Complications after esophageal cancer surgery has been shown to decrease long-term quality-of-life and to increase the risk of postoperative mortality, making patient selection important. The physical strength of the individual patient is likely to affect the patient’s chance of withstanding a major surgical intervention. The aim of this study was to evaluate if validated physical tests can predict the risk of postoperative complications after a thoraco-abdominal esophagectomy. All patients who had a thoraco-abdominal esophagectomy at three Swedish university hospitals from 2014–2017 were eligible for inclusion in this prospective study. In addition to a bicycle test, patients were evaluated preoperatively by a physiotherapist using eight validated physical tests. Data on postoperative complications were extracted from the Swedish National Registry for Esophageal and Gastric Cancer. Patients were divided into two groups according to Clavien Dindo (CD) classification of the most severe complication (CD 1–2 and CD 3–5). Tests results were compared between the groups. We also compared performance in each validated test to the risk of specific complications. A total of 114 patients were enrolled. 26 patients were excluded because of missing data leaving 88 patients for statistical analyses. Total 90-days mortality was 2.3%. Patients who suffered from an anastomotic leak after surgery had a significantly lower performance in the bicycle test. Performance in the preoperative shoulder abduction- and 6-minute-walk tests were significantly lower in patients who suffered from pneumonia or cardiovascular complications. Patients scoring in the lowest quartile in the hand grip-strength test had a higher frequency of complications rated as CD 3–5. No other significant differences could be shown between the CD groups. In this prospective multicentre study, we found a connection between patient performance on four different preoperative physical tests (bicycle test, shoulder abduction test, 6-minute walk test and hand grip-strength test) and the risk of postoperative complications. We believe that these relatively simple tests can help the surgeon when evaluating the surgical risk for the individual patient.

PURPOSE:Oligometastatic gastroesophageal cancer is a clinical entity with no standard treatment recommendation. Treatment with curative intent has recently emerged as an option for selected patients in contrast to the traditional palliative treatment strategy. This prospective study aimed to assess the safety and efficacy of combined systemic and local treatment with curative intent for patients with oligometastatic gastroesophageal cancer. METHODS:In a multicenter study, consecutive patients with gastroesophageal cancer and metastases in the liver and/or extra-regional lymph nodes were screened for inclusion. Eligible patients were offered curatively intended perioperative chemotherapy followed by surgical resection or liver ablation. Primary endpoints were treatment safety and feasibility. Secondary outcomes included postoperative mortality, treatment response, progression-free survival, and overall survival. Subgroup analyses were stratified based on oligometastatic location. RESULTS:A total of 29 (82.9%) patients completed treatment with surgical resection (93.1%), liver ablation (3.4%), or definitive chemoradiotherapy (3.4%). Postoperative complications were found in 19 (73.1%) patients, whereas postoperative mortality was 0%. The most common complications included infection (34.6%) and respiratory complications (34.6%). Median overall survival was 20.9 months (interquartile range 11.2-42.6) from diagnosis and 17.0 months (interquartile range 6.4-35.9) from surgery in patients who were treated with neoadjuvant chemotherapy followed by surgery. Median progression-free survival was 5.8 months (interquartile range 3.1-11.3). CONCLUSION:This study found curative treatment to be a relatively safe option, with an overall survival of 20.8 months and no postoperative mortality.

Anastomotic defect (AD) after esophagectomy can lead to severe complications with need for surgical or endoscopic intervention. Early detection enables early treatment and can limit the consequences of the AD. As of today, there are limited methods to predict AD. In this study, we have used microdialysis (MD) to measure local metabolism at the intrathoracic anastomosis. Feasibility and possible diagnostic use were investigated. Sixty patients planned for Ivor Lewis esophagectomy were enrolled. After construction of the anastomosis, surface MD (S-MD) probes were attached to the outer surface of the esophageal remnant and the gastric conduit in close vicinity of the anastomosis and left in place for 7 postoperative days (PODs). Continuous sampling of local tissue concentrations of metabolic substances (glucose, lactate, and pyruvate) was performed postoperatively. Outcome, defined as AD or not according to Esophagectomy Complications Consensus Group definitions, was recorded at discharge or at first postoperative follow up. Difference in concentrations of metabolic substances was analyzed retrospectively between the two groups by means of artificial neural network technique. S-MD probes can be attached and removed from the gastric tube reconstruction without any adverse events. Deviating metabolite concentrations on POD 1 were associated with later development of AD. In subjects who developed AD, no difference in metabolic concentrations between the esophageal and the gastric probe was recorded. The technical failure rate of the MD probes/procedure was high. S-MD can be used in a clinical setting after Ivor Lewis esophagectomy. Deviation in local tissue metabolism on POD 1 seems to be associated with development of AD. Further development of MD probes and procedure is required to reduce technical failure.

Abstract Cancer treatment is increasingly tailored to the individual patient. Treatment decisions are based on the evaluation of clinical stage which in turn is based on the result of the diagnostic pre-treatment work-up. The aim of this study was to investigate the accuracy of clinical staging of esophageal and gastric cancer in Sweden and what factors influence the quality of the staging procedure. Methods All patients operated for esophageal or gastric cancer, without neoadjuvant treatment, in Sweden from 2006 to 2018 was extracted from the Swedish national registry for esophageal and gastric cancer. Clinical TNM (cTNM) and pathological TNM (pTNM) was compared. The most common preoperative modalities for staging were endoscopy and CT-scan. Data on sex, age, smoking habits, multidisciplinary cancer conferences (yes/no), time of surgery (categorized in 5-year periods), number of resected lymph nodes and region of surgery were extracted from the registry. Uni- and multivariate logistic regression analyses were made comparing patients with correct cTNM to patients with incorrect cTNM. Results A total of 2500 patients met the inclusion criteria. 1173 patients were excluded because of missing data leaving 1327 patients for analyses. cTNM stage and pTNM stage was identical in 38% of patients. In 35% of patients there was a +/−1 stage difference comparing cTNM to pTNM. For esophageal cancer T-stage was on target in 32% and N-stage in 50% of cases. For gastric cancer the corresponding figures were 35% and 48% respectively. Multivariate regression analyzes showed that operation in the later time periods, a higher number of resected lymph nodes and discussion at multidisciplinary cancer conference improved staging accuracy. Conclusion In this study we found that 73% of patients were staged on target or +/− one stage-level. Operation in the later time periods, a higher number of resected lymph nodes and discussion at multidisciplinary cancer conference improved staging accuracy. This data indicate that treatment decisions should be made in a multidisciplinary setting. We believe that the gradual centralization of surgery and treatment decisions in Sweden during this time-period partly explains the improved accuracy over time.

Background: The majority of patients with incurable esophageal adenocarcinoma suffer from dysphagia. We assessed a novel treatment strategy with initial short-course radiotherapy followed by chemotherapy with the primary aim to achieve long-term relief of dysphagia. Methods: This phase II trial included treatment-naive patients with dysphagia due to esophageal adenocarcinoma not eligible for curative treatment. External beam radiotherapy with 20 Gy in five fractions to the primary tumor was followed by four cycles of chemotherapy (FOLFOX regimen). Dysphagia was assessed using a five-grade scale. Results: From October 2014 to May 2018 a total of 29 patients were enrolled. The rate of dysphagia improvement was 79%, median duration of improvement 6.7 months (12.2 months for responders) and median overall survival 9.9 months. In the pre-specified per protocol analysis (23 patients) the rate of dysphagia improvement was 91%, median duration of improvement 12.2 months (14.0 months for responders) and median overall survival 16.0 months. The most common grade 3-4 adverse events were neutropenia (29%), infection (25%), anorexia (11%), esophagitis (11%) and fatigue (11%). Conclusion: Initial palliative short-course radiotherapy followed by chemotherapy is a promising treatment strategy that can provide long-lasting relief of dysphagia in patients with esophageal adenocarcinoma.

Background Time of diagnosis (TOD) of benign esophageal perforation is regarded as an important risk factor for clinical outcome, although convincing evidence is lacking. The aim of this study is to assess whether time between onset of perforation and diagnosis is associated with clinical outcome in patients with iatrogenic esophageal perforation (IEP) and Boerhaave’s syndrome (BS). Methods We searched MEDLINE, Embase and Cochrane library through June 2018 to identify studies. Authors were invited to share individual patient data and a meta-analysis was performed (PROSPERO: CRD42018093473). Patients were subdivided in early (≤ 24 h) and late (> 24 h) TOD and compared with mixed effects multivariable analysis while adjusting age, gender, location of perforation, initial treatment and center. Primary outcome was overall mortality. Secondary outcomes were length of hospital stay, re-interventions and ICU admission. Results Our meta-analysis included IPD of 25 studies including 576 patients with IEP and 384 with BS. In IEP, early TOD was not associated with overall mortality (8% vs. 13%, OR 2.1, 95% CI 0.8–5.1), but was associated with a 23% decrease in ICU admissions (46% vs. 69%, OR 3.0, 95% CI 1.2–7.2), a 22% decrease in re-interventions (23% vs. 45%, OR 2.8, 95% CI 1.2–6.7) and a 36% decrease in length of hospital stay (14 vs. 22 days, p < 0.001), compared with late TOD. In BS, no associations between TOD and outcomes were found. When combining IEP and BS, early TOD was associated with a 6% decrease in overall mortality (10% vs. 16%, OR 2.1, 95% CI 1.1–3.9), a 19% decrease in re-interventions (26% vs. 45%, OR 1.9, 95% CI 1.1–3.2) and a 35% decrease in mean length of hospital stay (16 vs. 22 days, p = 0.001), compared with late TOD. Conclusions This individual patient data meta-analysis confirms the general opinion that an early (≤ 24 h) compared to a late diagnosis (> 24 h) in benign esophageal perforations, particularly in IEP, is associated with improved clinical outcome.

Background and aim: Preoperative testing of physical performance is common for patients undergoing an esophagectomy, but little evidence exists suggesting which measures are most suitable. This study compared outcome measures currently used at participating hospitals (spirometry, cycle ergometer test) against other validated tests - Maximal Inspiratory Pressure (MIP), Maximal Expiratory Pressure (MEP), Timed Up and Go (TUG), 6 Minute Walk Test (6MWT), heel raise test, shoulder abduction test, Timed Stands Test (TST) and handgrip strength. Methods: 109 patients were recruited from three university hospitals in Sweden. Participants were tested using a protocol testing respiratory and peripheral muscle strength, lung function, endurance and fitness. Results: There were strong correlations between the cycle ergometer and grip strength (r=0.619), 6MWT (r=0.572), MIP (r=0.619) and MEP (r=0.529). A strong correlation was also seen between spirometry and grip strength (r=0.508-0.574). A moderate correlation was found between spirometry, MIP (r=0.405-0.470) and MEP (r=0.366-0.452), the cycle ergometer, TUG (r=-0.321) and TST (r=-0.308) and between 6MWT and PEF (r=-0.333). Conclusion: The strong correlations between different measures suggest that in cases where the standard tests are inadvisable or impractical, simple tests like grip strength and 6MWT could be used instead.

Background: For locally advanced Siewert type II and III tumors we have performed total gastrectomy including resection of the distal 2/3 of the esophagus, through separate abdominal and right chest incisions (THX-ABD). The procedure involves wide lymphadenectomy in the abdomen/chest and a Rouxen-Y jejunostomy to the level of the azygos vein or above. The aim of the study was to investigate short-and long-term results for this rarely used procedure. Methods: Retrospective study of 83 radio-chemotherapy naive patients with adenocarcinoma at the gastro-esophageal junction (Siewert type II n = 65 and type III n = 18) operated upon 1986-2011. Results: 2/83 (2.4%) patients died in hospital. 70/83 (84%) patients had R0-resections. 82/83 (99%) patients had free longitudinal resection margins. Overall 5-year survival was 22/83 (27%). Conclusion: THX-ABD can be performed with high rates of R0 resections and with low in-hospital mortality. Long-term survival rate was not better compared with less extensive surgical procedures. (C) 2018 Elsevier Inc. All rights reserved.

Abstract Background Anastomotic leakage (AL) after oesophageal surgery is a serious complication, leading to increased postoperative mortality. Early detection and treatment is essential. The aim of this study was to investigate if inflammatory serum parameters in the early postoperative course after oesophageal cancer surgery, could predict development of an AL. Methods All patients in Sweden with AL after thoraco-abdominal surgery for oesophageal or gastroesophageal junction cancer from 2006–01-01 to 2017–01-31 were collected from the Swedish National Registry for esophageal and gastric cancer (NREV). Two matched controls for each AL-patient were also selected from the registry. Pre-, per- and postoperative variables were collected from NREV. The following parameters were collected from patient charts: number of days from surgery to AL, diagnostic modality, method of treatment, serum levels of C-reactive protein (CRP), White blood cell count (WBC) and serum-Albumin taken on postoperative day 1 to 7 (POD1–7). Thoracic- and cervical anastomosis were analysed separately. Perioperative data and inflammatory markers were compared between controls and AL-patients. Receiver Operating Characteristic (ROC) curves was constructed to identify optimal cut-off values and a multivariate analysis was performed to identify independent risk factors. Results A total of 155 patients with AL and 307 controls (n = 462) were analysed. In patients with thoracic anastomosis median levels of CRP and WBC were significantly different on POD 2–7 and on POD 4–7 comparing AL-patients to controls. In patients with cervical anastomosis there was a significant difference in WBC levels on POD 1–7. ROC-curve analysis identified CRP on POD3 (cut-off 221) and POD4 (cut-off 203) as the best candidates for predicting AL in patients with a thoracic anastomosis, displaying an area under curve of 0.754 (Sensitivity 59%, Specificity 83%) and 0.731 (Sensitivity: 57%, Specificity 82%). Conclusion In this nation-wide register study we found that a model combining S-CRP levels on POD 3 and POD 4 after a thoraco-abdominal esophagectomy, could identify patients with increased risk of anastomotic leakage several days before it was diagnosed. However, since the sensitivity of this test is relatively low for predicting AL, it must be assessed in a larger clinical context. Disclosure All authors have declared no conflicts of interest.

An increase of regulatory T cells, defined as CD25high- and/or FOXP3+-expressing CD4+ T cells, within tumors has been reported in several studies. Tregs promote tumor growth by modulating the antitumor immune response, mainly through inhibition of T-cell-mediated tumor cell killing: this has been suggested to be dependent on IL-10 and/or TGF-β. In stomach cancer, the mechanisms behind the accumulation of Tregs in tumor tissue has not been fully elucidated, and neither has Treg gene expression in situ.

ABSTRACT Infection with Helicobacter pylori is associated with development of ulcer disease and gastrointestinal adenocarcinoma. The infection leads to a large infiltration of immune cells and the formation of organized lymphoid follicles in the human gastric mucosa. Still, the immune system fails to eradicate the bacteria, and the substantial regulatory T cell (Treg) response elicited is probably a major factor permitting bacterial persistence. Dendritic cells (DCs) are professional antigen-presenting cells that can activate naive T cells, and maturation of DCs is crucial for the initiation of primary immune responses. The aim of this study was to investigate the presence and localization of mature human DCs in H. pylori -infected gastric mucosa. Gastric antral biopsy specimens were collected from patients with H. pylori -associated gastritis and healthy volunteers, and antrum tissue was collected from patients undergoing gastric resection. Immunohistochemistry and flow cytometry showed that DCs expressing the maturation marker dendritic cell lysosome-associated membrane glycoprotein (DC-LAMP; CD208) are enriched in the H. pylori -infected gastric mucosa and that these DCs are specifically localized within or close to lymphoid follicles. Gastric DC-LAMP-positive (DC-LAMP + ) DCs express CD11c and high levels of HLA-DR but little CD80, CD83, and CD86. Furthermore, immunofluorescence analyses demonstrated that DC-LAMP + DCs are in the same location as FoxP3-positive putative Tregs in the follicles. In conclusion, we show that DC-LAMP + DCs with low costimulatory capacity accumulate in the lymphoid follicles in human H. pylori -infected gastric tissue, and our results suggest that Treg-DC interactions may promote chronic infection by rendering gastric DCs tolerogenic.

BACKGROUND:For many years there has been a debate as to which is the method of choice in treating patients with esophageal perforation. The literature consists mainly of small case series. Strategies for aiding patients struck with this disease is changing as new and less traumatic treatment options are developing. We studied a relatively large consecutive material of esophageal perforations in an effort to evaluate prognostic factors, diagnostic efforts and treatment strategy in these patients.METHODS:125 consecutive patients treated at the University Hospital of Lund from 1970 to 2006 were studied retrospectively. Prognostic factors were evaluated using the Cox proportional hazards model.RESULTS:Pre-operative ASA score was the only factor that significantly influenced outcome. Neck incision for cervical perforation (n = 8) and treatment with a covered stent with or without open drainage for a thoracic perforation (n = 6) had the lowest mortality. Esophageal resection (n = 8) had the highest mortality. A CAT scan or an oesophageal X-ray with oral contrast were the most efficient diagnostic tools. The preferred treatment strategy changed over the course of the study period, from a more aggressive surgical approach towards using covered stents to seal the perforation.CONCLUSION:Pre-operative ASA score was the only factor that significantly influenced outcome in this study. Treatment strategies are changing as less traumatic options have become available. Sealing an esophageal perforation with a covered stent, in combination with open or closed drainage when necessary, is a promising treatment strategy.

BACKGROUND:Despite a decreasing incidence of peptic ulcer disease, most previous studies report a stabile incidence of ulcer complications. We wanted to investigate the incidence of peptic ulcer complications in Sweden before and after the introduction of the proton pump inhibitors (PPI) in 1988 and compare these data to the sales of non-steroid anti-inflammatory drugs (NSAID) and acetylsalicylic acid (ASA).METHODS:All cases of gastric and duodenal ulcer complications diagnosed in Sweden from 1974 to 2002 were identified using the National hospital discharge register. Information on sales of ASA/NSAID was obtained from the National prescription survey.RESULTS:When comparing the time-periods before and after 1988 we found a significantly lower incidence of peptic ulcer complications during the later period for both sexes (p < 0.001). Incidence rates varied from 1.5 to 7.8/100000 inhabitants/year regarding perforated peptic ulcers and from 5.2 to 40.2 regarding peptic ulcer bleeding. The number of sold daily dosages of prescribed NSAID/ASA tripled from 1975 to 2002. The number of prescribed sales to women was higher than to males. Sales of low-dose ASA also increased. The total volume of NSAID and ASA, i.e. over the counter sale and sold on prescription, increased by 28% during the same period.CONCLUSION:When comparing the periods before and after the introduction of the proton pump inhibitors we found a significant decrease in the incidence of peptic ulcer complications in the Swedish population after 1988 when PPI were introduced on the market. The cause of this decrease is most likely multifactorial, including smoking habits, NSAID consumption, prevalence of Helicobacter pylori and the introduction of PPI. Sales of prescribed NSAID/ASA increased, especially in middle-aged and elderly women. This fact seems to have had little effect on the incidence of peptic ulcer complications.

Gastric adenocarcinoma is closely associated with Helicobacter pylori infection. It is also much more frequent in patients with common variable immunodeficiency or selective IgA-deficiency than in the general population. To investigate a possible link between local antibody production and gastric tumors, we studied gastric B cell infiltration and local IgA production in patients with H. pylori induced gastric adenocarcinomas. These studies showed that total and H. pylori-specific IgA antibody levels were substantially lower in gastric tissue from the cancer patients compared to those from asymptomatic H. pylori carriers. However, serum IgA levels were similar in the cancer patients and asymptomatic carriers. As could be expected, H. pylori infected asymptomatic carriers had considerably increased IgA antibody levels compared to uninfected subjects. We conclude that patients suffering from gastric adenocarcinoma have a dramatically decreased local IgA production in the stomach compared to asymptomatic H. pylori infected individuals.

Human Helicobacter pylori infection gives rise to an active chronic gastritis and is a major risk factor for the development of duodenal ulcer disease and gastric adenocarcinoma. The infection is accompanied by a large accumulation of immunoglobulin A (IgA)-secreting cells in the gastric mucosa, and following mucosal immunization only H. pylori-infected volunteers mounted a B-cell response in the gastric mucosa. To identify the signals for recruitment of gastric IgA-secreting cells, we investigated the gastric production of CCL28 (mucosa-associated epithelial chemokine) and CCL25 (thymus-expressed chemokine) in H. pylori-infected and uninfected individuals and the potential of gastric B-cell populations to migrate toward these chemokines. Gastric tissue from H. pylori-infected individuals contained significantly more CCL28 protein and mRNA than that from uninfected individuals, while CCL25 levels remained unchanged. Chemokine-induced migration of gastric lamina propria lymphocytes isolated from patients undergoing gastric resection was then assessed using the Transwell system. IgA-secreting cells and IgA(+) memory B cells from H. pylori-infected tissues migrated toward CCL28 but not CCL25, while the corresponding cells from uninfected patients did not. Furthermore, IgG-secreting cells from H.pylori-infected patients did not migrate to CCL28 but instead to CXCL12 (SDF-1 alpha). However, chemokine receptor expression did not correlate to the migratory pattern of the different B-cell populations. These studies are the first to show increased CCL28 production during gastrointestinal infection in humans and provide an explanation for the large influx of IgA-secreting cells to the gastric mucosa in H. pylori-infected individuals.

Material and methods: In all, 237 consecutive patients with a perforated peptic ulcer admitted from 1974-1992 and 125 consecutive patients with an oesophageal perforation admitted from 1970-2006 to Lund University hospital were studied retrospectively. Prognostic factors were evaluated using the Cox proportional hazards model. All cases of gastro-duodenal ulcer perforations diagnosed in Sweden from 1974 to 2002 were identified using the National Hospital Discharge Register and incidence figures were calculated. Information on sales of ASA/NSAID´s was obtained from the National Prescription Survey. Results and conclusions: Incidence of peptic-ulcer perforations has decreased in Sweden since the late 1980?s, after the introduction of the proton pump inhibitors (PPI), despite an increase in sales of NSAID/ASA of 28% during this period. The reason for this is probably multifactorial (cohort phenomena, smoking habits, Helicobacter pylori), but the increasing use of PPI might have protected the population from NSAID complications and thus contributed to the fall in incidence. In oesophageal perforations, a CAT scan or a contrast plain film investigation had the highest degree of true positive investigations. Regarding peptic ulcer perforations a plain film was the most widely used investigation and it was true positive in 75% of cases. In oesophageal perforations, pre-operative ASA-score was the only factor that significantly influenced outcome. Perforations in the thoracic part of the oesophagus had worse prognosis than perforations in the neck. Treatment with a covered stent with or without open drainage had the lowest mortality. Diversion by a pharyngostoma did not improve survival. In patients with a peptic ulcer perforation, age >75 years, significant co-morbidity, location in the stomach and > 24 hours from symptoms to operation, had a negative impact on outcome. Treatment with simple closure resulted in the lowest mortality.