Safety and biological outcomes following a phase 1 trial of GD2-specific CAR-T cells in patients with GD2-positive metastatic melanoma and other solid cancers.

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and refractory B-cell malignancies. If CAR-T cell therapy for non-hematological malignancies is to achieve the same stage of clinical development, then iterative early-phase clinical testing can add value to the clinical development process for evaluating CAR-T cell products containing different CAR designs and manufactured under differing conditions. METHODS: We conducted a phase 1 trial of third-generation GD2-specific CAR-T cell therapy, which has previously been tested in neuroblastoma patients. In this study, the GD2-CAR-T therapy was evaluated for the first time in metastatic melanoma patients in combination with BRAF/MEK inhibitor therapy, and as a monotherapy in patients with colorectal cancer and a patient with fibromyxoid sarcoma. Feasibility and safety were determined and persistence studies, multiplex cytokine arrays on sera and detailed immune phenotyping of the original CAR-T products, the circulating CAR-T cells, and, in select patients, the tumor-infiltrating CAR-T cells were performed. RESULTS: We demonstrate the feasibility of manufacturing CAR-T products at point of care for patients with solid cancer and show that a single intravenous infusion was well tolerated with no dose-limiting toxicities or severe adverse events. In addition, we note significant improvements in CAR-T cell immune phenotype, and expansion when a modified manufacturing procedure was adopted for the latter 6 patients recruited to this 12-patient trial. We also show evidence of CAR-T cell-mediated immune activity and in some patients expanded subsets of circulating myeloid cells after CAR-T cell therapy. CONCLUSIONS: This is the first report of third-generation GD2-targeting CAR-T cells in patients with metastatic melanoma and other solid cancers such as colorectal cancer, showing feasibility, safety and immune activity, but limited clinical effect. TRIAL REGISTRATION NUMBER: ACTRN12613000198729.

Outcomes of Serum Food-Specific Immunoglobulin G 4 to Guide Elimination Diet in Patients With Eosinophilic Esophagitis.

INTRODUCTION: Eosinophilic esophagitis (EoE) is associated with atopy; however, recent studies have identified an association with food-specific immunoglobulin G 4 (FS-IgG 4 ) rather than immunoglobulin E antibodies. This study aimed to evaluate the role of serum FS-IgG 4 in guiding an elimination diet and its outcomes. METHODS: Patients with and without EoE were enrolled in a prospective, controlled, single tertiary center trial. Serum FS-IgG 4 titers, esophageal eosinophil counts, and dysphagia symptom questionnaire scores were assessed, and participants with elevated FS-IgG 4 (ImmunoCAP, cutoff of 10 mgA/L) commenced 6-week targeted elimination diet. Repeat serum FS-IgG 4 and endoscopic and histologic examination were performed at 6-week follow-up. RESULTS: Twenty-two patients with active EoE and 13 controls were recruited. Serum FS-IgG 4 to milk, wheat, soy, eggs, and nuts was significantly higher in EoE ( P = 0.0002, P = 0.002, P = 0.003, P = 0.012, and P < 0.001, respectively). Elevated serum FS-IgG 4 to 1 or more food groups (median 2) was identified in 21/22 (95.4%) patients with EoE; 20/21 underwent 6-week dietary elimination. Median reductions in dysphagia symptom questionnaire score and EoE endoscopic reference score after elimination were 8 ( P = 0.0007) and 1 ( P = 0.002), respectively. Nine (45%) patients had histological remission (<15 eosinophils per high-power field). Fall in median esophageal eosinophil count was not statistically significant (50 vs 23; P = 0.068). Serum FS-IgG 4 did not decline by 6-week follow-up. DISCUSSION: Serum FS-IgG 4 to milk, wheat, soy, egg, and nuts was present at higher levels in EoE, with targeted elimination resulting in 45% histologic remission rate. Serum FS-IgG 4 has potential as a noninvasive biomarker in EoE. When successful, FS-IgG 4 -led elimination diet can negate need for medications and be viewed more favorably by patients because of its smaller endoscopic burden compared with empirical elimination diets.

Composite Assessment Using Intestinal Ultrasound and Calprotectin Is Accurate in Predicting Histological Activity in Ulcerative Colitis: A Cohort Study.

BACKGROUND: Beyond endoscopic remission, histological remission in ulcerative colitis (UC) is predictive of clinical outcomes. Intestinal ultrasound (IUS) may offer a noninvasive surrogate marker for histological activity; however, there are limited data correlating validated ultrasound and histological indices. AIM: Our aim was to determine the correlation of IUS activity in UC with a validated histological activity index. METHODS: Twenty-nine prospective, paired, same-day IUS/endoscopy/histology/fecal calprotectin (FC) cases were included. Intestinal ultrasound activity was determined using the Milan Ultrasound Criteria, histological activity using the Nancy Histological Index, endoscopic activity using Mayo endoscopic subscore and Ulcerative Colitis Endoscopic Index of Severity, and clinical activity using the Simple Clinical Colitis Activity Score. RESULTS: Histological activity demonstrated a significant linear association with overall IUS activity (coefficient 0.14; 95% CI, 0.03-0.25; P = .011). Intestinal ultrasound activity was also significantly associated with endoscopic activity (0.32; 95% CI, 0.14-0.49; P < 0.001), total Mayo score (0.31; 95% CI, 0.02-0.60; P = .036) but not FC (0.10; 95% CI, -0.01 to 0.21; P = .064) or clinical disease activity (0.04; 95% CI, -0.21 to 0.28; P = .768). A composite of IUS and FC showed the greatest association (1.31; 95% CI, 0.43-2.18; P = .003) and accurately predicted histological activity in 88% of cases (P = .007), with sensitivity of 88%, specificity 80%, positive predictive value 95%, and negative predictive value 57%. CONCLUSIONS: Intestinal ultrasound is an accurate noninvasive marker of histological disease activity in UC, the accuracy of which is further enhanced when used in composite with FC. This can reduce the need for colonoscopy in routine care by supporting accurate point-of-care decision-making in patients with UC.

Association Between RAS/BRAF Mutations and Complete Response Following Total Neoadjuvant Therapy in Patients with Rectal Cancer: A Prospective Multicentered Study.

BACKGROUND: The impact of RAS/BRAF mutation on primary response rates after total neoadjuvant therapy (TNT) in patients with advanced rectal cancer is unclear. The aim of this study was to assess complete response rates after TNT according to RAS/BRAF mutation status. METHODS: A prospective observational study was performed in patients with rectal cancer who underwent TNT with curative intent at three South Australian hospitals between 2019 and 2023. Patients were classified according to their mutation status: mutant RAS/BRAF (mutRAS) or wild-type RAS/BRAF (wtRAS). The primary endpoint was overall complete response (oCR) rate, defined as the proportion of patients who achieved clinical complete response (cCR) and/or pathological complete response (pCR). RESULTS: Of the 150 patients eligible for inclusion, 80 patients with RAS/BRAF status available were identified. Of these, 43 (53.8%) patients were classified as mutRAS and 37 (46.3%) patients as wtRAS. Patients with mutRAS had significantly lower cCR and oCR rates after TNT than patients with wtRAS (14% vs. 37.8%, p = 0.014; 11.6% vs. 43.2%, p = 0.001, respectively). There was no significant difference in pCR rate between the groups. Of the 80 rectal cancer patients tested, 35 (43.8%) had metastatic disease (M1). There was no significant difference in complete M1 response rates between the groups (17.6% vs. 38.9%, p = 0.254). CONCLUSION: RAS/BRAF mutations negatively impact primary tumor response rates after TNT in patients with advanced rectal cancer. Large-scale national studies are needed to determine whether RAS/BRAF status could be used to select optimal oncologic therapy in rectal cancer patients.

Spontaneous self-expulsion of an oesophageal duplication cyst.

A case report of an oesophageal duplication cyst in an adult patient with chronic cough and presenting with a "coughed out lump". This is an unusual presentation highlighting the importance of considering congenital duplication cysts in patients with chronic cough and no obvious respiratory cause.

Increase in distal esophageal wall thickness with time in adult patients with eosinophilic esophagitis.

Background and Aim: Eosinophilic esophagitis (EoE) is a chronic disease which may progress to a fibro-stenotic phenotype due to esophageal sub-epithelial fibrosis. Esophageal wall thickening in patients with EoE has been demonstrated in a few studies using endoscopic ultrasound (EUS). The aim of this study was to longitudinally assess the endoscopic appearance, wall thickness, histology, and dysphagia score of EoE patients. Methods: Patients with EoE were recruited and studied between February 2012 and April 2021. Patients were evaluated on two separate occasions at least 12 months apart with endoscopy, EUS, and esophageal mucosal biopsies. The dysphagia score and epidemiology data were also assessed. Results: A total of 16 EoE patients were included with a mean follow-up duration of 2.2 ± 1.2 years. In 14/16 (88%) patients, the total wall thickness of the distal esophagus significantly increased (P = 0.0012) as a result of thickening of the muscularis propria (P = 0.0218). However, only 1/14 (7%) patient had an increase in the dysphagia score, while 8/14 (57%) and 5/14 (36%) had a stable and reduced dysphagia score, respectively. No differences were found in the total thickness of other esophageal regions, dysphagia score, endoscopic appearance, and eosinophil count over time. Conclusion: Distal esophageal wall thickness increases with time in EoE patients, independent of the dysphagia score and eosinophil count.

Methods of tissue preparation after EUS-guided tissue acquisition without rapid on-site assessment: Results of a randomized study.

In the absence of rapid on-site evaluation (ROSE), it is not clear which method of tissue preparation is best to process tissue obtained from EUS guidance. Cytological smearing (CS), cell block (CB), and direct histology (DH) are the available techniques. AIM: To compare the diagnostic yield of three techniques of tissue preparation for EUS-guided tissue acquisition without ROSE. METHODS: Patients who were referred for EUS-FNA of peri-gastrointestinal masses were recruited. Without ROSE, each lesion was biopsied with three needle passes, and the order in which tissue is prepared was randomized to either (i) CS + CB, (ii) CB only, or (iii) DH only. The prepared specimens were reviewed. RESULTS: A total of 243 specimens were taken from 81 patients. Tissue diagnosis was achieved in 78/81 (96.3%) of patients, including 63 neoplasms (PDAC [n = 45], pancreatic neuroendocrine tumors [PNET; n = 4], cholangiocarcinoma [n = 5], metastatic disease [n = 4], lymphoma [n = 1], linitis plastica [n = 2], leiomyoma [n = 2]) and 15 benign pathologies (chronic pancreatitis [n = 8], reactive nodes [n = 5], inflammatory biliary stricture [n = 1], and pancreatic rest [n = 1]). The three non-diagnostic cases were found to be PDAC (n = 2) and PNET (n = 1). Sensitivity and diagnostic accuracy was highest with DH (94 and 95%), which was significantly better than that by CS + CB (43 and 54%; P = 0.0001) and CB-only preparations (32 and 48.6%; P < 0.0001). There was no significant difference between the CS + CB and CB-only arms (P > 0.22). CONCLUSION: Without ROSE, our findings suggest that with just a single pass, DH should be the tissue preparation method of choice given its significantly higher diagnostic accuracy compared with CS and/or CB techniques.

Distal esophageal wall thickness correlates with dysphagia in adult patients with eosinophilic esophagitis.

BACKGROUND: Thickening of the esophageal wall in patients with eosinophilic esophagitis (EoE) and gastro-esophageal reflux disease (GERD) has been shown in studies using endoscopic ultrasound (EUS). We hypothesise that transmural inflammation in EoE results in prominent esophageal wall thickening compared with the mucosal inflammation in GERD. The aim of this study was to compare the relationship among dysphagia, endoscopic appearance, wall thickness, histology, and motility in EoE and GORD. METHODS: EoE and GERD patients were prospectively studied between February 2012 and April 2021. Patients were studied on 2 separate occasions with endoscopy, EUS and mucosal biopsies, followed by high-resolution manometry. Epidemiology and dysphagia data were obtained. RESULTS: A total of 45 patients (31 EoE, 14 GERD) were included. There were no significant differences in age, sex, duration of disease and presence of esophageal motility disorders. EoE patients had a higher dysphagia score (P < 0.001), EREFS score (P < 0.001) and peak eosinophil count (P < 0.001) compared with GERD patients. Thickness of the submucosa in the distal esophagus in EoE was significantly higher than GERD (P = 0.003) and positively correlated with duration of disease (P = 0.01, R = 0.67). Positive correlation was also found between dysphagia score and distal total esophageal wall thickness (P = 0.03, R = 0.39) in EoE patients. No correlation was found between these variables in GERD patients. CONCLUSION: Distal esophageal wall thickness positively correlates with dysphagia score in EoE but not GERD. This appears to be related to the composition of the submucosa which can be identified using EUS.

Therapeutic Potential of the 4 Strategies to SUlfide-REduction (4-SURE) Diet in Adults with Mild to Moderately Active Ulcerative Colitis: An Open-Label Feasibility Study.

BACKGROUND: Diet therapy may bridge the therapeutic gap in ulcerative colitis (UC). OBJECTIVES: The novel 4-SURE diet (4-strategies-to-SUlfide-REduction), designed to modulate colonic fermentation and influence production of excess hydrogen sulfide, was examined in a feasibility study for tolerability, clinical efficacy, and effects on microbial endpoints. METHODS: Adults aged ≥18 y old with mild to moderately active UC were advised to increase intake of fermentable fibers, restrict total and sulfur-containing proteins, and avoid specific food additives for 8 wk. The primary outcome was tolerability of diet [100-mm visual analogue scale (VAS) with 100-mm being intolerable]. Secondary exploratory outcomes were self-reported adherence (always adherent ≥76-100%), clinical and endoscopic response (reduction in partial Mayo ≥2 and Mayo endoscopic subscore ≥1), modulation of fecal characteristics including markers of protein and carbohydrate fermentation, and food-related quality of life (IBD-FRQoL-29). Primary analysis was by intention to treat, performed using paired t and Wilcoxon signed-rank statistical tests. RESULTS: Twenty-eight adults with UC [mean (range) age: 42 (22-72) y, 15 females, 3 proctitis, 14 left-sided, and 11 extensive] were studied. Prescribed dietary targets were achieved overall. The diet was well tolerated (VAS: 19 mm; 95% CI: 7, 31 mm) with 95% frequently or always adherent. Clinical response occurred in 13 of 28 (46%) and endoscopic improvement in 10 of 28 participants (36%). Two participants (7%) worsened. Fecal excretion of SCFAs increased by 69% (P < 0.0001), whereas the proportion of branched-chain fatty acids to SCFAs was suppressed by 27% (-1.34%; 95% CI: -2.28%, -0.40%; P = 0.007). The FRQoL improved by 10 points (95% CI: 4, 16; P < 0.001). CONCLUSIONS: The 4-SURE dietary strategy is considered tolerable and an acceptable diet by adults with mild to moderately active UC. The dietary teachings achieved the prescribed dietary and fecal targets. Given signals of therapeutic efficacy, further evaluation of this diet is warranted in a placebo-controlled trial. This trial was registered at https://www.anzctr.org.au (Australian New Zealand Clinical Trials Registry) as ACTRN12619000063112.

Oncological outcomes after piecemeal endoscopic mucosal resection of large non-pedunculated colorectal polyps with covert submucosal invasive cancer.

OBJECTIVE: Management of covert submucosal invasive cancer (SMIC) discovered after piecemeal endoscopic mucosal resection (pEMR) of large (>20 mm) non-pedunculated colorectal polyps is challenging. The residual cancer risk is largely unknown. We sought to evaluate this in a large tertiary referral cohort. DESIGN: Cases of covert SMIC following pEMR were identified and followed. Oncological outcomes after surgery were divided based on residual intramural cancer, lymph node metastases (LNM) or both. Risk factors for residual intramural cancer and LNM were analysed based on the original pEMR histological variables. Risk parameters were analysed with respect to low and high-risk variables for residual intramural cancer and LNM. RESULTS: Among 3372 cases of large non-pedunculated colorectal polyps, 143 cases of covert SMIC (4.2%) were identified. 109 underwent surgical resection. Histological analysis of pEMR histology was available in 98 of 109 (90%) cases. 62 cases (63%) had no residual malignancy. 36 cases had residual malignancy (residual intramural cancer n=24; LNM n=5; both n=7). All cases of residual intramural cancer could be identified by a R1 histological deep margin. Cases with poor differentiation (PD) and/or lymphovascular invasion (LVI) had a high risk of LNM (12/33), with a very low risk without these criteria (<1%; 0/65). Cases at low risk for LNM with R0 deep margin have a low risk of residual intramural cancer (<1%; 0/35). CONCLUSION: The majority of cases of large non-pedunculated colorectal polyps with covert SMIC following pEMR will have no residual malignancy. The risk of residual malignancy can be ascertained from three key variables: PD, LVI and R1 deep margin.

Vasculogenic mimicry structures in melanoma support the recruitment of monocytes.

The progression of cancer is facilitated by infiltrating leukocytes which can either actively kill cancer cells or promote their survival. Our current understanding of leukocyte recruitment into tumors is largely limited to the adhesion molecules and chemokines expressed by conventional blood vessels that are lined by endothelial cells (ECs). However, cancer cells themselves can form their own vascular structures (a process known as vasculogenic mimicry (VM)); but whether they actively participate in the recruitment of leukocytes remains to be elucidated. Herein, we demonstrate that VM-competent human melanoma cell lines express multiple adhesion molecules (e.g. CD44, intercellular adhesion molecule (ICAM)-1 and junction adhesion molecules (JAMs)) and chemokines (e.g. CXCL8 and CXCL12) relevant for leukocyte recruitment. Microfluidic-based adhesion assays revealed that similar to ECs, VM-competent melanoma cells facilitate the rolling and adhesion of leukocytes, particularly monocytes, under conditions of shear flow. Moreover, we identified ICAM-1 to be a key participant in this process. Transwell assays showed that, similar to ECs, VM-competent melanoma cells facilitate monocyte transmigration toward a chemotactic gradient. Gene expression profiling of human melanoma patient samples confirmed the expression of numerous leukocyte capture adhesion molecules and chemokines. Finally, immunostaining of patient tissue microarrays revealed that tumors with high VM content also contained higher numbers of leukocytes (including macrophages). Taken together, this study suggests an underappreciated role of VM vessels in solid tumors via their active participation in leukocyte recruitment and begins to identify key adhesion molecules and chemokines that underpin this process.

Combined chemotherapy and endoscopic ultrasound-guided intratumoral 32P implantation for locally advanced pancreatic adenocarcinoma: a pilot study.

BACKGROUND: This study evaluated clinical outcomes of combined chemotherapy and endoscopic ultrasound (EUS)-guided intratumoral radioactive phosphorus-32 (32P) implantation in locally advanced pancreatic adenocarcinoma (LAPC). METHODS: Consecutive patients with newly diagnosed LAPC were recruited over 20 months. Baseline computed tomography and 18F-2-fluoro-2-deoxy-D-glucose (18FDG) positron emission tomography-computed tomography were performed and repeated after 12 weeks to assess treatment response. Following two cycles of conventional chemotherapy, patients underwent EUS-guided 32P implantation followed by six chemotherapy cycles. RESULTS: 12 patients with LAPC (median age 69 years [interquartile range 61.5-73.3]; 8 male) completed treatment. Technical success was 100 % with no procedural complications. At 12 weeks, median reduction in tumor volume was 8.2 cm3 (95 % confidence interval 4.95-10.85; P = 0.003), with minimal or no 18FDG uptake in nine patients (75 %). Tumor downstaging was achieved in six patients (50 %), leading to successful resection in five (42 %), including four R0 resections (80 %). CONCLUSIONS: EUS-guided 32P implantation was feasible, well tolerated, and resulted in a 42 % surgical resection rate. Further evaluation in a larger randomized multicenter trial is warranted.

Characteristics and progression of childhood-onset and adult-onset eosinophilic esophagitis.

BACKGROUND AND AIM: The prevalence and incidence of eosinophilic esophagitis (EoE) has been increasing over recent years. However, the natural history remains incompletely understood particularly the differences in disease characteristics and progression of childhood-onset and adult-onset EoE. The aim of this study was to evaluate the disease characteristics and progression of childhood-onset and adult-onset EoE. METHODS: A cross-sectional, questionnaire-based study, on 87 adults and 67 children from 2 major tertiary hospitals in South Australia was conducted. Data of those who were diagnosed with EoE between 1999 and 2018 were collected and correlated with medical records. RESULTS: Of the 87 adults with EoE, 34 (39%) were diagnosed at the age of < 18 years (childhood-onset EoE). Reflux symptoms were more common in childhood-onset EoE, whereas asthma was more common in adult-onset EoE. The median duration of symptoms prior to diagnosis of EoE was > 1-4 years in childhood-onset disease (44%) and ≥ 10 years in adult-onset disease (34%). Food impaction was significantly more common on initial presentation in those with adult-onset EoE, whereas weight loss was more common in childhood-onset EoE. At the time of questionnaire, regurgitation, abdominal pain, and bloating were more common in childhood-onset EoE. Those with childhood-onset EoE were more likely to have multiple symptoms at questionnaire when compared with their adult-onset counterparts. In both groups, 15% (5/34 childhood-onset EoE and 8/53 adult-onset EoE) were asymptomatic at the time of questionnaire. CONCLUSION: Childhood-onset EoE appears to be a progressive disease from childhood to adulthood, however with more inflammatory-type symptoms post transition compared to those with adult-onset EoE.

Endoscopic Ultrasound-guided Fine-needle Biopsy With or Without Rapid On-site Evaluation for Diagnosis of Solid Pancreatic Lesions: A Randomized Controlled Non-Inferiority Trial.

BACKGROUND AND AIMS: The benefit of rapid on-site evaluation (ROSE) on the diagnostic accuracy of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) has never been evaluated in a randomized study. This trial aimed to test the hypothesis that in solid pancreatic lesions (SPLs), diagnostic accuracy of EUS-FNB without ROSE was not inferior to that of EUS-FNB with ROSE. METHODS: A noninferiority study (noninferiority margin, 5%) was conducted at 14 centers in 8 countries. Patients with SPLs requiring tissue sampling were randomly assigned (1:1) to undergo EUS-FNB with or without ROSE using new-generation FNB needles. The touch-imprint cytology technique was used to perform ROSE. The primary endpoint was diagnostic accuracy, and secondary endpoints were safety, tissue core procurement, specimen quality, and sampling procedural time. RESULTS: Eight hundred patients were randomized over an 18-month period, and 771 were analyzed (385 with ROSE and 386 without). Comparable diagnostic accuracies were obtained in both arms (96.4% with ROSE and 97.4% without ROSE, P = .396). Noninferiority of EUS-FNB without ROSE was confirmed with an absolute risk difference of 1.0% (1-sided 90% confidence interval, -1.1% to 3.1%; noninferiority P < .001). Safety and sample quality of histologic specimens were similar in both groups. A significantly higher tissue core rate was obtained by EUS-FNB without ROSE (70.7% vs. 78.0%, P = .021), with a significantly shorter mean sampling procedural time (17.9 ± 8.8 vs 11.7 ± 6.0 minutes, P < .0001). CONCLUSIONS: EUS-FNB demonstrated high diagnostic accuracy in evaluating SPLs independently on execution of ROSE. When new-generation FNB needles are used, ROSE should not be routinely recommended. (ClinicalTrial.gov number NCT03322592.).

Multinational survey on the preferred approach to management of Barrett's esophagus in the Asia-Pacific region.

BACKGROUND: Major societies provide differing guidance on management of Barrett's esophagus (BE), making standardization challenging. AIM: To evaluate the preferred diagnosis and management practices of BE among Asian endoscopists. METHODS: Endoscopists from across Asia were invited to participate in an online questionnaire comprising eleven questions regarding diagnosis, surveillance and management of BE. RESULTS: Five hundred sixty-nine of 1016 (56.0%) respondents completed the survey, with most respondents from Japan (n = 310, 54.5%) and China (n = 129, 22.7%). Overall, the preferred endoscopic landmark of the esophagogastric junction was squamo-columnar junction (42.0%). Distal palisade vessels was preferred in Japan (59.0% vs 10.0%, P < 0.001) while outside Japan, squamo-columnar junction was preferred (59.5% vs 27.4%, P < 0.001). Only 16.3% of respondents used Prague C and M criteria all the time. It was never used by 46.1% of Japanese, whereas 84.2% outside Japan, endoscopists used it to varying extents (P < 0.001). Most Asian endoscopists (70.8%) would survey long-segment BE without dysplasia every two years. Adherence to Seattle protocol was poor with only 6.3% always performing it. 73.2% of Japanese never did it, compared to 19.3% outside Japan (P < 0.001). The most preferred (74.0%) treatment of non-dysplastic BE was proton pump inhibitor only when the patient was symptomatic or had esophagitis. For BE with low-grade dysplasia, 6-monthly surveillance was preferred in 61.9% within Japan vs 47.9% outside Japan (P < 0.001). CONCLUSION: Diagnosis and management of BE varied within Asia, with stark contrast between Japan and outside Japan. Most Asian endoscopists chose squamo-columnar junction to be the landmark for esophagogastric junction, which is incorrect. Most also did not consistently use Prague criteria, and Seattle protocol. Lack of standardization, education and research are possible reasons.

Young-onset colorectal cancer is associated with a personal history of type 2 diabetes.

BACKGROUND: Colorectal cancer (CRC) is rising in incidence in young adults, and this observation is currently unexplained. We investigated whether having a personal history of type 2 diabetes mellitus (T2D) was a potential risk factor for young-onset colorectal cancer (YOCRC). METHODS: The South Australian Young Onset (SAYO) CRC study is a series of young adults with CRC below age 55. Ninety unrelated YOCRC cases were recruited to the study. Personal history and detailed family history of T2D were obtained at face-to-face interview and confirmed from medical records. Whole exome sequencing was conducted on germline DNA from each CRC case. Controls for personal history studies of T2D were 240 patients with proven clear colonoscopies and no known CRC predispositions. RESULTS: The median age of YOCRC cases was 44 years (18-54) and of controls was 45 years (18-54), and 53% of both cases and controls were females (P = 0.99). Left-sided (distal) CRC was seen in 67/89 (75%) of cases. A personal history of T2D was confirmed in 17/90 (19%) YOCRC patients compared with controls (12/240, 5%; P < 0.001; odds ratio = 4.4; 95% confidence interval, 2.0-9.7). YOCRC patients frequently reported at least one first-degree relative with T2D (32/85, 38%). Ten of 87 (12%) of YOCRC cases had CRC-related pathogenic germline variants, however, no pathogenic variants in familial diabetes-associated genes were seen. CONCLUSIONS: Though the mechanism remains unclear, our observations suggest that there is enrichment for personal history of T2D in YOCRC patients. IMPACT: A diagnosis of T2D could therefore potentially identify a subset of young adults at increased risk for CRC and in whom early screening might be appropriate.

Signet-ring cell appearance of atrophic fat cells.

Cells with 'signet-ring' appearance were found at post-mortem examination of a man with a history of chronic illness, weight loss and multiple regions of 'bowel thickening' during life. Due to the decedent's history, the finding raised the possibility of disseminated signet-ring adenocarcinoma. However, the vacuoles did not stain for mucin and the cells did not stain for keratin. The cells did stain for calretinin and so a diagnosis of signet ring mesothelioma was considered. However, it was suggested that the cells with a cytoplasmic vacuole displacing the nucleus to one side producing the signet-ring appearance were instead atrophic fat cells. This was subsequently proven by Oil Red O staining.

The Expression Profile and Textural Characteristics of C595-Reactive MUC1 in Pancreatic Ductal Adenocarcinoma for Targeted Radionuclide Therapy.

Improvements in the prognosis of pancreatic ductal adenocarcinoma (PDAC) rely on the development of effective treatments to target advanced disease. Mucin 1 (MUC1) is a transmembrane glycoprotein which is involved in the metastatic progression of PDAC and is a receptor-of-interest for targeted radionuclide therapy. The aim of this study was to determine the feasibility of MUC1-based targeted radionuclide therapy for PDAC, by evaluating the expression profile of MUC1 in different pancreatic cells and tissues using the C595 antibody. MUC1 expression was evaluated in four PDAC cell lines (PANC-1, BxPC-3, CAPAN-1 and AsPC-1) using flow cytometry and immunocytochemistry. Immunohistochemistry was performed on primary and metastatic PDAC, pancreatitis, pancreatic intra-epithelial neoplasia and normal pancreatic tissue samples to identify potential changes in C595-reactive MUC1 expression across different disease groups. C595-reactive MUC1 expression was found to varying degrees in the cell lines (11.5-93.1%). A pixel analysis of the immunohistochemical staining demonstrated highest MUC1 expression in primary PDAC tissue (mean pixel value of 205.4), followed by other pancreatic cancer types (204.9), pancreatic intra-epithelial neoplasia (203.8), metastatic PDAC (201.5), chronic pancreatitis (198.1) and normal pancreatic tissue (191.4). The increased expression in malignant tissues and reduced expression in benign tissues indicate that C595-reactive MUC1 is a potential target for targeted radionuclide therapy of PDAC.

Distinguishing gastroesophageal reflux disease and eosinophilic esophagitis in adults: The role of esophageal mucosal immunoglobulin G4.

BACKGROUND AND AIM: Eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD) can be difficult to distinguish as many of their clinical and histological features overlap. Preliminary data suggest a potential association between EoE and immunoglobulin G4 (IgG4) but not GERD. This study aimed to examine the role of esophageal mucosal IgG4 staining when differentiating EoE from GERD. METHODS: Esophageal biopsy specimens from patients with proven EoE and GERD were evaluated, and immunohistochemical staining for IgG4 was performed by an experienced gastrointestinal pathologist blinded to the clinical and endoscopic data. The results on IgG4 staining were then correlated with clinical, endoscopic, and histological features. RESULTS: Sixty patients were included in the study, with 30 EoE (38.8 ± 12.8 years, 23 M:7 F) and 30 GERD (50.7 ± 14.3 years, 14 M:16 F) patients. The prevalence of a positive intercellular IgG4 stain was significantly higher in the EoE patients than those with GERD (23/29 vs 2/30; P < 0.0001). Positive IgG4 stain had the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 77%, 93%, 92%, and 80% for predicting the diagnosis of EoE, respectively. In both EoE and GERD patients, correlation was found between positive IgG4 staining and food bolus obstruction, dysphagia to solids, reflux, fixed rings, Barrett's esophagus, hiatus hernia, and esophagitis. In EoE patients, positive IgG4 staining was not correlated with the type of symptoms, endoscopic findings, histological findings, proton pump inhibitor therapy, or history of allergy/atopy. CONCLUSION: Given the high specificity and PPV of positive IgG4 staining in esophageal biopsies for EoE, this can be a useful marker to distinguish the disease from GERD.

Polyp Detection Rate as a Surrogate for Adenoma and Sessile Serrated Adenoma/Polyp Detection Rates.

INTRODUCTION: Quality measures for colonoscopy such as adenoma detection rate (ADR) have been proposed to be surveilled for ensuring minimum standards. However, its direct measurement is time consuming and often neglected. Extrapolating ADR and other quality measures from polyp detection rate (PDR) can be a pragmatic alternative. OBJECTIVE: To determine quotients for estimating ADR and sessile serrated adenoma/polyp detection rate (SSA/P-DR) from PDR in an Australian cohort. METHODS: Consecutive adult patient colonoscopies during a 1-year period were retrospectively assessed in a single Australian tertiary endoscopy center. Adenoma detection quotient (ADQ) and SSA/P detection quotient (SSA/P-DQ) were defined as the division of ADR and SSA/P-DR by PDR, respectively. The primary outcome was the number of procedures to achieve a stable cumulative ADQ and SSA/P-DQ. Secondary outcomes included evaluation of ADQ and SSA/P-DQ in different subsets. RESULTS: In total, 2,657 colonoscopies were performed by 15 endoscopists in 2016. The ADR, SSA/P-DR, and PDR found were 32.2, 6.7, and 47.3%, respectively. The ADQ and SSA/P-DQ values found were 0.68 and 0.14, respectively. After approximately 500 procedures, both ADQ and SSA/P-DQ became stable. Interclass correlation coefficient (ICC) for the prediction of ADR from ADQ was excellent for all endoscopists that performed >177 procedures in that year (ICC 0.84). CONCLUSIONS: ADQ and SSA/P-DQ values were consistent when over 500 procedures were analyzed. ADQ had an excellent correlation with ADR when >177 procedures per endoscopist were evaluated.