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Fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) regimen has shown strong efficacy as perioperative therapy for patients with locally advanced gastric (GC) and gastroesophageal (AEG) carcinoma. In the palliative situation, FLOT is recommended only for young fit patients. Data of efficacy and tolerability of FLOT in elderly patients are scarce and controversial. Thus, this study aimed to provide real-life experience of elderly patients with GC and AEG treated with FLOT as first-line palliative chemotherapy.Patients with advanced or metastatic GC or AEG and treated with FLOT as first-line palliative therapy between 2010 and 2021 were analyzed. Patients were grouped into 65 years old (n = 35) and ≥ 65 years old (n = 22) groups. Overall survival (OS), progression-free survival (PFS), feasibility and toxicity were analyzed.The median OS was 10.4 months with no significant difference between both groups (HR 0.86; 95% CI 0.48, 1.57; p = 0.632). The ECOG performance status showed powerful influence on OS in the subgroup analysis with median OS of 12.3 months for ECOG = 0 compared to 5.0 months for ECOG ≥ 1 (p = 0.015) as well as in multivariate analysis (HR 2.62; 95% CI 1.36, 5.04; p = 0.004).In the present study the ECOG performance status showed a stronger prognostic value than patient age in FLOT as first- line therapy in a real-life cohort with advanced and metastatic GC and AEG. The performance status should therefore be considered in the therapeutic decision making of elderly patients with GC and AEG.

Journal of gastrointestinal surgery 27(1), 47-55 (2023). doi:10.1007/s11605-022-05515-6, Published by Springer, New York, NY

Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. Funding: German Research Foundation (DFG).

Injuries of the acetabulum are often challenging in treatment and aftercare. One reason is the required surgical approach, which has high complication rates, including vascular lesion, hernias, and wound infection. We present an alternative endoscopic-assisted approach for the internal fixation of acetabular fractures to avoid the Pfannenstiel incision. An endoscopic approach similar to that used for endoscopic hernia surgery was used. The ilioinguinal approach’s lateral window was used to achieve reduction and insertion of a reconstruction plate. The purpose of this study is to describe a minimally invasive technique as a possible method to reduce hospitalization and complications. Another goal is to give detailed technical recommendations and to assess the potential pitfalls of this surgical approach. The APACHE technique is a safe and suitable minimally-invasive approach for the successful treatment of complex acetabular fractures and can be considered in similar cases., Technique Video Video 1 This video describes the key aspects of the anterior plating of the acetabulum in hemiendoscopic technique. The images show an anterior fracture of the left acetabulum. The first picture shows a schematic drawing of the abdomen and illustrates the approach to visualize the pubic bone and the acetabulum. A balloon trocar is placed in the preperitoneal space to bluntly dissect it for surgery. The second picture shows the infraumbilical midline incision of about 15 mm. One more incision can be seen more caudal also in the midline. The infraumbilical port is used primarily for the endoscope whereas further ports can be used for numerous instruments. The tissue is then dissected from medial to lateral starting from the pubic tubercle, using a raspatory and a laparoscopic scissor. The arcus mortis needs to be identified and clipped. The iliopectineal fascia is released and divided from the pelvic brim and os pubis by careful retraction of the femoral vessels cranially and laterally. This step is essential to place the plate safely beneath the vessels. The fracture reduction is achieved through the lateral window of the ilioinguinal approach. A large-fragment titanium reconstruction plate is used for plate fixation. The distal trocar is used to drill the threaded hole using a 3.2 mm twist drill bicortically into the superior pubic ramus.

Background The median arcuate ligament syndrome (MALS) is a rare disease caused by compression of the celiac artery (ORPHA: 293208). Surgical treatment of MALS aims to restore normal celiac blood flow by laparoscopic celiac artery decompression. However, surgical success rates vary widely between patients, therefore adequate selection of patients is essential to improve surgical outcome. Symptoms of MALS might also overlap with other chronic multi-system disorders such as mast cell activation syndrome (MCAS). So far, no clinical or radiological parameter was found to be predictive of the postoperative outcome. We therefore aimed to study preclinical parameters in one of the largest MALS cohorts with the aim to identify patients that would benefit from surgical MAL release. Results Analyzing 20 MALS patients that underwent surgical celiac artery decompression, we found 60% of patients (12/20) had a postoperative relief of their symptoms and a simultaneous decrease of analgetic use. No demographic, radiologic or operative parameter was able to predict postoperative symptom relief. However, mast cell activation syndrome correlated significantly (p=0.04) with persistent symptoms after the operation. Conclusions Overall, laparoscopic MAL release is the only effective treatment for MALS and can provide immediate symptomatic relief. Despite the missing predictive value of demographic and imaging data, our data show a correlation between persistent symptoms and a co-existing mast cell activation syndrome. This suggests that MACS symptoms might be interpreted as MALS symptoms in the presence of celiac artery stenosis and therefore surgical treatment should be evaluated carefully. Overall, selection of patients who are most likely to respond to surgical MAL release may best be accomplished by an interdisciplinary team of gastroenterologists, radiologists and surgeons.

Purpose In a post hoc analysis of the MAGIC trial, patients with curatively resected gastric cancer (GC) and mismatch repair (MMR) deficiency (MMRd) had better median overall survival (OS) when treated with surgery alone but worse median OS when treated with additional chemotherapy. Further data are required to corroborate these findings. Methods Between April 2013 and December 2018, 458 patients with curatively resected GC, including cancers of the esophagogastric junction Siewert type II and III, were identified in the German centers of the staR consortium. Tumor sections were assessed for expression of MLH1, MSH2, MSH6 and PMS2 by immunohistochemistry. The association between MMR status and survival was assessed. Similar studies published up to January 2021 were then identified in a MEDLINE search for a meta-analysis. Results MMR-status and survival data were available for 223 patients (median age 66 years, 62.8% male), 23 patients were MMRd (10.3%). After matching for baseline clinical characteristics, median OS was not reached in any subgroup. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd and MMRp had a HR of 0.67 (95% CI 0.13–3.37, P = 0.63) and 1.44 (95% CI 0.66–3.13, P = 0.36), respectively. The meta-analysis included pooled data from 385 patients. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd had an improved OS with a HR of 0.36 (95% CI 0.14–0.91, P = 0.03), whereas those with MMRp had a HR of 1.18 (95% CI 0.89–1.58, P = 0.26). Conclusion Our data support a positive prognostic effect for MMRd in GC patients treated with surgery only and a differentially negative prognostic effect in patients treated with perioperative chemotherapy. MMR status determined by preoperative biopsies may be used as a predictive biomarker to select patients for perioperative chemotherapy in curatively resectable GC.

Muscularis Externa Macrophages (ME-Macs) and enteric glial cells (EGCs) are closely associated cell types in the bowel wall, and important interactions are thought to occur between them during intestinal inflammation. They are involved in developing postoperative ileus (POI), an acute, surgery-induced inflammatory disorder triggered by IL-1 receptor type I (IL1R1)-signaling. In this study, we demonstrate that IL1R1-signaling in murine and human EGCs induces a reactive state, named enteric gliosis, characterized by a strong induction of distinct chemokines, cytokines, and the colony-stimulating factors 1 and 3. Ribosomal tagging revealed enteric gliosis as an early part of POI pathogenesis, and mice with an EGC-restricted IL1R1-deficiency failed to develop postoperative enteric gliosis, showed diminished immune cell infiltration, and were protected from POI. Furthermore, the IL1R1-deficiency in EGCs altered the surgery-induced glial activation state and reduced phagocytosis in macrophages, as well as their migration and accumulation around enteric ganglia. In patients, bowel surgery also induced IL-1-signaling, key molecules of enteric gliosis, and macrophage activation. Together, our data show that IL1R1-signaling triggers enteric gliosis, which results in ME-Mac activation and the development of POI. Intervention in this pathway might be a useful prophylactic strategy in preventing such motility disorders and gut inflammation.

Background and Aims: Symptoms of patients with gastric cancer (GC) are often unspecific and differences in symptoms between patients with cardia and non-cardia GC have been poorly investigated. We aimed to characterize symptoms of patients with cardia and non-cardia GC. Methods: Patients with cardia (Siewert type II and III) and non-cardia GC were recruited in the German multicenter cohort of the Gastric Cancer Research (staR) study between 2013 and 2017. Alarm, dyspeptic and reflux symptoms at the time of presentation were documented using a self-administered questionnaire. Results: A completed self-administered questionnaire was available for 568/759 recruited patients (132 cardia GC, 436 non-cardia GC, male 61%, mean age 64 years). Dyspeptic symptoms were more common in patients with non-cardia GC (69.0 vs. 54.5%, p=0.0024). Cardia GC patients reported more frequently alarm symptoms (69.7 vs. 44.7%, p

Simple Summary Gastric cancer is characterized by poor survival rates despite surgery and chemotherapy. Current research focuses on biomarkers to improve diagnosis and prognosis, and to enable targeted treatment strategies. The aim of our review was to give an overview over the wide range of novel biomarkers in gastric cancer. These biomarkers are targets of a specific treatment, such as antibodies against human epidermal growth factor receptor 2. Other promising biomarkers for targeted therapies that have shown relevance in clinical trials are vascular endothelial growth factor, programmed cell death protein 1, and Claudin 18.2. There is a vast number of biomarkers based on DNA, RNA, and protein expression, as well as detection of circulating tumor cells and the immune tumor microenvironment. Abstract Overall survival of gastric cancer remains low, as patients are often diagnosed with advanced stage disease. In this review, we give an overview of current research on biomarkers in gastric cancer and their implementation in treatment strategies. The HER2-targeting trastuzumab is the first molecular targeted agent approved for gastric cancer treatment. Other promising biomarkers for targeted therapies that have shown relevance in clinical trials are VEGF and Claudin 18.2. Expression of MET has been shown to be a negative prognostic factor in gastric cancer. Targeting the PD-1/PD-L1 pathway with immune checkpoint inhibitors has proven efficacy in advanced gastric cancer. Recent technology advances allow the detection of circulating tumor cells that may be used as diagnostic and prognostic indicators and for therapy monitoring in gastric cancer patients. Prognostic molecular subtypes of gastric cancer have been identified using genomic data. In addition, transcriptome profiling has allowed a comprehensive characterization of the immune and stromal microenvironment in gastric cancer and development of novel risk scores. These prognostic and predictive markers highlight the rapidly evolving field of research in gastric cancer, promising improved treatment stratification and identification of molecular targets for individualized treatment in gastric cancer.

Biliary tract cancer (BTC) refers to a heterogenous group of epithelial malignancies arising along the biliary tree. The highly aggressive nature combined with its silent presentation contribute to the dismal prognosis of this tumor. Tumor-infiltrating immune cells (TIICs) are frequently present in BTC and there is growing evidence regarding their role as therapeutic targets. In this study, we analyzed the immune cell infiltration in BTC and developed a promising immune signature score to predict prognosis in BTC. Immunohistochemistry (IHC) was carried out on tissue microarray sections from 45 patients with resectable cholangiocarcinoma for the detection of 6-sulfoLacNAc+ monocytes (slanMo), BDCA-2+ plasmacytoid dendritic cells (pDC), CD8+ or CD4+T-lymphocytes, CD103+ cells, GATA3+ cells, Toll-like receptor (TLR) 3, 7 and 9-expressing cells as well as programmed cell death protein 1 and programmed cell death ligand 1 positive cells. Data from the IHC staining were analyzed and correlated with clinicopathological and survival data. High expression of TLR7, TLR9, and GATA3 was associated with improved overall survival (OS, Log-rank p&lt, 0.05). In addition, TLR9 was associated with better disease-free survival (Log-rank p&lt, 0.05). In the multivariate Cox proportional-hazards model for OS, the TLR/TLR9/GATA3 score was found to be an independent prognostic factor for OS (“Score 2” vs. “Score 0”: HR 11.17 95% CI 2.27–54.95, p &lt, 0.01).

Objectives Patients with autoimmune gastritis (AIG) are reported to have an increased risk of developing gastric cancer (GC). In this study, we assess the characteristics and outcomes of GC patients with AIG in a multicenter case-control study. Methods Between April 2013 and May 2017, patients with GC, including cancers of the esophagogastric junction (EGJ) Siewert type II and III, were recruited. Patients with histological characteristics of AIG were identified and matched in a 1:2 fashion for age and gender to GC patients with no AIG. Presenting symptoms were documented using a self-administered questionnaire. Results Histological assessment of gastric mucosa was available for 572/759 GC patients. Overall, 28 (4.9%) of GC patients had AIG (67 ± 9 years, female-to-male ratio 1.3:1). In patients with AIG, GC was more likely to be localized in the proximal (i.e. EGJ, fundus, corpus) stomach (odds ratio (OR) 2.7, 95% confidence interval (CI) 1.0–7.1). In GC patients with AIG, pernicious anemia was the leading clinical sign (OR 22.0, 95% CI 2.6–187.2), and the most common indication for esophagogastroduodenoscopy (OR 29.0, 95% CI 7.2–116.4). GC patients with AIG were more likely to present without distant metastases (OR 6.2, 95% CI 1.3–28.8) and to be treated with curative intention (OR 3.0, 95% CI 1.0–9.0). The five-year survival rates with 95% CI in GC patients with and with no AIG were 84.7% (83.8–85.6) and 53.5% (50.9–56.1), respectively (OR 0.25, 95% CI 0.08–0.75, p = 0.001). Conclusions Pernicious anemia leads to earlier diagnosis of GC in AIG patients and contributes significantly to a better clinical outcome.

Aim: We investigated the significance of PD-L2 DNA methylation in gastric adenocarcinomas. Methods: We analyzed the methylation at different CpG sites within the PD-L2-encoding gene PDCD1LG2 with regard to correlations and associations with gene expression, clinicopathological parameters, molecular features and immune cell infiltrates in two publicly available cohorts (The Cancer Genome Atlas and Singapore cohorts) of a total of 594 gastric adenocarcinoma patients. Results: PD-L2 methylation is significantly associated with transcriptional activity, survival, Epstein–Barr virus infection, PD-L2 gene amplification, CD8+ T-cell infiltration, microsatellite instability and high mutational load (tumor mutational burden, hypermutation). Conclusion: PD-L2 methylation is associated with known predictive biomarkers of response to anti-PD-1 immunotherapies.

Postoperative ileus (POI) is a common complication after abdominal surgery. Invasive stimulation of the cervical vagus nerve is known to reduce inflammatory response and ameliorated POI after surgery in a mouse model. However, the transcutaneous vagus nerve stimulation (tVNS) is a possible non-invasive approach. In this clinical study, we aimed to investigate the effect of tVNS on the activation of the stomach muscle in humans. Patients requiring open laparotomy were screened for this prospective proof of concept clinical study. After open laparotomy, muscle activity of the stomach was measured by a free running electromyography (EMG) before and during tVNS on the ear. Frequency and amplitude of compound gastric action potentials were the electrophysiological parameters we assessed to reveal the changes in electro motor gastric activity. Gastrin levels as a surrogate marker for vagus nerve activation was analyzed before, 1 and 3 h after tVNS. Fourteen patients were included, no severe adverse events and no medical device related adverse events occurred. tVNS led to significant reduction of action potential frequency and significant elevation of action potential amplitude in the stomach compared to control. Gastrin levels were significantly elevated 3 h after tVNS compared to levels before tVNS. Application of tVNS is a safe and feasible procedure during surgical intervention. Our results provide evidence that tVNS activates efferent visceral vagal fibers. Therefore, this low risk and easy to perform method could be useful to prevent postoperative ileus. DRKS00013340.

Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic CDH1 or CTNNA1 germline variant. However, the underlying mechanism for around 80% of the patients with a family or personal history of DGC and LBC has so far not been elucidated. In this cohort study, patients meeting the 2015 HDGC clinical testing criteria were included, and subsequently, CDH1 sequencing was performed. Of the 207 patients (161 families) in this study, we detected 21 pathogenic or likely pathogenic CDH1 variants (PV) in 60 patients (28 families) and one CTNNA1 PV in two patients from one family. Sixty-eight percent (n = 141) of patients were female. The overall PV detection rate was 18% (29/161 families). Criterion 1 and 3 of the 2015 HDGC testing criteria yielded the highest detection rate of CDH1/CTNNA1 PVs (21% and 28%). PV carriers and patients without proven PV were compared. Risk of gastric cancer (GC) (38/62 61% vs. 102/140 73%) and age at diagnosis (40 &plusmn, 13 years vs. 44 &plusmn, 12 years) were similar between the two groups. However, GC was more advanced in gastrectomy specimens of patients without PV (81% vs. 26%). LBC prevalence in female carriers of a PV was 20% (n = 8/40). Clinical phenotypes differed strongly between families with the same PV. Emphasis should be on detecting more causative genes predisposing for HDGC and improve the management of patients without a proven pathogenic germline variant.

Background. Bariatric surgery is a widely used treatment for morbid obesity. Prediction of postoperative weight loss currently relies on prediction models, which mostly overestimate patients&rsquo, weight loss. Data about the influence of Non-alcoholic fatty liver disease (NAFLD) on early postoperative weight loss are scarce. Methods. This prospective, single-center cohort study included 143 patients receiving laparoscopic gastric bypass surgery (One Anastomosis-Mini Gastric Bypass (OAGB-MGB) or Roux-en-Y Gastric Bypass (RYGB)). Liver biopsies were acquired at surgery. NAFLD activity score (NAS) assigned patients to &ldquo, No NAFLD&rdquo, &ldquo, NAFL&rdquo, or &ldquo, NASH&rdquo, Follow up data were collected at 3, 6 and 12 months. Results. In total, 49.7% of patients had NASH, while 41.3% had NAFL. Compared with the No NAFLD group, NAFL and NASH showed higher body-mass-index (BMI) at follow-up (6 months: 31.0 kg/m2 vs. 36.8 kg/m2 and 36.1 kg/m2, 12 months: 27.0 kg/m2 vs. 34.4 and 32.8 kg/m2) and lower percentage of total body weight loss (%TBWL): (6 months: 27.1% vs. 23.3% and 24.4%, 12 months: 38.5% vs. 30.1 and 32.6%). Linear regression of NAS points significantly predicts percentage of excessive weight loss (%EWL) after 6 months (Cologne-weight-loss-prediction-score). Conclusions. Histopathological presence of NAFLD might lead to inferior postoperative weight reduction after gastric bypass surgery. The mechanisms underlying this observation should be further studied.

The prognosis for advanced Hepatocellular carcinoma (HCC)is still very poor. Despite initial usefulness of immune checkpoint inhibitor (PD-1), phase 3 trials failed to show significant benefit of PD-1 inhibition with nivolumab or pembrolizumab in the first and second line therapy of HCC. Clinical evidence of PD-1 inhibition in patients with advanced and heavily pretreated HCC outside clinical trials is extremely limited. In this study, we analyzed the clinical experience with PD-1 inhibition in patients with heavily pretreated HCC.Between May 2016 and January 2019 14 patients with advanced and heavily pretreated HCC were treated with nivolumab or pembrolizumab at the University Hospital Bonn, Germany. Base line characteristics prior to immunotherapy, immunohistochemistry of different immunological markers, beneficial outcome and safety were recorded and retrospectively analyzed.Immunotherapy with PD-1 inhibition was well tolerated and resulted in significant clinical benefit as last line therapy. Median overall survival (OS) was 6.6 months (95%CI:3.9-11.8), progression-free survival (PFS) was 5.3 months (95%CI:2.4-11.7) and overall response rate (ORR) was 30.8%. One patient reached a complete remission.Despite numerous pretreatments, PD-1 inhibition was well tolerated and showed clinical benefit in patients with heavily pretreated HCC.

Acute-on-chronic liver failure (ACLF) is a syndrome with high short-term mortality. Precipitating events, including hemorrhage and infections, contribute to ACLF development, but the role of surgery remains unknown. We investigated the development of ACLF in patients with cirrhosis undergoing surgery. In total, 369 patients with cirrhosis were included in the study. The clinical and laboratory data were collected prior to and on days 1-2, 3-8, and 9-28, and at 3 and 12 months after surgery. Surgery type was classified as limited or extensive, as well as liver and nonliver surgery. A total of 39 patients had baseline ACLF. Surgery was performed during acute decompensation in 35% of the rest of the 330 patients, and 81 (24.5%) developed ACLF within 28 days after surgery. Surrogate markers of systemic inflammation were similar in patients who developed ACLF or not. Age, sex, serum sodium, baseline bacterial infection, and abdominal nonliver surgery were independent predictors for the development of ACLF after surgery. Patients who developed ACLF within 28 days after surgery had a higher mortality at 3, 6, and 12 months. Survival did not differ between patients with ACLF at surgery and those developing ACLF after surgery. Development of ACLF within 28 days after surgery and elevated alkaline phosphatase and international normalized ratio were independent predictors of 90-day mortality. Independent predictors of 1-year all-cause mortality were alkaline phosphatase, Model for End-Stage Liver Disease score, and preoperative hepatic encephalopathy, whereas nonliver surgery was associated with improved survival. ACLF frequently develops in patients with cirrhosis undergoing surgery, especially in those with active bacterial infection, lower serum sodium, and kidney or coagulation dysfunction. Prognoses of ACLF both at and after surgery are similarly poor. Patients with cirrhosis should be carefully managed perioperatively.

Objective. Neuroendocrine neoplasias (NENs) represent a rare and biologically heterogeneous group of malignancies. Treatment of NEN patients remains challenging due to lack of prospective evidence on the choice of ideal therapeutic sequence and therapeutic efficacy in specific individual scenarios. Methods. Clinical data on 110 consecutive patients suffering from NEN treated at a single German university center were analyzed, therapeutic regimens applied were assessed, and the outcome was evaluated. Results. Histological grading, Ki67 proliferation index, functional activity, and presence of metastases were identified as prognostic markers. 10-year overall survival rates were 92%, 44%, and 0% for G1, G2, and G3 tumors, and 60%, 39%, 69%, 53%, and 0% for Ki67 50%, respectively. Peptide receptor radionuclide therapy (PRRT) and cytostatic chemotherapy were the second most common options, with PRRT being used more frequently in NET G1 and G2 and chemotherapy in NEC G3. Combination chemotherapy with etoposide plus cisplatin or carboplatin showed disease control rates (DCRs) of overall 74%, with a short median progression-free survival (PFS) of 7 or 5 months, respectively. DCR and PFS for PRRT were 89% and 22 months when administered as monotherapy, versus 100% and 27 months upon combination with somatostatin analog (SSA) therapy. Of note, PRRT also achieved disease control as best response in 5/5 (100%) selected cases of NEC G3. Conclusion. Further prospective studies are warranted to help stratify available options for therapeutic intervention in NEN patients.

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 x 10(-04)) and on chromosome 8q24 at rs2585176 (P = 1.09 x 10(-09)). On chromosome 5p13 we found cis-eQTL effects with an up-regulation of PTGER4 expression in GC risk allele carrier (P = 9.27 x 10(-11)). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 x 10(-47)). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 x 10(-09)). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.

Zusammenfassung Hintergrund Die prophylaktische totale Gastrektomie ist die Therapie der Wahl bei Patienten mit nachgewiesener pathogener Keimbahnmutation im CDH1-Gen und hierdurch hohem Risiko für die Entwicklung eines diffusen hereditären Magenkarzinoms (HDGC). Minimalinvasive Operationsverfahren wurden in den letzten Jahren im Bereich der onkologischen Magenchirurgie etabliert. Patienten und Methoden Insgesamt 12 Patienten wurden zwischen 2013 und März 2018 in unserem Zentrum für erbliche Tumorerkrankungen aufgrund einer nachgewiesenen CDH1-Keimbahnmutation betreut und in unserer Klinik prophylaktisch gastrektomiert. Die perioperativen Ergebnisse wurden in einer Datenbank prospektiv erfasst. Ergebnisse Es erfolgte in 5 Fällen eine offene (Zeitraum: 2013 – 2015) und in 7 Fällen eine minimalinvasive (Zeitraum: 2016 – 2017) prophylaktische Gastrektomie. Das mediane Alter im Gesamtkollektiv (7 Frauen und 5 Männer) lag bei 42 (19 – 60) Jahren. Die durchschnittliche Operationszeit betrug 291 ± 72 Minuten (offen: 269 ± 70; minimalinvasiv: 307 ± 75). Die perioperative 60-Tage-Mortalität und die Anastomoseninsuffizienzrate betrugen 0%. Bei 3 Patienten kam es zu postoperativen Komplikationen (jeweils einmal II, IIIa, IVb nach Clavien-Dindo-Klassifikation), entsprechend einer Morbidität von 25% (3/12). Die postoperative Liegedauer lag bei 14,5 ± 6,2 Tagen (offen: 16,2 ± 7,9; minimalinvasiv: 13,3 ± 5,0). Bei 10 Patienten (10/12; 83%) wurden in der histologischen Aufarbeitung intramukosale Karzinome (pT1a) diagnostiziert, 9 davon mit multifokaler Ausbreitung. Fortgeschrittene Karzinome (≥ pT1b) und Lymphknotenmetastasen lagen in keinem Fall vor. Schlussfolgerung Patienten mit Verdacht auf ein erhöhtes Risiko für ein hereditäres diffuses Magenkarzinom sollten in einem interdisziplinären Zentrum für erbliche Tumorerkrankungen betreut werden. Die minimalinvasive (laparoskopische) prophylaktische totale Gastrektomie ist ein machbares und sicheres risikoreduzierendes Verfahren bei Patienten mit CDH1-Genmutation und erblichem Magenkrebs. Demzufolge sollte, bei fehlenden Kontraindikationen und vorhandener Expertise, die minimalinvasive Operation bei diesem speziellen Kollektiv das Standardverfahren sein.

Zusammenfassung Hintergrund Malignome des Ösophagus zählen zu den häufigsten krebsbedingten Todesursachen. Den einzigen kurativen Therapieansatz stellt die radikale Ösophagektomie, eingebettet in ein multimodales Therapiekonzept, dar. Ziel der Untersuchung war die Analyse von Langzeitentwicklungen in der operativen Therapie des Ösophaguskarzinoms und deren Einflüsse auf das kurz- (1-JÜR), mittel- (5-JÜR) und langfristige (10-JÜR) Überleben. Patienten und Methoden Es wurden retrospektiv 301 Patienten am Universitätsklinikum Bonn untersucht, bei denen zwischen 1989 und 2012 eine Ösophagusresektion durchgeführt wurde. Um mögliche Trends im Management und Veränderungen hinsichtlich der Prognose zu analysieren, wurden 2 Kohorten (Kohorte A: operiert 1989 – 2000, Kohorte B: operiert 2001 – 2012) gebildet und bez. demografischer Daten, Tumorentität, Stadium, Komplikationsrate und Überleben miteinander verglichen. Ergebnisse In der Kohorte B wurden signifikant ältere Patienten in niedrigeren Tumorstadien mit einer größeren Lymphknotenausbeute operiert, eine Zunahme des Adenokarzinoms (AC) war zu beobachten. Während sich die Gesamtmorbidität nicht signifikant veränderte, konnte eine geringere Rate an Anastomoseninsuffizienzen in Kohorte B (5,5%) verglichen mit Kohorte A (12,3%) bei gleichzeitigem Anstieg der kardialen Ereignisse (A: 3,6% vs. B: 12,3%) nachgewiesen werden. Die 30-Tage-Krankenhausmortalität lag bei insgesamt 2,7% und fiel von 5% (Kohorte A) signifikant (p = 0,05) auf 0,7% (Kohorte B). Das mittlere Überleben betrug in der Kohorte A 46 ± 6,5 Monate. In Kohorte B überlebten Patienten mit 53 ± 7,2 Monaten signifikant länger (p = 0,03). In der univariaten Analyse hatten das lokale Tumorstadium, der Resektionsgrad, die Anzahl der befallenen Lymphknoten (LK), der Lymphknotenquotient (LNR) sowie das Auftreten postoperativer Komplikationen einen Einfluss auf das Überleben, wohingegen in der multivariaten Analyse nur noch T-Stadium, R-Status und LNR als unabhängige Prognosefaktoren galten. Schlussfolgerung Patienten, die sich einer onkologischen Ösophagusresektion unterziehen, sind heutzutage älter als noch vor einigen Jahren. Die frühzeitigere Tumordiagnose, eine radikalere Operationstechnik mit radikalerer Lymphknotendissektion und weniger Anastomoseninsuffizienzen sowie eine verbesserte perioperative Medizin scheinen diesen demografischen Nachteil zu kompensieren. Die größte prognostische Bedeutung beim Ösophaguskarzinom hat die LNR.

// Anna Yordanova 1, * , Soha Mahjoob 1, * , Philipp Lingohr 2 , Jorg Kalff 2 , Andreas Turler 3 , Holger Palmedo 4 , Hans-Jurgen Biersack 1 , Glen Kristiansen 5 , Jamshid Farahati 6 , Markus Essler 1 and Hojjat Ahmadzadehfar 1 1 Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany 2 Department of Surgery, University Hospital Bonn, Bonn, Germany 3 Department of General and Visceral Surgery, Johanniter-Krankenhaus Bonn, Bonn, Germany 4 Institute of Radiology and Nuclear Medicine, PET-CT Center, Bonn, Germany 5 Institute of Pathology, University Hospital Bonn, Bonn, Germany 6 Department of Nuclear Medicine, Bethesda Hospital, Duisburg, Germany * These authors have contributed equally to this work Correspondence to: Hojjat Ahmadzadehfar, email: hojjat.ahmadzadehfar@ukbonn.de Keywords: sestamibi, MIBI, thyroid nodules, thyroid cancer, cold nodule Received: June 20, 2017 Accepted: September 16, 2017 Published: October 17, 2017 ABSTRACT [ 99m Tc]Tc-Sestamibi (MIBI) is an increasingly used tool for evaluation of thyroid nodules. However, there is a lack of evidence about the accuracy of this method in the European population. The aim of this study was to assess the utility of MIBI for the differentiation of thyroid nodules in a large cohort. 161 patients underwent MIBI, followed by a thyroidectomy. We used a dual phase MIBI protocol. Interpretation of the images included a scoring system from 0 (absent) to 3 (increased); this was to provide a scale for the uptake of the thyroid nodule in comparison to the paranodular tissue. Additionally, we evaluated the tracer uptake trend in late images compared to early images. We used the final histopathology as the reference standard. Scores 0-1 in early images, scores 0-2 in late images, and an absence of increasing uptake in the thyroid nodule in late images, showed the best predictive values to exclude malignancy, respectively (negative predictive value (NPV) 89%). Highest sensitivity (91%) for malignant nodules was evident in early images with a score 1-3. Highest specificity (91%) was obtained when the negative was defined as an absence of uptake-increase, in the late images. This study confirms that the most valuable feature of MIBI is the high NPV. Thus, with the appropriate interpretation method, high sensitivity and specificity, and moderate PPV can be obtained.

// David Stahl 1 , Martin Braun 1 , Andrew J. Gentles 2 , Philipp Lingohr 3 , Adeline Walter 4 , Glen Kristiansen 1 and Ines Gutgemann 1 1 Institute of Pathology, University Hospital Bonn, Bonn, Germany 2 Center for Cancer Systems Biology (CCSB), Stanford University, Stanford, California, USA 3 Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany 4 Department of Gynecology and Obstetrics, University Hospital Bonn, Bonn, Germany Correspondence to: Ines Gutgemann, email: Ines.guetgemann@ukbonn.de Keywords: BUB1, immunohistochemistry, biomarker, gastric adenocarcinoma, gastric cancer Received: March 17, 2017 Accepted: June 19, 2017 Published: July 18, 2017 ABSTRACT Gastric adenocarcinomas are associated with a poor prognosis due to the fact that the tumor has often metastasized by the time of diagnosis and prognostic markers are urgently needed to tailor treatment. We examined the expression of the mitotic spindle checkpoint protein BUB1 (budding uninhibited by benzimidazoles 1) and Ki-67 protein expression by immunohistochemistry in 218 patients with primary gastric adenocarcinomas. Tumors with low frequency of BUB1 expression were associated with larger tumor size (pT) (p < 0.001), higher incidence of lymph node metastases (pN) (p = 0.027), distant metastases (pM) (p = 0.006) and higher UICC stage (p < 0.001). Furthermore, BUB1 expression was inversely correlated with residual tumor stage (p = 0.038). Abundant BUB1 protein expression correlated with frequent Ki-67 protein expression (p < 0.001) and low BUB1 expression was associated with shorter survival (p < 0.001). Univariate and multivariate analyses confirmed BUB1 to be an independent prognostic marker in gastric cancer (p = 0.021).

Neuroendocrine tumours (NET) are rare neoplasms, but the incidence is permanently increasing. Most of the NETs are slow proliferating and clinically silent, and for that reason, they are often diagnosed at a stage with advanced disease. The complexity and diversity of the NET-biology require the treatment of patients in specialised centres to guarantee a qualified, multidisciplinary treatment planning. At our institution, we developed an interdisciplinary model for the assessment and treatment of NET. The aim was to adapt the guidelines to the clinical practice, exchange of current knowledge, and a tailored approach to the individual patient. In our team are included medical professionals from pathology, radiology, oncology, gastroenterology, oncological surgery, and nuclear medicine. In this paper, we describe step-by-step a procedural algorithm for the management of patients with neuroendocrine tumours, focusing on midgut-NETs in terms of therapy.

Metabolic and alcoholic liver injuries result in nonalcoholic (NAFLD) or alcoholic (ALD) fatty liver disease, respectively. In particular, presence of fibrosis in NAFLD and ALD requires treatment, but development of drugs is hampered by the lack of suitable models with significant fibrosis. The carbon tetrachloride (CCl4) liver fibrosis model does not reflect human NAFLD or ALD, but CCl4 may serve as a fibrosis accelerator in addition to another injury. Ethanol in drinking water (16%) or Western diet (WD) were administered for 7 wk in mice either alone or in combination with CCl4 intoxications. Extent of fibrosis, steatosis, and inflammation was assessed by histology, transcription, and biochemistry. Furthermore, transcription of fibrosis, proliferation, and inflammation-related genes was studied on human liver samples with fibrosis resulting from hepatitis C virus infection ( n = 7), NAFLD ( n = 8), or ALD ( n = 7). WD or ethanol alone induced only mild steatosis and inflammation. Combination of CCl4 and WD induced the most severe steatosis together with significant liver fibrosis and moderate inflammation. Combination of CCl4 and ethanol induced the strongest inflammation, with significant liver fibrosis and moderate steatosis. The relationship pattern between fibrosis, proliferation, and inflammation of human ALD was mostly similar in mice treated with CCl4 and ethanol. The combination of CCl4 intoxication with WD validates previous data suggesting it as an appropriate model for human nonalcoholic steatohepatitis. Especially, CCl4 plus ethanol for 7 wk induces ALD in mice, providing a model suitable for further basic research and drug testing. NEW & NOTEWORTHY Alcoholic fatty liver disease with significant fibrosis is generated within 7 wk using carbon tetrachloride as a fibrosis accelerator and administering gradually ethanol (up to 16%) in mice. The similarity in the pattern of steatosis, inflammation, and fibrosis involved in alcoholic fatty liver disease to those of the human condition renders this mouse model suitable as a preclinical model for drug development.

Metabolic and alcoholic liver injuries result in nonalcoholic (NAFLD) or alcoholic (ALD) fatty liver disease, respectively. In particular, presence of fibrosis in NAFLD and ALD requires treatment, but development of drugs is hampered by the lack of suitable models with significant fibrosis. The carbon tetrachloride (CCl