Genotoxic Effect of Salmonella Paratyphi A Infection on Human Primary Gallbladder Cells.

Carcinoma of the gallbladder (GBC) is the most frequent tumor of the biliary tract. Despite epidemiological studies showing a correlation between chronic infection with Salmonella enterica Typhi/Paratyphi A and GBC, the underlying molecular mechanisms of this fatal connection are still uncertain. The murine serovar Salmonella Typhimurium has been shown to promote transformation of genetically predisposed cells by driving mitogenic signaling. However, insights from this strain remain limited as it lacks the typhoid toxin produced by the human serovars Typhi and Paratyphi A. In particular, the CdtB subunit of the typhoid toxin directly induces DNA breaks in host cells, likely promoting transformation. To assess the underlying principles of transformation, we used gallbladder organoids as an infection model for Salmonella Paratyphi A. In this model, bacteria can invade epithelial cells, and we observed host cell DNA damage. The induction of DNA double-strand breaks after infection depended on the typhoid toxin CdtB subunit and extended to neighboring, non-infected cells. By cultivating the organoid derived cells into polarized monolayers in air-liquid interphase, we could extend the duration of the infection, and we observed an initial arrest of the cell cycle that does not depend on the typhoid toxin. Non-infected intoxicated cells instead continued to proliferate despite the DNA damage. Our study highlights the importance of the typhoid toxin in causing genomic instability and corroborates the epidemiological link between Salmonella infection and GBC.IMPORTANCE Bacterial infections are increasingly being recognized as risk factors for the development of adenocarcinomas. The strong epidemiological evidence linking Helicobacter pylori infection to stomach cancer has paved the way to the demonstration that bacterial infections cause DNA damage in the host cells, initiating transformation. In this regard, the role of bacterial genotoxins has become more relevant. Salmonella enterica serovars Typhi and Paratyphi A have been clinically associated with gallbladder cancer. By harnessing the stem cell potential of cells from healthy human gallbladder explant, we regenerated and propagated the epithelium of this organ in vitro and used these cultures to model S. Paratyphi A infection. This study demonstrates the importance of the typhoid toxin, encoded only by these specific serovars, in causing genomic instability in healthy gallbladder cells, posing intoxicated cells at risk of malignant transformation.

Anastomotic leak predicts diminished long-term survival after resection for gastric and esophageal cancer.

BACKGROUND: Previous studies have reported on the association between perioperative morbidity and diminished oncologic outcomes in patients undergoing resection for colorectal or pancreatic cancer. However, the effect of anastomotic leak (AL) on the survival of patients with gastric or esophageal cancer remains unclear. METHODS: Clinicopathologic data of patients who underwent resection for gastric or esophageal cancer between 2005 and 2012 were assessed, and predictors for overall survival and disease-free survival were identified. In addition, we evaluated the impact of AL on oncologic outcomes. RESULTS: Curative resection for gastric or esophageal cancer was performed in 471 patients. The primary tumor was located in the stomach and esophagus in 53% and 47% of the patients, respectively. Forty-one patients (8.7%) suffered an AL. The AL rate was significantly higher following resection for esophageal cancer compared with the resection for gastric cancer (12.9% vs 5.3%, P = .001). Postoperative mortality (4%) was not significantly associated with the occurrence of AL (4% without AL vs 7% with AL, P = .2). After a median follow-up time of 35 months, the median overall survival and disease-free survival were 101 and 93 months, respectively. Factors associated with worse overall survival in multivariate analysis included AL (P = .001), American Society of Anesthesiologists physical status (P < .0001), advanced Union for International Cancer Control (UICC) stage (P < .0001), and poorly differentiated carcinoma (G3; P = .04). In the multivariate analysis for predictors of disease-free survival, AL (P = .037), advanced UICC stage (P < .0001), poorly differentiated carcinoma (G3; P = .044), and lymphangiosis carcinomatosa (P = .004) were independently associated with a high risk for recurrence. CONCLUSION: AL following resection for gastric and esophageal cancer has a negative prognostic impact on long-term survival, independent from tumor stage and biology. Further investigation of the interactions between AL and the development of tumor recurrence as well as the establishment of standardized perioperative care protocols are necessary for the improvement of outcomes after gastric and esophageal resection.

Response to preoperative chemotherapy predicts survival in patients undergoing hepatectomy for liver metastases from gastric and esophageal cancer.

BACKGROUND: The role of hepatectomy for patients with liver metastases from gastric and esophageal cancer (GELM) is not well defined. The present study examined the morbidity, mortality, and long-term survivals after liver resection for GELM. METHODS: Clinicopathological data of patients who underwent hepatectomy for GELM between 1995 and 2012 at two European high-volume hepatobiliary centers were assessed, and predictors of overall survival (OS) were identified. In addition, the impact of preoperative chemotherapy for GELM on OS was evaluated. RESULTS: Forty-seven patients underwent hepatectomy for GELM. The primary tumor was located in the stomach, cardia, and distal esophagus in 27, 16, and 4 cases, respectively. Twenty patients received preoperative chemotherapy before hepatectomy. After a median follow-up time of 76 months, 1-, 3-, and 5-year OS rates were 70, 37, and 24%, respectively. Postoperative morbidity and mortality rates were 32 and 4%, respectively. Outcomes were comparable between the two centers. Preoperative chemotherapy for GELM (5-year OS: 45 vs 9%, P = .005) and the lack of posthepatectomy complications (5-year OS: 34 vs 0%, P < .0001) were significantly associated with improved OS in univariate and multivariate analyses. When stratifying OS by radiologic response of GELM to preoperative chemotherapy, patients with progressive disease despite preoperative treatment had significantly worse OS (5-year OS: 0 vs 70%, P = .045). CONCLUSION: For selected patients with GELM, liver resection is safe and should be regarded as a potentially curative approach. A multimodal treatment strategy including systemic therapy may provide better patient selection resulting in prolonged survival in patients with GELM undergoing hepatectomy.

Salvage surgery due to bowel obstruction in advanced or relapsed ovarian cancer resulting in short bowel syndrome and long-life total parenteral nutrition: surgical and clinical outcome.

OBJECTIVE: Salvage surgery for patients with highly advanced or relapsed epithelial ovarian cancer (EOC) complicated by bowel obstruction and resulting in short bowel syndrome (SBS) constitutes a therapeutic dilemma. Our aim was to evaluate surgical and clinical outcome in these highly palliative situations. METHODS: We evaluated all patients with EOC who underwent salvage extraperitoneal en bloc intestinal resection with terminal ileostomy or jejunostomy resulting in SBS and total parenteral nutrition owing to bowel obstruction between May 2003 and January 2012 in our institution. RESULTS: Thirty-seven patients were identified (median age, 58 years; range, 22-71 years), 3 (8.1%) with primary and 34 (91.6%) with relapsed EOC. Five patients (13.5%) were platinum sensitive. Median residual intestinal length was 70 cm (range, 10-180 cm); 21 patients (56.8%) had a residual intestinal length less than 1 m. Operative 30-day mortality and major morbidity rates were 10% and 51%, respectively. Median overall survival was 5.6 months (range, 0.1-49 months). One-year and 2-year overall survival rates were 18.3% (95% confidence interval, 5.1%-31.5%) and 8.1% (95% confidence interval, 0%-18.0)%, respectively. Within a median follow-up period of 5 months (range, 0.2-49 months), 4 patients (10.8%) are still alive. No significant differences in survival were seen between patients with or without major complications, tumor residuals, or residual intestinal length of less than 1 m versus greater than 1 m. CONCLUSIONS: Salvage palliative surgery in EOC due to bowel obstruction resulting in SBS and in need of long-life total parenteral nutrition is associated with high morbidity rates and low overall survival. These surgeries should ideally be performed only in a multidisciplinary setting with adequate infrastructure and possibility of home care support. Conservative management should be the route of action in the absence of acute abdomen or intestinal perforation.

Formation of a chronic pain syndrome due to mesh shrinkage after laparoscopic intraperitoneal onlay mesh (IPOM).

The case of a 58-year-old male patient who developed a chronic pain syndrome after laparoscopic intraperitoneal onlay mesh for treatment of a large symptomatic umbilical hernia combined with rectus diastasis is reported. Twelve months after an uncomplicated initial surgery, the patient presented with progressive signs of a foreign body sensation and pain in the anterior abdominal wall. Computed tomography examination revealed no pathologic findings but a marked shrinkage of the mesh implant. Because of further progressive symptoms, explorative laparotomy was performed. Mesh shrinkage and adhesions with a surrounding chronic tissue reaction were found as the cause of the pain syndrome. This case demonstrates a case of a chronic pain syndrome due to mesh shrinkage 12 months after initial ventral hernia repair. Mesh shrinkage should therefore be taken into consideration in patients with progressive pain chronic syndromes after laparoscopic ventral hernia repair.

Prolyl hydroxylase domain 2 protein is a strong prognostic marker in human gastric cancer.

OBJECTIVE: According to recent research, prolyl hydroxylase domain 2 protein (PHD2) plays an important role in human carcinogenesis by inducing neovascularization and tumor growth. The aim of this study was to evaluate PHD2 expression patterns in primary gastric adenocarcinoma and to test for a potential predictive value of PHD2 expression in gastric cancer patients. METHODS: In a total of 121 patients, PHD2 expression was investigated by immunohistochemistry in paraffin-embedded tissue and correlated with clinicopathological parameters and patient survival. RESULTS: 64 of 121 gastric carcinomas (52.9%) showed PHD2 expression in tumor cell cytoplasm. In univariate analysis, PHD2-negative patients had a significantly shortened survival in comparison with PHD2-postive patients (19.5 vs. 32.7 months, p = 0.02). Independent prognostic significance could be shown in multivariate analysis for PHD2 expression (p = 0.005), age at diagnosis (p = 0.012), lymph node status (p = 0.016) and R status (p = 0.026). CONCLUSION: Cytoplasmic PHD2 expression has a strong impact on survival in gastric cancer patients. Therefore, PHD2 represents a useful predictive biomarker in the evaluation of high-risk patients. Furthermore, these results underline the importance of PHD2 in gastric carcinogenesis and may identify PHD2 as a putative target for future gastric cancer therapy.

First surgical experience of intraperitoneal treatment with the trifunctional antibody catumaxomab (anti-EpCam x anti-CD3) for epithelial ovarian cancer.

AIM: Intraperitoneal (i.p.) treatment with the trifunctional antibody catumaxomab is a novel promising option in the clinical management of advanced or recurrent epithelial ovarian cancer (EOC). As yet, no data exists sregarding the surgical experience after i.p. catumaxomab application. Therefore we analyzed the surgical outcome of EOC patients, previously treated with i.p. catumaxomab, with special focus on the effect on adhesion formation and morbidity. PATIENTS AND METHODS: We conducted a retrospective evaluation of patients with EOC, who were previously treated with catumaxomab, either at time of primary cytoreduction (n=6) or due to malignant ascites in the recurrent situation (n=4), and who underwent surgery due to various indications between 01/2007 and 03/2010. Surgical outcome, grade of adhesions and operative morbidity were analyzed based on surgical reports and a validated intraoperative documentation tool 'Intraoperative Mappinf of Ovarian Cancer'. RESULTS: Ten patients with EOC (FIGO stage III-IV; median age 68 years; range: 45-77 years) were evaluated. The mean time between catumaxomab treatment and surgery was 187 days (range: 8-481 days). Mean operation-time was 185 minutes (range:69-32). The indications for surgery were as follows: 3 patients due to anastomotic insufficiency after primary tumor debulking; 2 patients due to secondary tumor debulking; 4 patients due to ileus in recurrent EOC; and 2 patients for restoring intestinal continuity. At the post-catumaxomab surgery 7 patients presented massive intraoperative adhesion grade 3 (score system 0-3), while 3 patients developed repeated abscesses. Four out of the six patients operated due to recurrent EOC, presented extensive tumor load with severe peritoneal carcinosis. Nevertheless, none of the relapsed patients had at surgery ascites >500 ml. CONCLUSION: Surgery after i.p. catumaxomab appears feasible, however, larger prospective evaluations are warranted to assess its true impact on adhesion formation and postoperative morbidity.

Clinical outcome of tertiary surgical cytoreduction in patients with recurrent epithelial ovarian cancer.

BACKGROUND: The value of tertiary cytoreductive surgery (TCS) on overall survival (OS) of patients with relapsed epithelial ovarian cancer (ROC) is not well defined. Aim of the present study was to evaluate the operative and clinical outcome after TCS. METHODS: We systematically evaluated all consecutive patients undergoing TCS. Tumor dissemination pattern, operative morbidity, residual tumor, and survival are described based on a validated intraoperative documentation tool. Predictors of survival and complete tumor resection are analyzed with Cox regression or logistic regression models. RESULTS: Between October 2000 and December 2008, 135 patients (median age, 51 years; range, 22-80 years) of mainly initial FIGO stage ≥ III (106 patients, 78.5%) were evaluated. In 53 patients (39.3%) a complete tumor-resection was obtained. The 1-month operative mortality was 6%. During a median follow-up period of 9.6 months (range, 0.1-75 months), 78 patients (57.8%) died, while 52 patients (38.5%) experienced a further relapse. Median OS was 19.1 months for the total collective (95% confidence interval [95% CI], 14.84-23.35). Median OS was 37.8 months (95% CI, 12.7-62.7) for patients without residual tumor; versus 19.0 months (95% CI, 9.8-28.2) for residual tumor ≤ 1 cm and 6.9 months (95% CI, 3.05-10.7) for residual tumor > 1 cm (P < .001). The presence of peritoneal carcinomatosis did not seem to significantly affect OS. Complete tumor resection was identified as the strongest predictor of OS. Other independent predictors of OS were interval to primary diagnosis ≥ 3 years (hazard ratio [HR], 0.28; 95% CI, 0.14-0.59) and serous papillary histology (HR, 0.23; 95% CI, 0.09-0.56). A total of 42 patients (31.1%) presented at least 1 major complication. Multivariate analysis identified tumor involvement of the middle abdomen and peritoneal carcinomatosis as independent predictors of complete tumor resection. CONCLUSIONS: Postoperative tumor residual disease remains the strongest predictor of survival even in TCS setting. To identify the optimal candidates for TCS, the predictive value of ascites and peritoneal carcinomatosis should be confirmed by future prospective trials.

Primary versus interval debulking surgery in advanced ovarian cancer: results from a systematic single-center analysis.

OBJECTIVE: To evaluate the difference in operative and clinical outcome for patients with primary advanced ovarian cancer (AOC) after optimal primary debulking surgery (PDS) versus interval debulking surgery (IDS). METHODS: Tumor dissemination pattern and surgical outcome, as defined by morbidity, progression-free (PFS) survival and overall survival (OS) were systematically analyzed in AOC patients who underwent surgery in our institution between September 2000 and August 2009. Overall survival and PFS were calculated by Kaplan-Meier curves. Univariate and Cox regression analysis were performed to identify the impact of IDS on surgical outcome and survival. RESULTS: Overall, 372 consecutive patients with histologically proven AOC (FIGO [International Federation of Gynecology and Obstetrics] stage III/IV) were evaluated. Forty patients (10.8%) underwent IDS after a median of 5 cycles (range, 2-6 cycles) platinum- and taxane-based chemotherapy, and 332 patients (89.2%) underwent PDS. Patients who underwent IDS had a significantly lower rate of tumor involvement of the lower (78.9% vs 98.8%; P < 0.001) and middle abdomen (68.4% vs 83.1%; P = 0.044) compared with PDS patients. During IDS, a significantly higher probability for complete tumor resection occurred when compared with PDS (85% vs 58.7%; P = 0.02) by equivalent rates of operative complications (36.4% vs 36.5%; P = 1.00). However, mean PFS was significantly reduced in IDS patients (14.6 vs 33.2 months; P < 0.001). Mean OS was also higher in PDS patients, but this reached a statistical significance only when complete tumor resection was obtained (65.4 vs 37.9 months; P = 0.005). Multivariate analysis identified that IDS was associated with an unfavorable OS and PFS. CONCLUSIONS: : It seems that PDS has a more favorable outcome than IDS on both OS and PFS in AOC patients, even though IDS leads to significantly higher rates of complete tumor resection.

The cost of graft failure and other severe complications after liver transplantation - experience from a German Transplant Center.

BACKGROUND: Orthotopic liver transplantation (OLT) is a cost consuming therapy for only a relatively small number of patients. The aim of the present study was to explore specific cost drivers in a German transplant centre. MATERIAL/METHODS: The analysis was done by combination of two separate databases with prospective clinical and case-related cost data. Several complications were compared for their impact on length of stay and on costs by uni- and multivariate analysis. RESULTS: The median cost of OLT was 30,120 Euro (range 18,330-397,450; mean 52,570), the median reimbursement was 33,227 Euro (range 30,879-344,142; mean 59,628) with a significant in-between correlation of r=0.951 (P<0.0001). Post-transplant complications significantly raised cost, with an increase of 62% by vascular complications, 175% by renal failure, 207% by biliary leakage, 227% by graft failure and 234% by sepsis. Multivariate analysis revealed reoperation, hypotension and graft failure as independent cost factors. Graft failure contributed for mean additional costs of 105,911 Euro (95%CI 75,695 to 136,126). In particular, the cost of ICU therapy increased from 16,884 Euro up to 92,239 Euro (P<0.0001). CONCLUSIONS: Cost and reimbursement of OLT are relatively moderate in Germany. Graft failure was identified as the major cost-determining factor. The cost impact of post-transplant complications is mainly caused by the length of stay.

Establishing Nd:YAG laser-based left lateral liver resection: comparison of open, laparoscopic, and hand-assisted approach in a porcine Model.

INTRODUCTION: Aim of this study was to assess the feasibility and safety of a 1064 nm Nd:YAG laser for left lateral liver resection in a porcine model. Laparoscopy and hand-assisted laparoscopic surgery were evaluated and compared with conventional open surgery. METHODS: Animals were randomized for open, hand assisted, and laparoscopic left lateral liver lobe resection. Primary endpoints were intraoperative blood loss, dissection time, laboratory changes, and abdominal wall adhesions. In addition intraoperative cardiopulmonary data, postoperative clinical parameters, and necropsy findings were analyzed. RESULTS: Liver resection was successful in all animals without intraoperative or postoperative mortality. Laparoscopic dissection time was significantly increased. Average blood loss was 340 mL for open surgery and 320 mL for hand-assisted surgery. Blood loss during laparoscopy was significantly smaller with a mean of 180 mL. Postmortem findings revealed extensive adhesions for open surgery whereas hand assisted and laparoscopic animals showed limited adhesions in the upper abdomen. CONCLUSIONS: Nd:YAG laser-based liver resection is a potentially safe and feasible technique. The minimal access approaches show comparable results to the open technique with reduced abdominal trauma and less adhesions. Laparoscopy was more time consuming but showed reduced blood loss compared with both other groups.

Management of esophageal perforations.

BACKGROUND: Esophageal perforations remain a life-threatening event requiring rapid diagnosis and treatment. Surgical repair and interventional endoscopic or conservative treatment are the common treatment methods. METHODS: From 1998 to 2006, the authors retrospectively analyzed 62 patients treated for esophageal perforation. Data were evaluated for cause of perforation, symptoms, therapeutic regimen, complications, and mortality. RESULTS: The causes of perforation were iatrogenic or suicidal (n = 33) or spontaneous (n = 29). In the first group, the causes were dilation of stenosis (n = 16), endoscopy (n = 7), transesophageal echography (n = 4), ingestion of acid or leach (n = 2), intubation (n = 2), ingestion of a foreign body (n = 1), and migration of a screw after osteosynthesis (n = 1). The spontaneous perforations were caused by tumors (n = 19), Boerhaave syndrome (n = 6), unknown origin (n = 3), and Barrett's ulcer (n = 1). The most frequent symptoms were dysphagia (n = 50), pain (n = 35), fever (n = 24), and vomiting (n = 18). At the time of perforation, 28 patients presented with cancer. Of these 28 patients, 18 had esophageal cancer. The treatment included surgery (n = 32), which consisted of double-layer suture (n = 26) or esophageal resection (n = 6). A total of 30 patients were treated interventionally with a stent (n = 21), clips (n = 1), or without further measures (n = 8). The patients in the surgery group presented with severe primary and postoperative general conditions including renal failure (25%), respiratory insufficiency (65.5%), and need for catecholamines (62.5%). This multiorgan involvement was found only occasionally in the conservative group. The overall hospital mortality rate was 14.5%, involving 9 patients (5 in the surgery group and 4 in the conservative group). Early treatment led to better survival than late treatment with a delay exceeding 24 h. CONCLUSION: The treatment method still must be chosen on an individual basis. It appears that surgical treatment is necessary in cases of severe general conditions. The data from this study show that surgical repair and conservative treatment may be used successfully. The best outcome was obtained after immediate treatment.

Initial results of MR-guided liver resection in a high-field open MRI.

BACKGROUND: The goal of this study was to evaluate high-field open magnetic resonance imaging (MRI) for intraoperative real-time imaging during hand-assisted laparoscopic liver resection. MR guidance has several advantages compared to ultrasound and may represent a future technique for abdominal surgery. Various MRI-safe and -compatible instruments were developed, tested, and applied to realize minimally invasive liver surgery under MR guidance. As proof of the concept, liver resection was performed in a porcine model. METHODS: All procedures were conducted in a 1.0-T open MRI unit. Imaging quality and surgical results were documented during three cadaveric and two live animal procedures. A nonferromagnetic hand port was used for manual access and the liver tissue was dissected using a Nd:YAG laser. RESULTS: The intervention time ranged from 126 to 145 min, with a dissection time from 11 to 15 min. Both live animals survived the intervention with a blood loss of 250 and 170 ml and a specimen weight of 138 and 177 g. A dynamic T2W fast spin-echo sequence allowed real-time imaging (1.5 s/image) with good delineation of major and small hepatic vessels. The newly developed MR-compatible instruments and camera system caused only minor interferences and artifacts of the MR image. CONCLUSION: MR-guided liver resection is feasible and provides additional image information to the surgeon. We conclude that MR-guided laparoscopic liver resection improves the anatomical orientation and may increase the safety of future minimally invasive liver surgery.

Evidence-based perioperative management: strategic shifts in times of fast track surgery.

Changes in perioperative management is an ever evolving subject. The primary aim is to improve patient care and more recently to increase economic efficacy. Data from various randomized studies have caused a shift from traditional care concepts towards evidence based multimodal treatment strategies. They may lead to dramatic changes in perioperative patient care such as the routine use of nasogastric decompression, mechanical bowel preparation and established nutrition schemes. Further aspects of modern perioperative patient care include epidural analgesia, antibiotic prophylaxis, intraoperative fluid management and early mobilization. It has been generally accepted that these multimodal treatment concepts also known as "fast track surgery" show no differences in patient morbidity while significantly reducing patient discomfort and duration of hospitalization. However, despite the evidence-based superiority, widespread implementation has not yet occurred. The aim of this review is to highlight and discuss current changes and to show future perspectives of perioperative treatment strategies.

Indications for hand-assisted laparoscopic radiofrequency ablation for liver tumors.

PURPOSE: Radiofrequency ablation has established itself as the preferred treatment for irresectable liver tumors. It can be performed either percutaneously, laparoscopically, or by open surgery. The choice of approach depends on the patient and tumor-related variables. The laparoscopic approach appears to be the safest and most effective method for small tumors on the liver surface. It also provides additional information on the intrahepatic tumor burden with the use of intraoperative ultrasound and staging laparoscopy. Furthermore, the pneumoperitoneum reduces the flow of the portal vein and increases the efficacy of the ablation. Depending on the location of the tumor, mobilization of the liver or lysis of adhesions from previous surgery can require open surgery. Our aim was to study the combined use of laparoscopy and laparotomy by using hand-assisted laparoscopic radiofrequency ablation. MATERIALS AND METHODS: We performed hand-assisted laparoscopy to ablate nine tumors in seven patients, enabling us to combine most of the advantages of laparoscopy and open surgery. The radiofrequency ablation was technically simple to perform. A laparoscopy of the entire abdominal cavity and a thorough examination of the entire liver via ultrasound was also performed. RESULTS: The electrode was accurately placed in all patients. In four patients, a complete mobilization of the right lobe was performed to obtain the easiest possible access to the tumor. In three patients, severe adhesions from previous surgeries were removed prior to insertion of the laparoscopic tools. The ablation was completed safely and successfully in all patients. CONCLUSION: Our overall impression of the hand-assisted laparoscopic approach is that it seems to have a major advantage in comparison with simple laparoscopy, specifically for adhesions from previous surgeries and when the right liver lobe requires mobilization. Also, needle placement seems to be far more accurate than with simple laparoscopy.