acid mucins. We compared these factors between adenomas, noninvasive cancers, and invasive cancers, both LST-G and LST-NG. RESULTS: Ninety-three LST-G (53 adenomas [LST-GA] and 40 cancers [LST-GC]) and 55 LST-NG (24 adenomas [LST-NGA] and 31 cancers [LST-NGC]) were evaluated. Although p53 positivity was lower in LST-GA than in LST-NGA (P < 0.001), there was no difference between LST-GC and LST-NGC. Ki-67 LI was higher in LST-NGA than in LST-GA (P < 0.001) and higher in LST-NGC than in LST-GC of noninvasive cancers (P < 0.001). Microvessel density and degree of fibrosis were higher in LST-NGA than in LST-GA (P < 0.001), and intensities of iNOS and NT were also higher in LST-NGA than in LST-GA (P < 0.001). Expression of acid mucins was lower in LST-NGA than in LST-GA (P < 0.001). Although there were significant differences in p53 positivity, Ki-67 LI, microvessel density, degree of fibrosis, intensities of iNOS and NT, and expression of acid mucins between LST-GA and LST-NGA, these factors were only slightly different between LST-GC and LST-NGC of invasive cancers. CONCLUSIONS: Unlike LST-GA, LST-NGA possessed phenotypic features similar to cancer.

On the Metabolism of Exogenous Ketones in Humans.

Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate "ketogenic" diet, but adherence to such diets can be difficult. An alternative way to increase blood D-ß-hydroxybutyrate (D-ßHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium ßHB. Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of ßHB. Both drinks elevated blood D-ßHB concentrations (D-ßHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3-4 h. KS drinks were found to contain 50% of the L-ßHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-ßHB and L-ßHB was <1.5% of the total ßHB ingested and was in proportion to the blood AUC. D-ßHB, but not L-ßHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-ßHB concentrations was determined in 16 participants. Food lowered blood D-ßHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-ßHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-ßHB AUC of 1.3-1.4 moles.min. Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.

Tissue Drug Concentrations of Anti-tumor Necrosis Factor Agents Are Associated with the Long-term Outcome of Patients with Crohn's Disease.

BACKGROUND: Many reports indicate that a high-serum trough level of anti-tumor necrosis factor (TNF) agents is required for sustained remission in patients with Crohn's disease The pharmacokinetics of anti-TNF agents in inflamed intestinal tissue, however, is not well investigated. We investigated the association between the tissue concentration of anti-TNF agents and long-term disease outcome. METHODS: This was a prospective single-center study that enrolled 25 patients with Crohn's disease who were administered infliximab or adalimumab. All participants underwent endoscopy 2 weeks after administration of the anti-TNF agents, and biopsy samples were obtained from both inflamed and noninflamed intestinal tissue. Tissue concentrations of anti-TNF agents were evaluated and the correlation with serum trough levels was compared. The relation between the tissue drug concentration and clinical course over 24 months was also investigated. RESULTS: Concentrations of anti-TNF agents were significantly higher in inflamed tissue than in noninflamed tissue. Patients with high-serum trough concentrations of anti-TNF agents had significantly higher drug levels in the noninflamed tissue than those with low-serum trough concentrations, but no difference in the levels was detected in the inflamed tissue. Patients with high-drug levels in the noninflamed tissue had a significantly higher sustained response rate than patients with low-drug levels. CONCLUSIONS: Concentrations of anti-TNF agents in the noninflamed tissue can reflect sustained remission and may be a useful biomarker for monitoring therapeutic intensity in patients with Crohn's disease treated with anti-TNF agents (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B623).

Adherence to an elemental diet for preventing postoperative recurrence of Crohn's disease.

PURPOSE: An elemental diet (ED) can suppress inflammation in patients with Crohn's disease (CD); however, adherence to this diet is difficult. We examined the correlation between ED adherence and the postoperative recurrence of CD. METHODS: The subjects of this study were 38 patients who underwent intestinal resection with anastomosis. We defined ED adherence as consuming the average daily ED dose (≥900 kcal/day) for 2 years after surgery. Patients who did not adhere to the ED were allocated to the non-ED group. We diagnosed symptomatic recurrence using the CD activity index and endoscopic recurrence using the Rutgeerts' score. RESULTS: The ED and non-ED groups comprised 21 and 17 patients, respectively, with ED adherence of 55.3% (21/38). At the initial endoscopy, symptomatic and endoscopic recurrence rates were 4.8 and 14.3%, respectively, in the ED group, and 23.5 and 41.2%, respectively, in the non-ED group (P = 0.152 and P = 0.078, respectively). The overall symptomatic recurrence-free duration was significantly longer than the endoscopic recurrence-free duration (P = 0.022). Symptomatic and endoscopic recurrence-free durations were longer in the ED group than in the non-ED group (P = 0.003 and P = 0.021, respectively), and ED adherence was a prognostic factor for endoscopic recurrence (HR = 2.777, 95% CI = 1.036-8.767, P = 0.042). CONCLUSION: Maintaining ED adherence for 2 years after surgery improved the symptomatic and endoscopic recurrence-free durations.

Cardiac metastasis from colon cancer effectively treated with 5-fluorouracil, leucovorin, and oxaliplatin (modified FOLFOX6) plus panitumumab: a case report.

BACKGROUND: Cardiac metastasis from colorectal cancer is rare. There is little evidence supporting the effectiveness of chemotherapy, and standard therapy for metastatic cardiac tumors has not been established. CASE PRESENTATION: A 76-year-old woman presented with a right ventricle tumor that was detected incidentally on screening cardiac ultrasonography. The initial computed tomography (CT) scan showed the cardiac tumor, which was approximately 40 mm in size, and multiple pulmonary nodules. Serum levels of tumor markers CEA and CA19-9 were elevated aberrantly. The suspected primary tumor, a well-differentiated adenocarcinoma of the transverse colon with wild-type KRAS was found by colonoscopy, and treatment with 5-fluorouracil, leucovorin, and oxaliplatin (modified FOLFOX6) plus panitumumab was initiated. After 4 courses of the therapy, a CT scan showed that the cardiac tumor size had markedly decreased and the pulmonary nodules had diminished. The serum levels of CEA and CA19-9 were also markedly decreased. After 12 courses of chemotherapy during 10 months of treatment, the patient continued to show a partial response, and she remained asymptomatic with continuation of the treatment through 15 courses. CONCLUSION: To the best of our knowledge, this is the first report of the efficacy of combination therapy using cytotoxic and molecular targeted agents against cardiac metastasis from colon cancer.

Age at onset is associated with the seasonal pattern of onset and exacerbation in inflammatory bowel disease.

BACKGROUND: Environmental factors are suggested to affect the pathogenesis of several diseases, including inflammatory bowel disease (IBD). The seasonality of disease onset and exacerbation in IBD, however, are not well established. We herein aimed to clarify the disease seasonality and to investigate the underlying characteristics in IBD patients exhibiting seasonality of the disease course. METHODS: This was a multicenter observational study comprising 20 institutions (Osaka Gut Forum) in Japan. Data were collected from November 2013 to August 2014 using survey forms for physicians and questionnaires for patients. Multivariate analysis was performed to clarify the independent factors affecting disease seasonality. RESULTS: A total of 1055 patients, including 298 patients with Crohn's disease (CD) and 757 patients with ulcerative colitis (UC), were enrolled. The proportion of CD patients with disease onset in the summer was significantly larger than that in the other seasons, while UC patients exhibited no seasonality of disease onset. More than half of the IBD patients (51.1%) experienced seasonal exacerbation of IBD, and winter was the most common season for disease exacerbation in both CD and UC patients. Seasonality of disease onset and exacerbation was observed in young-onset patients (≤40 years old), but not in elderly-onset patients. Age at onset was independently associated with the seasonality of both disease onset and exacerbation. CONCLUSIONS: Seasonality of disease onset and exacerbation was observed especially in young-onset IBD patients. Underlying pathophysiologic triggers for disease initiation and exacerbation may be influenced by age at disease onset.

Indigo Naturalis ameliorates murine dextran sodium sulfate-induced colitis via aryl hydrocarbon receptor activation.

BACKGROUND: Indigo Naturalis (IN) is used as a traditional herbal medicine for ulcerative colitis (UC). However, the mechanisms of action of IN have not been clarified. We aimed to evaluate the efficacy of IN for ameliorating colonic inflammation. We further investigated the mechanisms of action of IN. METHODS: Colitis severity was assessed in dextran sodium sulfate-induced colitis and trinitrobenzene sulfonic acid-induced colitis models with or without the oral administration of IN or indigo, which is a known major component of IN. Colonic lamina propria (LP) mononuclear cells isolated from IN-treated mice were analyzed with quantitative reverse transcription polymerase chain reaction (qRT-PCR) and flow cytometry. LP and splenic mononuclear cells cultured in vitro with IN or indigo were also analyzed. The role of the candidate receptor for indigo, the aryl hydrocarbon receptor (AhR), was analyzed using Ahr-deficient mice. RESULTS: Colitis severity was significantly ameliorated in the IN and indigo treatment groups compared with the control group. The mRNA expression levels of interleukin (Il)-10 and Il-22 in the LP lymphocytes were increased by IN treatment. The treatment of splenocytes with IN or indigo increased the expression of anti-inflammatory cytokines and resulted in the expansion of IL-10-producing CD4+ T cells and IL-22-producing CD3-RORγt+ cells, but not CD4+Foxp3+ regulatory T cells. The amelioration of colitis by IN or indigo was abrogated in Ahr-deficient mice, in association with diminished regulatory cytokine production. CONCLUSIONS: IN and indigo ameliorated murine colitis through AhR signaling activation, suggesting that AhR could be a promising therapeutic target for UC.