A Hybrid Type III Effectiveness-Implementation Trial to Optimize Medication Safety With Oral Antitumor Therapy in Real-World: The AMBORA Competence and Consultation Center.

PURPOSE: Implementation science endeavors to facilitate the translation of evidence-based research into clinical routine. The clinical pharmacological/pharmaceutical care program evaluated in the randomized AMBORA trial on medication safety with oral antitumor therapeutics (OAT) optimizes care delivery and provides significant benefits for patients, treatment teams, and health care systems. Thus, we aimed to investigate the implementation of this care program within the AMBORA Competence and Consultation Center (AMBORA Center). METHODS: The AMBORA Center within a University Comprehensive Cancer Center offered several services (eg, patient consultations) and was evaluated according to the RE-AIM framework. This multicenter hybrid type III trial focused on implementation outcomes (eg, patient recruitment, referring units, evaluation of services) while concurrently investigating effectiveness (eg, side effects, medication errors). Quantitative and qualitative assessments were combined. RESULTS: The AMBORA Center conducted over 800 consultations with 420 patients in seven institutions. The primary end point of counseling 70% of patients treated with OAT was not reached. Patients were referred by 15 treatment units compared with 11 units in the AMBORA trial. On the basis of heterogeneous referral rates and characteristics across the institutions, barriers and facilitators of the implementation process were derived. Several survey results (eg, stakeholder interviews, online/paper-based questionnaires) reflected a high appreciation of services by patients and health care professionals. The severity of 60.1% (178 of 296) of detected side effects improved, and 86.3% (297 of 344) of medication errors were resolved. CONCLUSION: Despite not reaching the primary implementation outcome, the AMBORA Center included more treatment units and demonstrated patient benefit of the AMBORA care program by meeting all effectiveness outcomes. We outlined quantitative and qualitative implementation characteristics to enhance outreach and foster further dissemination of centers to optimize medication safety with OAT.

Blood Vessel-Targeted Therapy in Colorectal Cancer: Current Strategies and Future Perspectives.

The vasculature is a key player and regulatory component in the multicellular microenvironment of solid tumors and, consequently, a therapeutic target. In colorectal carcinoma (CRC), antiangiogenic treatment was approved almost 20 years ago, but there are still no valid predictors of response. In addition, treatment resistance has become a problem. Vascular heterogeneity and plasticity due to species-, organ-, and milieu-dependent phenotypic and functional differences of blood vascular cells reduced the hope of being able to apply a standard approach of antiangiogenic therapy to all patients. In addition, the pathological vasculature in CRC is characterized by heterogeneous perfusion, impaired barrier function, immunosuppressive endothelial cell anergy, and metabolic competition-induced microenvironmental stress. Only recently, angiocrine proteins have been identified that are specifically released from vascular cells and can regulate tumor initiation and progression in an autocrine and paracrine manner. In this review, we summarize the history and current strategies for applying antiangiogenic treatment and discuss the associated challenges and opportunities, including normalizing the tumor vasculature, modulating milieu-dependent vascular heterogeneity, and targeting functions of angiocrine proteins. These new strategies could open perspectives for future vascular-targeted and patient-tailored therapy selection in CRC.

Surgical and oncological outcome after extended lymph node dissection for carcinoma of the stomach and the esophagogastric junction: a retrospective analysis from an experienced single center.

Introduction: Gastric cancer remains the fourth leading cause of cancer-related death in Europe, while the proportion of adenocarcinomas of the esophagogastric junction has risen by more than one third over recent years. In 2018, 14,700 new cases of gastric cancer were estimated in Germany, while the 5-year relative survival rate is reported to be 33% for women and 30% for men; in the USA almost the same rate was reported, with 31% 5-year survival. Material and methods: Between 2001 and 2014, 590 patients with a diagnosis of gastric cancer underwent surgery in our institution, including 120 Siewert type II/III carcinomas of the esophagogastric junction. All patients underwent distal resection of the stomach, gastrectomy or total gastrectomy combined with transhiatal distal esophageal resection. All operations included D2-D3 lymph node dissection (LND). Data were recorded by the cancer registry of the department of surgery and analyzed retrospectively. Results: The patients were classified according to the TNM (UICC 2010) and Lauren classification. 29% of the patients underwent primary surgery and 31% received neoadjuvant therapy. The median number of harvested lymph nodes was 33 for patients diagnosed with gastric cancer, and 29 for esophagogastric adenocarcinomas, respectively. The anastomotic leak rate was 3%. In this study, the 5-year overall survival rate was 51% concerning gastric carcinomas, 44% for Siewert type II and 47% for Siewert III cancers of the esophagogastric junction. Conclusions: Increased survival with low complication rates were achieved after individualized and multimodal treatment concepts combined with consistently applied extended lymphadenectomy.

IL-20 controls resolution of experimental colitis by regulating epithelial IFN/STAT2 signalling.

OBJECTIVE: We sought to investigate the role of interleukin (IL)-20 in IBD and experimental colitis. DESIGN: Experimental colitis was induced in mice deficient in components of the IL-20 and signal transducer and activator of transcription (STAT)2 signalling pathways. In vivo imaging, high-resolution mini-endoscopy and histology were used to assess intestinal inflammation. We further used RNA-sequencing (RNA-Seq), RNAScope and Gene Ontology analysis, western blot analysis and co-immunoprecipitation, confocal microscopy and intestinal epithelial cell (IEC)-derived three-dimensional organoids to investigate the underlying molecular mechanisms. Results were validated using samples from patients with IBD and non-IBD control subjects by a combination of RNA-Seq, organoids and immunostainings. RESULTS: In IBD, IL20 levels were induced during remission and were significantly higher in antitumour necrosis factor responders versus non-responders. IL-20RA and IL-20RB were present on IECs from patients with IBD and IL-20-induced STAT3 and suppressed interferon (IFN)-STAT2 signalling in these cells. In IBD, experimental dextran sulfate sodium (DSS)-induced colitis and mucosal healing, IECs were the main producers of IL-20. Compared with wildtype controls, Il20-/-, Il20ra-/- and Il20rb-/- mice were more susceptible to experimental DSS-induced colitis. IL-20 deficiency was associated with increased IFN/STAT2 activity in mice and IFN/STAT2-induced necroptotic cell death in IEC-derived organoids could be markedly blocked by IL-20. Moreover, newly generated Stat2ΔIEC mice, lacking STAT2 in IECs, were less susceptible to experimental colitis compared with wildtype controls and the administration of IL-20 suppressed colitis activity in wildtype animals. CONCLUSION: IL-20 controls colitis and mucosal healing by interfering with the IFN/STAT2 death signalling pathway in IECs. These results indicate new directions for suppressing gut inflammation by modulating IL-20-controlled STAT2 signals.

Real-World Data for Lenvatinib in Hepatocellular Carcinoma (ELEVATOR): A Retrospective Multicenter Study.

Background: Lenvatinib is approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). The efficacy of lenvatinib in Caucasian real-world patients is insufficiently defined. The purpose of this study was to evaluate the efficacy of lenvatinib in a multi-center cohort (ELEVATOR) from Germany and Austria. Methods: A retrospective data analysis of 205 patients treated with first-line systemic lenvatinib at 14 different sites was conducted. Overall survival, progression free survival, overall response rate and adverse event rates were assessed and analyzed. Results: Patients receiving lenvatinib in the real-world setting reached a median overall survival of 12.8 months, which was comparable to the results reported from the REFLECT study. Median overall survival (mOS) and progression free survival (mPFS) was superior in those patients who met the inclusion criteria of the REFLECT study compared to patients who failed to meet the inclusion criteria (mOS 15.6 vs 10.2 months, HR 0.55, 95% CI 0.38-0.81, p=0.002; mPFS 8.1 vs 4.8 months HR 0.65, 95% CI 0.46-0.91, p=0.0015). For patients with an impaired liver function according to the Albumin-Bilirubin (ALBI) grade, or reduced ECOG performance status ≥2, survival was significantly shorter compared to patients with sustained liver function (ALBI grade 1) and good performance status (ECOG performance status 0), respectively (HR 1.69, 95% CI 1.07-2.66, p=0.023; HR 2.25, 95% CI 1.19-4.23, p=0.012). Additionally, macrovascular invasion (HR 1.55, 95% CI 1.02-2.37, p=0.041) and an AFP ≥200 ng/mL (HR 1.56, 95% CI 1.03-2.34, p=0.034) were confirmed as independent negative prognostic factors in our cohort of patients with advanced HCC. Conclusion: Overall, our data confirm the efficacy of lenvatinib as first-line treatment and did not reveal new or unexpected side effects in a large retrospective Caucasian real-world cohort, supporting the use of lenvatinib as meaningful alternative for patients that cannot be treated with IO-based combinations in first-line HCC.

Efficacy and Safety of Angioplasty Balloon Interposition in CT-Guided Percutaneous Thermal Ablation of Hepatic Malignancies to Protect Adjacent Organs.

PURPOSE: To evaluate the feasibility and safety of placing angioplasty balloons between the liver surface and adjacent organs in CT-guided thermal ablation of subcapsular liver malignancies in case of inadequate success of conventional dissection techniques. MATERIALS AND METHODS: A retrospective, single-centre database query identified 327 hepatic malignancies in 153 patients treated in 215 sessions from 2016 to 2018 by thermal ablation. Demographic data, tumour size, distance to adjacent structures, complications and long-term outcomes were assessed when ancillary procedures were performed to protect adjacent organs. RESULTS: In 21 of 327 (6.4%) ablations, thermal protection was necessary. Balloon interposition was successfully performed in 9 cases in 8 patients after hydrodissection or gas insufflation failed to separate adherent organs. Median pre- and post-balloon insertion distance was 0 mm [0-2 mm] and 17 mm [8-20 mm]. No balloons were damaged, ruptured or slid away from their initial position. Technical success of MWA and protection of adherent structures were achieved in all procedures. In a median follow-up of 11.5 months [0-49 months], the local control rate was 88.9% as 1 patient was treated twice with an interval of 3 months for local recurrence. Three non-process-related major complications and 1 minor complication occurred. CONCLUSION: Balloon interposition is a safe and feasible method to enable thermal ablation to a greater number of patients, even after established thermo-protective techniques fail to separate the colon or stomach from the liver surface.

The outcome of patients with inflammatory bowel disease-associated colorectal cancer is not worse than that of patients with sporadic colorectal cancer-a matched-pair analysis of survival.

PURPOSE: Patients with inflammatory bowel disease (IBD) have an increased risk for colorectal cancer (CRC). In IBD patients, cancer is often diagnosed in advanced stages and conflicting data on survival compared to sporadic CRC have been reported. The aim of this study was to directly compare clinical characteristics and prognosis of patients with IBD-CRC and sporadic CRC. METHODS: The clinical and pathological data of 63 patients with IBD-CRC and 3710 patients with sporadic CRC treated at the University Hospital of Erlangen between 1995 and 2015 were compared. Forty-seven M0 patients with IBD were matched with sporadic CRC patients after curative resection (R0) according to tumor localization, stage, sex, and year of treatment. Overall and disease-free survival were compared. RESULTS: Sixty-three patients presented IBD-CRC. Fifty were affected with ulcerative colitis (UC) and 13 with Crohn's disease (CD). CRC was diagnosed within 1.45 years since last endoscopic surveillance. Twelve patients (19%) had a diagnosis of primary sclerosing cholangitis. In matched analysis, IBD patients were diagnosed with CRC at younger age compared to sporadic CRC and were more likely to have right-sided CRC (40% versus 23.3%) and rare histological subtypes (19% versus 9.2%). No differences in 5-year overall (78.7 versus 80.9 months) and 5-year disease-free survival (74.5 versus 70.2 months) were noted. CONCLUSION: IBD-CRC patients were younger and more frequently had right-sided carcinomas compared to sporadic CRC. CRC in IBD patients did not show survival difference compared to matched-pair sporadic CRC patients without distant metastases after curative resection. Surveillance might be important for early detection of CRC in IBD patients.

A Possible Distinct Molecular Subtype (Quintuple-Wildtype) of Metastatic Colorectal Cancer in First-Line Anti-EGFR Therapy with Cetuximab Plus FOLFIRI - Palliative Precision Therapy and a Multidisciplinary Treatment Approach: Interim Analysis of the IVOPAK II Trial with Early Results.

OBJECTIVE: The study aimed to prospectively evaluate a new molecular biomarker panel (KRAS, NRAS, BRAF, PIK3CA, and ERBB2) for palliative first-line treatment of colorectal cancer (CRC), including a multidisciplinary treatment approach. The rate of secondary metastasis resections was assessed. PATIENTS AND METHODS: A total of 40 patients with definitively nonresectable metastatic CRC were enrolled from 10 centers before the interim analysis (June 2019) of the IVOPAK II trial (Interdisciplinary Care with Quality Control in Palliative Treatment of Colorectal Cancer). After determination of 5 molecular biomarkers in the tumor (KRAS, exons 2-4; NRAS, exons 2-4; BRAF V600E; PIK3CA; and ERBB2), patients in the IVOPAK II study received FOLFIRI plus cetuximab for all-RAS/quintuple-wildtype disease and FOLFIRI plus bevacizumab in the case of RAS mutations. The current article presents the early description of the clinical outcome of the interim analysis of IVOPAK II comparing the all-RAS/quintuple-wildtype and RAS-mutations populations, including a multidisciplinary-treated case report of a quintuple-wildtype patient. RESULTS: The quintuple-wildtype population treated with FOLFIRI plus cetuximab in first-line exhibited a significantly higher response rate and enhanced early tumor shrinkage in the interim analysis than the RAS-mutations population, as well as a high rate of secondary metastatic resections. CONCLUSION: Initial results of this new biomarker panel (quintuple-wildtype) are promising for anti-EGFR therapy with cetuximab plus doublet chemotherapy (FOLFIRI) in first-line treatment of metastatic CRC. These results warrant confirmation with higher case numbers in the IVOPAK II trial.

Real Life Study of Lenvatinib Therapy for Hepatocellular Carcinoma: RELEVANT Study.

Introduction: In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes. Methods: The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries. Results: We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0-1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months). Conclusions: Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.

Muscle-Derived Cytokines Reduce Growth, Viability and Migratory Activity of Pancreatic Cancer Cells.

The evidence that regular physical exercise reduces the risk of developing cancer is well described. However, the interaction between physical exercise and cancer is not fully clarified yet. Several myokines released by skeletal muscle appear to have a direct anti-tumour function. There are few data on myokine secretion after exercise in patients with advanced tumours. Pancreatic cancer (PC) is a very aggressive and usually fatal cancer. To investigate the effects of exercise in PC, the blood of advanced-stage PC patients was analysed after 12 weeks of resistance training using whole-body electromyostimulation. After the 12-week training period, the patient serum inhibited the proliferation and the motility of PC cells and enhanced PC cell apoptosis. The impact of exercise training was also investigated in an exercise-mimicking in vitro model using electric pulse stimulation of human myotubes and revealed similar anti-tumour effects on PC cells, clearly indicating direct cancer-protective properties of activated skeletal muscle. Protein and gene expression analyses in plasma from exercise-trained patients and in myotube cultures after in vitro exercise showed that interleukin 10 (IL10), C-X-C motif ligand 1 (CXCL1) and C-C motif chemokine ligand 4 (CCL4) are myokines released from activated skeletal muscle. In accordance with the effects of serum from exercise-trained patients, the supplementation with recombinant IL10, CXCL1 and CCL4 impaired growth and migration of PC cells. Treatment of PC cells with these myokines upregulated caspase 3/7 expression and the cleavage of poly(ADP-ribose) polymerase, leading to enhanced PC cell death. The identification of myokines with anti-tumour properties in advanced-stage PC patients after exercise opens a new perspective in supportive therapy with sports and exercise for cancer patients.

The Ominous Ouzo Party - A Case Series of Four Patients with Accidental Alkali Ingestion.

BACKGROUND: Ingestion of alkaline fluids is a common problem, which can lead to perforations, strictures and malignancy. We present a rare case series of several patients who accidentally ingested the same alkaline substance in different doses. METHODS: We investigated four patients with accidental ingestion of dishwashing liquid. All patients underwent gastroscopy within 24h after inpatient admission. Gastroesophageal lesions were classified according to the Zargar classification for corrosive ingestions. RESULTS: Esophagogastric lesions were predominantly found at the distal esophagus and the small curvature of the stomach. The severity of these lesions ranged from mild erosions (Zargar 2A) to marked necrosis (Zargar 3A). Our data suggest that the degree of these lesions correlated with the amount of ingested toxin and duration of the inpatient stay. However, a low symptom severity or inconspicuous otolaryngologic examination did not exclude severe gastroesophageal lesions. CONCLUSION: Our data suggest that the severity of gastroesophageal lesions correlates with the amount of ingested alkaline substance. Symptom burden and an otolaryngologic examination are not sufficiently predictive for the severity of gastroesophageal lesions. The composition and quantity of the swallowed liquid should be determined.

Combined De-Repression of Chemoresistance Associated Mitogen-Activated Protein Kinase 14 and Activating Transcription Factor 2 by Loss of microRNA-622 in Hepatocellular Carcinoma.

Chemoresistance is a major hallmark driving the progression and poor prognosis of hepatocellular carcinoma (HCC). Limited chemoresponse of HCC was demonstrated to be mediated by mitogen-activated protein kinase 14 (MAPK14) and activating transcription factor 2 (ATF2). Recently, we have demonstrated loss of control of RAS-RAF-ERK-signaling as a consequence of miR-622 downregulation in HCC. However, the majority of target genes of this potent tumorsuppressive microRNA had remained elusive. The MAPK14-ATF2-axis represents a collateral pathway ensuring persisting ERK-activation in the presence of sorafenib-mediated RAF-inhibition. In contrast to the function of the MAPK14-ATF2-axis, both the expression and regulation of MAPK14 and ATF2 in human HCC remained to be clarified. We found combined overexpression of MAPK14 and ATF2 in human HCC cells, tissues and in sorafenib resistant cell lines. High expression of MAPK14 and ATF2 was associated with reduced overall survival in HCC patients. Deciphering the molecular mechanism promoting combined upregulation of MAPK14 and ATF2 in HCC, we revealed that miR-622 directly targets both genes, resulting in combined de-repression of the MAPK14-ATF2-axis. Together, miR-622 represents a superior regulator of both RAS-RAF-ERK as well as MAPK14-ATF2-signaling pathways in liver cancer.

Identification of novel targets of miR-622 in hepatocellular carcinoma reveals common regulation of cooperating genes and outlines the oncogenic role of zinc finger CCHC-type containing 11.

The poor prognosis of advanced hepatocellular carcinoma (HCC) is driven by diverse features including dysregulated microRNAs inducing drug resistance and stemness. Lin-28 homolog A (LIN28A) and its partner zinc finger CCHC-type containing 11 (ZCCHC11) cooperate in binding, oligouridylation and subsequent degradation of tumorsuppressive let-7 precursor microRNAs. Functionally, activation of LIN28A was recently shown to promote stemness and chemoresistance in HCC. However, the expression and regulation of LIN28A in HCC had been unclear. Moreover, the expression, regulation and function of ZCCHC11 in liver cancer remained elusive. In contrast to "one-microRNA-one-target" interactions, we identified common binding sites for miR-622 in both LIN28A and ZCCHC11, suggesting miR-622 to function as a superior pathway regulator. Applying comprehensive microRNA database screening, human hepatocytes and HCC cell lines, patient-derived tissue samples as well as "The Cancer Genome Atlas" (TCGA) patient cohorts, we demonstrated that loss of tumorsuppressive miR-622 mediates derepression and overexpression of LIN28A in HCC. Moreover, the cooperator of LIN28A, ZCCHC11, was newly identified as a prognostic and therapeutic target of miR-622 in liver cancer. Together, identification of novel miR-622 target genes revealed common regulation of cooperating genes and outlines the previously unknown oncogenic role of ZCCHC11 in liver cancer.

Endoscopic recanalization of complete esophageal obstruction.

BACKGROUND AND AIMS: Complete esophageal obstruction (CEO) is a rare complication after radiochemotherapy that dramatically impairs quality of life. Within this study, we assessed the outcome of two different endoscopic techniques for lumen restoration in patients with CEO. METHODS: 17 patients were included. Esophageal recanalization was performed in an antegrade approach (Group A) or through combined antegrade and retrograde recanalization and dilatation (CARD, Group B). Technical success, complications, and dysphagia development during follow-up (FU) were compared between the groups. RESULTS: In Group A (n = 6), esophageal recanalization was performed by a single endoscopist with a median duration of 47 min. In two patients, antegrade recanalization led to formation of a false lumen (i.e., submucosal tunneling) followed by mediastinitis. In Group B, 21 CARD procedures were performed in 11 patients with a technical success rate of 100%. Procedure time was longer compared to Group A; however, no intra- or postprocedural complications were observed in Group B. CONCLUSIONS: In our experience and cohort, CARD was a successful procedure for recanalization of CEO, which exhibits a more favorable safety profile over antegrade recanalization. Further randomized studies to evaluate the treatment of CEO with CARD are needed.

How Much Liver Tissue Is Required for Sufficient Histological Staging in Patients with Primary Biliary Cholangitis?

INTRODUCTION: Histological alterations in primary biliary cholangitis (PBC) are heterogeneously distributed throughout the liver. Thus, the quality of histological staging is probably dependent on the available amount of liver tissue. The goals of this study were to test this hypothesis and to define biopsy conditions for obtaining sufficient tissue. METHODS: In this retrospective analysis, we investigated 34 patient cases who fulfilled the criteria of the European Association for the Study of the Liver (EASL) for PBC and underwent a mini-laparoscopic liver biopsy between 2011 and 2018 using 16 or 18G needles. For histological assessment of fibrosis, we used the Ishak score, and the amount of tissue was measured by the number of portal fields. Histological staging was compared with the macroscopic mini-laparoscopic fibrosis score (MLFS), and non-invasive liver stiffness measurements using acoustic radiation force impulse (ARFI) imaging and the FIB-4 score. RESULTS: Biopsy was successful in 33 of 34 patients (97%). Fibrosis assessment by MLFS and ARFI correlated strongly with each other (r = 0.7088, p = 0.000017). However, the correlation of both methods with the histological staging was weaker (MLFS vs. histology: r = 0.4231, p = 0.0142; ARFI vs. histology: r = 0.3564, p = 0.0577). The correlation of ARFI and MLFS with the histological staging was better in the subgroup of biopsies with at least 10 portal fields (= SG≥10PF) (MLFS vs. histology: r = 0.6369, p = 0.006; ARFI vs. histology: r = 0.7538, p = 0.0012). FIB-4 correlated weakly with the histological staging, which was statistically not significant (all samples: r = 0.2693, p = 0.1296; SG≥10PF: r = 0.2244, p = 0.3866). The number of portal fields correlated well with the length of the samples (r = 0.6436, p = 0.00012). The probability to attain at least 10 portal fields depended on the needle diameter and number of samples (1 × 16G or 18G [n = 10]: 30.0%; 2 × 18G [n = 15]: 53.3%; 2 × 16G [n = 5]: 100%; p = 0.0414). CONCLUSION: ARFI and MLFS are probably well suited for the assessment of liver fibrosis in patients with PBC. A minimum of 10 portal fields could improve the histological assessment in PBC and can probably be achieved by obtaining two 16G biopsies.

Primary aortoduodenal fistula - overlooked because of guidelines?

Primary aortoduodenal fistula is an uncommon yet mostly lethal finding. We present a case of a 63 year-old male who exhibited significant upper gastrointestinal bleeding and hemorrhagic shock. Repeated endoscopies did not detect any source of bleeding. Emergency laparotomy disclosed an aortoduodenal fistula. Despite intense medical efforts for several months the patient did not fully recover and treatment was limited to palliative care. In light of the substantial mortality associated with this condition, computed tomography imaging should be performed in case of doubt to prevent delayed diagnosis.

Effects of whole-body electromyostimulation combined with individualized nutritional support on body composition in patients with advanced cancer: a controlled pilot trial.

BACKGROUND: Physical exercise and nutritional treatment are promising measures to prevent muscle wasting that is frequently observed in advanced-stage cancer patients. However, conventional exercise is not always suitable for these patients due to physical weakness and therapeutic side effects. In this pilot study, we examined the effect of a combined approach of the novel training method whole-body electromyostimulation (WB-EMS) and individualized nutritional support on body composition with primary focus on skeletal muscle mass in advanced cancer patients under oncological treatment. METHODS: In a non-randomized controlled trial design patients (56.5% male; 59.9 ± 12.7 years) with advanced solid tumors (UICC III/IV, N = 131) undergoing anti-cancer therapy were allocated to a usual care control group (n = 35) receiving individualized nutritional support or to an intervention group (n = 96) that additionally performed a supervised physical exercise program in form of 20 min WB-EMS sessions (bipolar, 85 Hz) 2×/week for 12 weeks. The primary outcome of skeletal muscle mass and secondary outcomes of body composition, body weight and hand grip strength were measured at baseline, in weeks 4, 8 and 12 by bioelectrical impedance analysis and hand dynamometer. Effects of WB-EMS were estimated by linear mixed models. Secondary outcomes of physical function, hematological and blood chemistry parameters, quality of life and fatigue were assessed at baseline and week 12. Changes were analyzed by t-tests, Wilcoxon signed-rank or Mann-Whitney-U-tests. RESULTS: Twenty-four patients of the control and 58 of the WB-EMS group completed the 12-week trial. Patients of the WB-EMS group had a significantly higher skeletal muscle mass (0.53 kg [0.08, 0.98]; p = 0.022) and body weight (1.02 kg [0.05, 1.98]; p = 0.039) compared to controls at the end of intervention. WB-EMS also significantly improved physical function and performance status (p < 0.05). No significant differences of changes in quality of life, fatigue and blood parameters were detected between the study groups after 12 weeks. CONCLUSIONS: Supervised WB-EMS training is a safe strength training method and combined with nutritional support it shows promising effects against muscle wasting and on physical function in advanced-stage cancer patients undergoing treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02293239 (Date: November 18, 2014).

Treatment of Zenker's diverticulum using a novel grasping-type scissors forceps allows fast, safe, and effective endoscopic diverticulotomy.

BACKGROUND AND STUDY AIMS: Although several endoscopic techniques have been described for Zenker's diverticulotomy, no standardized endoscopic approach has been established in clinical routine to date. This study aimed to assess the efficacy and safety of endoscopic diverticulotomy using the Clutch Cutter. PATIENTS AND METHODS: Cricopharyngeal myotomy was performed in six prospectively enrolled patients with symptomatic Zenker's diverticulum, using the Clutch Cutter. Procedural details such as duration, complications, and technical success were recorded and compared to the outcomes of 15 patients who received needle-knife-based myotomy. RESULTS: Myotomy with the Clutch Cutter was feasible in all six patients with complete diverticulotomy in a single session in all patients. Mean procedure time of the Clutch Cutter myotomy was 19 minutes without major complications. During follow-up, one patient had diverticulum recurrence after 10 months, which was successfully re-treated. Mean procedure time with the needle-knife was 43 minutes and a mean of 2.7 myotomy sessions was required for complete diverticulotomy. CONCLUSION: Endoscopic diverticulotomy using the Clutch Cutter is safe, effective, and fast. Larger studies comparing myotomy using the Clutch Cutter with other endoscopic techniques are highly warranted.

I-scan optical enhancement for the in vivo prediction of diminutive colorectal polyp histology: Results from a prospective three-phased multicentre trial.

BACKGROUND AND AIMS: Dye-less chromoendoscopy is an emerging technology for colorectal polyp characterization. Herein, we investigated whether the newly introduced I-scan optical enhancement (OE) can accurately predict polyp histology in vivo in real-time. METHODS: In this prospective three-phased study, 84 patients with 230 diminutive colorectal polyps were included. During the first two study phases, five endoscopists assessed whether analysis of polyp colour, surface and vascular pattern under i-scan OE can differentiate in vivo between adenomatous and hyperplastic polyps. Finally, junior and experienced endoscopists (JE, EE, each n = 4) not involved in the prior study phases made a post hoc diagnosis of polyp histology using a static i-scan OE image database. Histopathology was used as a gold-standard in all study phases. RESULTS: The overall accuracy of i-scan OE for histology prediction was 90% with a sensitivity, specificity, positive (PPV) and negative prediction value (NPV) of 91%, 90%, 86% and 94%, respectively. In high confidence predictions, the diagnostic accuracy increased to 93% with sensitivity, specificity, PPV and NPV of 94%, 91%, 89% and 96%. Colonoscopy surveillance intervals were predicted correctly in ≥ 90% of patients. In the post hoc analysis EE predicted polyp histology under i-scan OE with an overall accuracy of 91%. After a single training session, JE achieved a comparable diagnostic performance for predicting polyp histology with i-scan OE. CONCLUSION: The histology of diminutive colorectal polyps can be accurately predicted with i-scan OE in vivo in real-time. Furthermore, polyp differentiation with i-scan OE appears to require only a short learning curve.

Activation of Epithelial Signal Transducer and Activator of Transcription 1 by Interleukin 28 Controls Mucosal Healing in Mice With Colitis and Is Increased in Mucosa of Patients With Inflammatory Bowel Disease.

BACKGROUND & AIMS: We investigated the roles of interleukin 28A (also called IL28A or interferon λ2) in intestinal epithelial cell (IEC) activation, studying its effects in mouse models of inflammatory bowel diseases (IBD) and intestinal mucosal healing. METHODS: Colitis was induced in C57BL/6JCrl mice (controls), mice with IEC-specific disruption of Stat1 (Stat1IEC-KO), mice with disruption of the interferon λ receptor 1 gene (Il28ra-/-), and mice with disruption of the interferon regulatory factor 3 gene (Irf3-/-), with or without disruption of Irf7 (Irf7-/-). We used high-resolution mini-endoscopy and in vivo imaging methods to assess colitis progression. We used 3-dimensional small intestine and colon organoids, along with RNA-Seq and gene ontology methods, to characterize the effects of IL28 on primary IECs. We studied the effects of IL28 on the human intestinal cancer cell line Caco-2 in a wound-healing assay, and in mice colon wounds. Colonic biopsies and resected tissue from patients with IBD (n = 62) and patients without colon inflammation (controls, n = 23) were analyzed by quantitative polymerase chain rection to measure expression of IL28A, IL28RA, and other related cytokines; biopsy samples were also analyzed by immunofluorescence to identify sources of IL28 production. IECs were isolated from patient tissues and incubated with IL28; signal transducer and activator of transcription 1 (STAT1) phosphorylation was measured by immunoblots and confocal imaging. RESULTS: Lamina propria cells in colon tissues of patients with IBD, and mice with colitis, had increased expression of IL28 compared with controls; levels of IL28R were increased in the colonic epithelium of patients with IBD and mice with colitis. Administration of IL28 induced phosphorylation of STAT1 in primary human and mouse IECs, increasing with dose. Il28ra-/-, Irf3-/-, Irf3-/-Irf7-/-, as well as Stat1IEC-KO mice, developed more severe colitis after administration of dextran sulfate sodium than control mice, with reduced epithelial restitution. Il28ra-/- and Stat1IEC-KO mice also developed more severe colitis in response to oxazolone than control mice. We found IL28 to induce phosphorylation (activation) of STAT1 in epithelial cells, leading to their proliferation in organoid culture. Administration of IL28 to mice with induced colonic wounds promoted mucosal healing. CONCLUSIONS: IL28 controls proliferation of IECs in mice with colitis and accelerates mucosal healing by activating STAT1. IL28 might be developed as a therapeutic agent for patients with IBD.