[Differentiated surgical approach for adenocarcinoma of the gastroesophageal junction]. / Differenziertes chirurgisches Vorgehen bei Adenokarzinomen des ösophagogastralen Übergangs.

For adenocarcinoma of the gastroesophageal junction (GEJ) the classification of Siewert with its three subtypes is well established as a practical approach to surgical treatment. Transthoracic esophagectomy with gastric tube formation is generally accepted as the surgical standard for adenocarcinoma of the distal esophagus (GEJ type I). Intrathoracic esophagogastrostomy has become the most frequently used anastomotic technique (Ivor Lewis esophagectomy). Both the abdominal and thoracic part can be safely performed with a minimally invasive access. For subcardiac gastric cancer (GEJ type III) transhiatal extended gastrectomy is the resection of choice. For true cardiac carcinomas (GEJ type II) it has not yet been decided which of the abovementioned surgical procedures offers the best long-term survival. If technically possible in terms of a complete resection, transhiatal extended gastrectomy should be preferred because of a better postoperative quality of life. For GEJ type II tumors a minimally invasive approach is not recommended if the extent of resection cannot be safely determined preoperatively.

Mutations during the Adaptation of H9N2 Avian Influenza Virus to the Respiratory Epithelium of Pigs Enhance Sialic Acid Binding Activity and Virulence in Mice.

The natural reservoir for influenza viruses is waterfowl, and from there they succeeded in crossing the barrier to different mammalian species. We analyzed the adaptation of avian influenza viruses to a mammalian host by passaging an H9N2 strain three times in differentiated swine airway epithelial cells. Using precision-cut slices from the porcine lung to passage the parental virus, isolates from each of the three passages (P1 to P3) were characterized by assessing growth curves and ciliostatic effects. The only difference noted was an increased growth kinetics of the P3 virus. Sequence analysis revealed four mutations: one each in the PB2 and NS1 proteins and two in the HA protein. The HA mutations, A190V and T212I, were characterized by generating recombinant viruses containing either one or both amino acid exchanges. Whereas the parental virus recognized α2,3-linked sialic acids preferentially, the HA190 mutant bound to a broad spectrum of glycans with α2,6/8/9-linked sialic acids. The HA212 mutant alone differed only slightly from the parental virus; however, the combination of both mutations (HA190+HA212) increased the binding affinity to those glycans recognized by the HA190 mutant. Remarkably, only the HA double mutant showed a significantly increased pathogenicity in mice. In contrast, none of those mutations affected the ciliary activity of the epithelial cells which is characteristic for virulent swine influenza viruses. Taken together, our results indicate that shifts in the HA receptor affinity are just an early adaptation step of avian H9N2 strains; further mutational changes may be required to become virulent for pigs.IMPORTANCE Swine play an important role in the interspecies transmission of influenza viruses. Avian influenza A viruses (IAV) of the H9N2 subtype have successfully infected hosts from different species but have not established a stable lineage. We have analyzed the adaptation of IAV-H9N2 virus to target cells of a new host by passaging the virus three times in differentiated porcine respiratory epithelial cells. Among the four mutations detected, the two HA mutations were analyzed by generating recombinant viruses. Depending on the infection system used, the mutations differed in their phenotypic expression, e.g., sialic acid binding activity, replication kinetics, plaque size, and pathogenicity in inbred mice. However, none of the mutations affected the ciliary activity which serves as a virulence marker. Thus, early adaptive mutation enhances the replication kinetics, but more mutations are required for IAV of the H9N2 subtype to become virulent.

[Perioperative management of transthoracic oesophagectomies : Fundamentals of interdisciplinary care and new approaches to accelerated recovery after surgery]. / Perioperatives Management der transthorakalen Ösophagektomie : Grundlagen der interdisziplinären Patientenversorgung und neue Konzepte zur beschleunigten postoperativen Erholung.

Locally advanced carcinomas of the oesophagus require multimodal treatment. The core element of curative therapy is transthoracic en bloc oesophagectomy, which is the standard procedure carried out in most specialized centres. Reconstruction of intestinal continuity is usually achieved with a gastric sleeve, which is anastomosed either intrathoracically or cervically to the remaining oesophagus. This thoraco-abdominal operation is associated with significant postoperative morbidity, not least because of a vast array of pre-existing illnesses in the surgical patient. For an optimal outcome, the careful interdisciplinary selection of patients, preoperative risk evaluation and conditioning are essential. The caseload of the centres correlates inversely with the complication rate. The leading surgical complication is anastomotic leakage, which is diagnosed endoscopically and usually treated with the aid of endoscopic procedures. Pulmonary infections are the most frequent non-surgical complication. Thoracic epidural anaesthesia and perfusion-orientated fluid management can reduce the rate of pulmonary complications. Patients are ventilated protecting the lungs and are extubated as early as possible. Oesophagectomies should only be performed in high-volume centres with the close cooperation of surgeons and anaesthesia/intensive care specialists. Programmes of enhanced recovery after surgery (ERAS) hold further potential for the patient's quicker postoperative recovery. In this review article the fundamental aspects of the interdisciplinary perioperative management of transthoracic oesophagectomy are described.

Management of Tracheo- or Bronchoesophageal Fistula After Ivor-Lewis Esophagectomy.

BACKGROUND: The development of tracheo- or bronchoesophageal fistula (TBF) after Ivor-Lewis esophagectomy remains to be a rare complication associated with a high mortality rate. METHODS: In this retrospective study, the charts of patients with TBF after esophagectomy were analyzed in terms of individual patient characteristics, esophagotracheal complications, respiratory function, management, and outcome. RESULTS: Between January 2000 and December 2014, 1204 patients underwent Ivor-Lewis esophagectomy for esophageal cancer; 13 patients (1.1 %) developed a TBF. In all 13 patients, a concomitant leakage of the intrathoracic esophagogastrostomy was evident, either prior to diagnosis of TBF (metachronous TBF) or simultaneously (synchronous TBF). TBF was predominantly located in the left main bronchus (n = 6, 46.1 %) or trachea (n = 5, 38.5 %). Management of TBF included re-thoracotomy (n = 7), interventional endoscopic (n = 10) or bronchoscopic therapy (n = 4). In the majority of patients (n = 8), management consisted of two subsequent treatment modalities. In 3 out of four patients, TBF was successfully treated by endoscopic stenting only. Five patients (38.5 %) died following a septic course with multiple organ failure. CONCLUSIONS: The development of TBF after Ivor-Lewis esophagectomy is always combined with anastomotic leakage of the esophagogastrostomy. Treatment options primarily depend on the vascularization of the gastric conduit, the severity of the concomitant aspiration pneumonia, and the volume of the air leakage.

Genetic damage and repair in human rectal cells for biomonitoring: sex differences, effects of alcohol exposure, and susceptibilities in comparison to peripheral blood lymphocytes.

INTRODUCTION: Cells other than lymphocytes may be preferable as surrogate biomarkers during exposure monitoring. In nutritional toxicology, cells from colorectal tissues are particularly relevant for studying associations between food and cancer. Thus, we have previously shown that colonic cells of males have higher levels of DNA damage than females, which (among other factors) could be due to a higher consumption of alcoholic beverages by males. To test this hypothesis, we have performed a first exploratory study to compare DNA damage in rectal cells from biopsies of male patients with alcohol abuse and of male and female controls. Peripheral blood lymphocytes were additionally monitored to assess systemic exposure loads. METHODS: Cells were isolated and subjected to microgelelectrophoresis +/- endonuclease III to measure DNA breaks and oxidized pyrimidine bases ("comet-assay"). Cell aliquots were treated with H(2)O(2) for 5min in suspension culture and processed immediately or after 60min to determine induced damage and its persistence. RESULTS: Pooled data from subjects of all groups revealed that oxidative DNA damage in rectal cells directly correlated to damage in lymphocytes. Female controls had lower levels of DNA damage than male controls, confirming the previous studies. An unexpected result was that male alcohol abusers had significantly less genetic damage than male controls. Also, repair was detected in lymphocytes of male alcohol abusers and female controls, but not in male controls. CONCLUSION: This is the first time the comet-assay has been used to detect genotoxicity in human rectal cells as a biomonitoring tool. Our pilot study confirms earlier reports on sex differences and indicates a good correlation between damage in rectal cells and damage in lymphocytes and implies that alcohol exposure enhances endogenous defence.

Detection of genotoxic effects in human gastric and nasal mucosa cells isolated from biopsy samples.

To assess genotoxic burdens from chemicals, it is necessary to relate observations in experimental animals to humans. The success of this extrapolation would be increased by including data on chemical activities in human tissues. Therefore, we have developed techniques to assess DNA damage in human gastric and nasal mucosa (GM, NM) cells. Biopsy samples were obtained during gastroscopy from macroscopically healthy tissue of the stomach or from healthy nasal epithelia during surgery. The specimens were incubated for 30-45 min at 37 degrees C with a digestive solution. We obtained 1.5-8 x 10(6) GM cells and 5-10 x 10(5) NM cells per donor, both with viabilities of 80-95%. The cells were incubated in vitro for 1 hr at 37 degrees C with the test compounds added in their appropriate solvents. In GM cells, we studied N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), sodium dichromate (Na2Cr2O7), nickel sulphate (NiSO4), cadmium sulphate (CdSO4), and lindane. In NM cells, lindane was investigated. Each compound was assessed for DNA damaging activity in cells of at least three different human donor samples using the microgel single cell assay. Similar studies were performed with GM and NM cells obtained from Sprague-Dawley rats. We have found human GM cells to be more sensitive to the genotoxic activity of MNNG than rat GM cells (low effective concentration [LEC] = 0.16 and 0.625 micrograms/ml for human and rat, respectively). Human cells were also more sensitive to the cytotoxic/genotoxic activity of NiSO4 (LEC = 5 and 19 mumoles/ml for human and rat, respectively). CdSO4 was genotoxic in human GM cells (LEC = 0.03-0.125 mumoles/ml), whereas no dose-related genotoxicity was observed in rat GM at concentrations up to 0.5 mumoles/ml. In contrast, approximately equal responses regarding genotoxicity and cytotoxicity were observed in rat and human GM for Na2Cr2O7 (0.25-1 mumoles/ml). Lindane, however, was genotoxic in three out of four rat GM but not in human GM cells (0.5-1 mumoles/ml), whereas it was active in both rat and human NM cells. Together with other recently published in vivo findings, our results with lindane can be interpreted according to a parallelogram approach. In view of possible human exposure situations and the sensitivities of the two target tissues from both species, the data imply that lindane will pose a health risk to humans by inhalation but not by ingestion.

Antigenotoxic properties of lactic acid bacteria in vivo in the gastrointestinal tract of rats.

In view of the high incidence of dietary-related tumors, one important research goal is to identify the participating genotoxic carcinogens and the nutritional factors that may counteract their activities. We therefore have further developed a method to assess DNA damage in tumor target tissues of the gastrointestinal tract. Subsequently the prevention of this inducible DNA damage by lactic acid bacteria and by milk products fermented with probiotics was studied as well. The microgel electrophoresis technique was applied to cells of the esophageal, gastric, duodenal, and colonic mucosa. Cells were grouped according to their degree of DNA damage, the simplest measure of which is to discriminate between those with damage (comets) and those without damage. When these cells were isolated from animals treated with a genotoxic carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and exposed to MNNG for 1-24 hours, it was possible to follow the course of genotoxicity throughout the gastrointestinal tract. After the animals were treated with the lactic acid bacteria under study, it was possible to detect antigenotoxic properties as well. The gavage of 10(10) viable Lactobacillus casei cells in 10 ml of 0.9% NaCl per kilogram body weight immediately before the oral administration of MNNG (5 mg/kg body wt) resulted in a reduction of induced DNA damage in gastric and colonic mucosa cells. A sequential treatment schedule was even more effective: when the animals were treated orally with lactic acid bacteria or yogurt (10 ml/kg body wt) in the morning followed by MNNG (7.5 mg/kg body wt) eight hours later and the colon cells were isolated 16 hours later, the percentages of cells remaining intact were distinctly higher in the combination groups (68 +/- 10 and 68 +/- 19 for L. casei and a "Bio" yogurt, respectively) than in the group receiving only MNNG (45 +/- 17). The effect of heating L. casei was studied and was found to yield less clear-cut effects in preventing genotoxicity. The method is an efficient tool to elucidate antigenotoxic properties of food components in vivo in those target tissues actually afflicted by dietary-related tumors.