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Proton pump inhibitors (PPIs) are the main treatment recommended and used for gastro-esophageal reflux disease (GERD). However, they fail to control symptoms in a substantial proportion of patients who have PPI-refractory GERD, which is defined as persistent symptoms attributable to objective findings of gastro-esophageal reflux. There remains a lack of dedicated guidelines to direct the management of these patients, some of whom could benefit greatly from surgical treatment. Too often patients remain long-term on ineffective treatment or stop treatment with lack of active review often resulting in their dissatisfaction going unnoticed. Also, concerns over efficacy and side effects of surgical procedures can be off-putting for both patients and physicians. It has been suggested that response to PPIs is predictive of surgical outcome. In this Perspective article we instead recommend that the key determinant should be whether symptoms are caused by GERD. We also discuss the traditional and newer surgical treatment options for people with PPI-refractory GERD. Labenz and Schoppmann discuss the approach to treatment for patients with gastro-esophageal reflux disease that is resistant to standard medical treatment with proton pump inhibitors. They highlight the scope of the problem and the principles of various treatment options with a focus on surgical options, in appropriate patients.

Background Dysphagia remains the most significant concern after anti-reflux surgery, including magnetic sphincter augmentation (MSA). The aim of this study was to evaluate postoperative dysphagia rates, its risk factors, and management after MSA. Methods From a prospectively collected database of all 357 patients that underwent MSA at our institution, a total of 268 patients were included in our retrospective study. Postoperative dysphagia score, gastrointestinal symptoms, proton pump inhibitor intake, GERD-HRQL, Alimentary Satisfaction, and serial contrast swallow imaging were evaluated within standardized follow-up appointments. To determine patients’ characteristics and surgical factors associated with postoperative dysphagia, a multivariable logistic regression analysis was performed. Results At a median follow-up of 23 months, none of the patients presented with severe dysphagia, defined as the inability to swallow solids or/and liquids. 1% of the patients underwent endoscopic dilatation, and 1% had been treated conservatively for dysphagia. 2% of the patients needed re-operation, most commonly due to recurrent hiatal hernia. Two patients underwent device removal due to unspecific discomfort and pain. No migration of the device or erosion by the device was seen. The LINX® device size ≤ 13 was found to be the only factor associated with postoperative dysphagia (OR 5.90 (95% CI 1.4–24.8)). The postoperative total GERD-HRQL score was significantly lower than preoperative total score (2 vs. 19;  p  = 0.001), and daily heartburn, regurgitations, and respiratory complains improved in 228/241 (95%), 131/138 (95%) and 92/97 (95%) of patients, respectively. Conclusions Dysphagia requiring endoscopic or surgical intervention was rare after MSA in a large case series. LINX® devices with a size < 13 were shown to be an independent risk factor for developing postoperative dysphagia.

AF1q associates with tumor progression and metastases upon WNT signaling. The downstream WNT target CD44 has demonstrated prognostic significance in gastric cancer (GC). This study evaluates the impact of AF1q on tumor stage and survival in GC patients. Immunohistochemical marker expression was analyzed and data were processed to correlation and survival analysis. Out of 182 GC samples, 178 (97.8%) showed moderate to high AF1q expression ( p  < 0.001), these samples correlated with positive lymph node stage ( p  = 0.036). In a subgroup analysis of patients with nodal-positive GC (n = 129, 70.9%), enhanced tumoral AF1q expression resulted in impaired recurrence-free survival (RFS, p  = 0.030). Enhanced tumoral CD44 expression resulted in impaired disease-specific survival (DSS) in the subgroup of patients with nodal-positive GC ( p  = 0.031) as well as in the overall GC group ( p  = 0.005). AF1q demonstrated as an independent prognostic marker for RFS ( p  = 0.035) and CD44 for DSS ( p  = 0.036). AF1q has shown potential for prognostication of RFS in GC patients and is predominantly expressed in nodal-positive GC. Testing AF1q provides a possibility of identifying patients with locoregional (and advanced) disease, particularly at risk for disease recurrence. Implementing AF1q into the diagnostic process may facilitate screening, prognosis estimation as well as consideration of preoperative multimodal treatment in patients qualifying for elective upfront surgery.

Background Due to excellent weight loss success in the short-time follow-up, sleeve gastrectomy (SG) has gained popularity as sole and definitive bariatric procedure. In the long-term follow-up, weight loss failure and intractable severe reflux can necessitate further surgical intervention. Methods A retrospective analysis of laparoscopic conversions from SG to Roux-en-Y gastric bypass (RYGB) was performed to assess the efficacy for reflux relief and weight loss success. Results A total of eight out of 73 patients (11%) underwent conversion to RYGB for severe reflux ( n  = 3) or weight regain ( n  = 5) after a median interval of 33 months following laparoscopic sleeve gastrectomy. In one of the patients, a banded gastric bypass was performed. In both groups, conversion to RYGB was successful, as proton pump inhibitor medication could be discontinued in all patients presenting with severe reflux, and a significant weight loss could be achieved in the patients with weight regain within a median follow-up of 33 months. Postoperative complications were observed in only one patient as leakage at the gastrojejunostomy was successfully treated by temporary stent placement. Conclusion Conversion to RYGB is an effective treatment for weight regain or intractable reflux symptoms following SG. Thus, SG can be performed, intended as sole and definitive bariatric intervention, with conversion from SG to RYGB as an exit strategy for these complications.

BRAF V600E mutation in serrated lesions of the colon has been implicated as an important mutation and as a specific marker for the serrated carcinogenic pathway. Recent findings point to microvesicular hyperplastic polyps that have similar histologic and molecular features to sessile serrated adenomas/polyps, as potential colorectal carcinoma precursors. The aim of this study was to evaluate BRAF V600E mutation status by immunohistochemistry in serrated lesions of the colon with regard to histomorphology. We investigated 194 serrated lesions of the colon, comprising 42 sessile serrated adenomas/polyps, 16 traditional serrated adenomas, 136 hyperplastic polyps and 20 tubular/tubulovillous adenomas (conventional adenomas) with the novel BRAF V600E mutation-specific antibody VE1. In addition, BRAF exon 15 and KRAS exon 2 status was investigated by capillary sequencing in selected cases. All sessile serrated adenomas/polyps (42/42, 100%), 15/16 (94%) traditional serrated adenomas and 84/136 (62%) hyperplastic polyps were VE1+. None of the VE1− serrated lesions showed BRAF V600E mutation. Forty out of 42 (95%) sessile serrated adenomas/polyps displayed areas with microvesicular hyperplastic polyp-like features. In microvesicular hyperplastic polyps, VE1 positivity was significantly associated with nuclear atypia (P=0.003); however, nuclear atypia was also present in VE1− cases. Immunostaining with VE1 allows not only the detection of BRAF V600E mutation but also the correlation with histomorphology on a cellular level in serrated lesions. VE1 enables a subclassification of microvesicular hyperplastic polyps according to the mutation status. This improved classification of serrated lesions including immunohistochemical evaluation of BRAF V600E mutation may be the key to identify lesions with higher potential to progression into sessile serrated adenoma/polyp, and further to BRAF V600E-mutated colorectal cancer.

Objective A definitive diagnosis of gastroesophageal reflux disease (GERD) depends on endoscopic and/or pH‐study criteria. However, high resolution manometry (HRM) can identify factors predicting GERD, such as ineffective esophageal motility (IEM), esophago‐gastric junction contractile integral (EGJ‐CI), evaluating esophagogastric junction (EGJ) type and straight leg raise (SLR) maneuver response. We aimed to build and externally validate a manometric score (Milan Score) to stratify the risk and severity of the disease in patients undergoing HRM for suspected GERD. Methods A population of 295 consecutive patients undergoing HRM and pH‐study for persistent typical or atypical GERD symptoms was prospectively enrolled to build a model and a nomogram that provides a risk score for AET > 6%. Collected HRM data included IEM, EGJ‐CI, EGJ type and SLR. A supplemental cohort of patients undergoing HRM and pH‐study was also prospectively enrolled in 13 high‐volume esophageal function laboratories across the world in order to validate the model. Discrimination and calibration were used to assess model's accuracy. Gastroesophageal reflux disease was defined as acid exposure time >6%. Results Out of the analyzed variables, SLR response and EGJ subtype 3 had the highest impact on the score (odd ratio 18.20 and 3.87, respectively). The external validation cohort consisted of 233 patients. In the validation model, the corrected Harrel c‐index was 0.90. The model‐fitting optimism adjusted calibration slope was 0.93 and the integrated calibration index was 0.07, indicating good calibration. Conclusions A novel HRM score for GERD diagnosis has been created and validated. The MS might be a useful screening tool to stratify the risk and the severity of GERD, allowing a more comprehensive pathophysiologic assessment of the anti‐reflux barrier. Trial registration ClinicalTrials.gov (Identifier: NCT05851482).

Formation of lymphatic metastasis is the initial step of generalized spreading of tumor cells and predicts poor clinical prognosis. Lymphatic vessels generally arise within the peritumoral stroma, although the lymphangiopoietic vascular endothelial growth factors (VEGF)-C and -D are produced by tumor cells. In a carefully selected collection of human cervical cancers (stage pT1b1) we demonstrate by quantitative immunohistochemistry and in situ hybridization that density of lymphatic microvessels is significantly increased in peritumoral stroma, and that a subset of stromal cells express large amounts of VEGF-C and VEGF-D. The density of cells producing these vascular growth factors correlates with peritumoral inflammatory stroma reaction, lymphatic microvessel density, and indirectly with peritumoral carcinomatous lymphangiosis and frequency of lymph node metastasis. The VEGF-C- and VEGF-D-producing stroma cells were identified in situ as a subset of activated tumor-associated macrophages (TAMs) by expression of a panel of macrophage-specific markers, including CD68, CD23, and CD14. These TAMs also expressed the VEGF-C- and VEGF-D-specific tyrosine kinase receptor VEGFR-3. As TAMs are derived from monocytes in the circulation, a search in peripheral blood for candidate precursors of VEGFR-3-expressing TAMs revealed a subfraction of CD14-positive, VEGFR-3-expressing monocytes, that, however, failed to express VEGF-C and VEGF-D. Only after in vitro incubation with tumor necrosis factor-α, lipopolysaccharide, or VEGF-D did these monocytes start to synthesize VEGF-C de novo . In conclusion VEGF-C-expressing TAMs play a novel role in peritumoral lymphangiogenesis and subsequent dissemination in human cancer.

Magnetic sphincter-augmentation (MSA) has been proven effective in the treatment of GERD. No consensus exists on whether crural closure should be performed. Our aim was to assess the impact of cruroplasty on reflux-control and quality of life. MSA-Patients treated between 03/2012-03/2017 were classified into those without hiatal hernia (“NHH”), those post-MSA (NHR) and those post-MSA/hiatal repair (HR). GERD-symptoms, PPI-intake, GERD-Health-related-Quality-of-Life (GERD-HRQL) and Alimentary Satisfaction were assessed. Sixty-eight patients underwent MSA, 26 patients had additional crural closure. PH-monitoring was negative in 80% of HR, 73% of NHR and 89% of NHH-patients. GERD-HRQL-total scores decreased significantly in all groups ( p  < 0.001). Alimentary satisfaction was 8/10 in HR/NHH and 10/10 in NHR-patients. Satisfaction with heartburn relief was high (HR: 96%, NR: 95%, NHH: 94%) as was the elimination of PPI-intake (HR/NHH: 87%, NR: 86%). Heartburn and regurgitations were eliminated in 100% of HR, 88% and 94% of NHR and 87% and 91% of NHH-patients. Endoscopic dilatation or device explantation was performed in 3% each. MSA leads to significant symptom relief, increased quality of life and alimentary satisfaction with low perioperative morbidity. Cruroplasty tends to result in better reflux control and symptom relief than exclusive MSA without increasing dysphagia rates.

Even though distinctive advances in the field of esophageal cancer therapy have occurred over the last few years, patients’ survival rates remain poor. FGF8, FGF18, and FGFR4 have been identified as promising biomarkers in a number of cancers; however no data exist on expression of FGF8, FGF18, and FGFR4 in adenocarcinomas of the esophago-gastric junction (AEG). A preliminary analysis of the Cancer Genome Atlas (TCGA) database on FGF8, FGF18, and FGFR4 mRNA expression data of patients with AEG was performed. Furthermore, protein levels of FGF8, FGF18, and FGFR4 in diagnostic biopsies and post-operative specimens in neoadjuvantly treated and primarily resected patients using immunohistochemistry were investigated. A total of 242 patients was analyzed in this study: 87 patients were investigated in the TCGA data set analysis and 155 patients in the analysis of protein expression using immunohistochemistry. High protein levels of FGF8, FGF18, and FGFR4 were detected in 94 (60.7%), 49 (31.6%) and 84 (54.2%) patients, respectively. Multivariable Cox proportional hazard regression models revealed that high expression of FGF8 was an independent prognostic factor for diminished overall survival for all patients and for neoadjuvantly treated patients. By contrast, FGF18 overexpression was significantly associated with longer survival rates in neoadjuvantly treated patients. In addition, FGF8 protein level correlated with Mandard regression due to neoadjuvant therapy, indicating potential as a predictive marker. In summary, FGF8 and FGF18 are promising candidates for prognostic factors in adenocarcinomas of the esophago-gastric junction and new potential targets for new anti-cancer therapies.

BackgroundMagnetic sphincter augmentation (MSA) is a surgical intervention for gastroesophageal reflux disease (GERD) which has been evaluated in numerous studies and has shown beneficial effects. Long-term effectiveness data for MSA as well as laparoscopic fundoplication (LF) in patients with GERD are needed.ObjectiveThe objective of this study was to evaluate the 3-year outcomes for MSA and LF in patients with GERD.MethodsThis prospective, multi-center, observational registry study evaluated MSA and LF in clinical practice over 3 years (ClinicalTrials.gov identifier: NCT01624506). Data collection included baseline characteristics, reflux symptoms, medication use, satisfaction and complications. Post-surgical evaluations were collected at yearly intervals.ResultsBetween December 2009 and December 2014, 631 patients (465 MSA and 166 LF) were enrolled in the registry. Both MSA and LF resulted in improvements in total GERD-HRQL score (mean reduction in GERD-HRQL from baseline to 3 years post-surgery: MSA 22.0 to 4.6 and LF 23.6 to 4.9) and in satisfaction (GERD-HRQL satisfaction increase from baseline to 3 years: MSA 4.6% to 78.2% and LF 3.7% to 76.5%). Most patients were able to belch as needed with both therapies (MSA 97.6% and LF 91.7% at 3 years). MSA allowed a higher percentage of patients the ability to vomit as needed (MSA 91.2% and LF 68.0% at 3 years). PPI usage declined from baseline to 3 years for both groups after surgery (MSA 97.8% to 24.2% and LF 95.8% to 19.5%). The mean procedure time was shorter for MSA than for LF. Intraoperative and procedure-related complication rates (≤ 2%) were low for both therapies.ConclusionsThis 3-year prospective observational registry study contributes to the mounting evidence for the effectiveness of MSA and LF. Despite the more severe nature of GERD in the LF group, the clinical outcomes for MSA and LF were favorable from an effectiveness and safety standpoint.