Classification of the oesophageal perforation.

OBJECTIVES: Esophageal perforations are a complex clinical scenario that have been poorly studied. To date, there is no grading of esophageal perforations, the reason being that the outcome is very heterogeneous, because the perforation is very heterogeneous. A grading of the severity of the perforation may guide treatment, and could ultimately affect morbidity and mortality. METHODS: The observation period of the study was four years. All patients with a perforation of the esophagus aged 18 to 90 years were included. All anastomotic insufficiencies or fistulas after surgery of the esophagus were excluded. The cause of the injury and the time interval between the event and the start of therapy were analyzed. The severity of each perforation was classified based on the results of a diagnostic CT scan, gastroscopy as well as clinical and laboratory findings. Therapy and signs of infection were evaluated. Endpoints of the study were patient recovery or death. The study was conducted as a retrospective single-center study at a university hospital of Düsseldorf. The study has been approved by the review board. Patients gave their informed consent before data collection. All data were analyzed using SPSS 29 (IBM SPSS Statistics software). RESULTS: Age, gender and cause of the esophageal perforation did not impact significantly on overall survival. The duration of injury > 24 h (p = 0.01), presence of mediastinitis (p = 0.01) and necrosis of the esophagus (p = 0.02) were associated with an unfavorable outcome. The correlation of the clinical grading of the severity of the perforation based on the endoscopic, radiological and clinical findings with the overall survival of patients was significant. Patients categorized into the four grades of severity (I-IV) had an overall survival of 100%, 100%, 70% and 50%, respectively. CONCLUSION: The severity of esophageal perforations can be systematically rated grades I to IV based on the radiological, endoscopic and clinical findings at diagnosis. Due to the grading and its correlation to the overall survival, a comparison of patients, their treatment and outcome becomes possible. In future, the grade of a perforation may guide treatment, and therefore affect morbidity and mortality.

Effectiveness of Video-Assisted Thoracoscopic Surgery with Bullectomy and Partial Pleurectomy in the Treatment of Primary Spontaneous Pneumothorax-A Retrospective Long-Term Single-Center Analysis.

Background: Video-assisted thoracoscopic surgery (VATS) with bullectomy and partial pleurectomy (VBPP) is an increasingly used and well-established surgical treatment for primary spontaneous pneumothorax (PSP). However, reports on its effectiveness and long-term outcomes are limited. The aim of this study was to assess and compare long-term recurrence rates following VBPP and chest tube (CT) treatment and to identify potential risk factors for disease recurrence in patients with PSP. Methods: A total of 116 patients treated either by VBPP or CT were included in this study. Long-term recurrence rates and associations between clinical parameters and recurrence of pneumothorax were analyzed. Results: Sixty-two patients (53.4%) underwent VBPP, whereas 54 (46.6%) patients underwent CT treatment only. During a median follow-up period of 76.5 months, VBPP patients experienced a significantly lower recurrence rate compared to CT patients (6/62 vs. 35/54; p < 0.0001). CT treatment (VBPP vs. CT; p < 0.001) and a large initial pneumothorax size (Collins < 4 vs. Collins ≥ 4; p = 0.018) were independent risk factors for pneumothorax recurrence. Conclusion: VBPP is an effective and safe surgical treatment for PSP. Therefore, patients with a large pneumothorax size might benefit from VBPP, as they are at high risk for disease recurrence.

Successful evaluation of a new animal model using mice for esophageal adenocarcinoma.

INTRODUCTION: For the better understanding of the pathophysiological events occurring in the sequence inflammation-metaplasia-carcinoma in esophageal adenocarcinoma, an animal model would be desirable. In the past, several rat models have been used yielding conflicting results. Some demonstrated a sequence similar to the human situation whereas others failed to initiate true esophageal adenocarcinoma or even Barrett's metaplasia. For the study of the molecular events involved in the carcinogenesis of Barrett's carcinoma, a mouse model would be much more promising since most of the genetically altered animals are mice. However, as of now no such model exists, in the past predominately due to the high mortality involved with the surgical procedure to create a mixed duodenogastric reflux. METHODS: Forty BALB-C mice weighing between 22 and 25 g underwent an esophagojejunostomy. The animals were sacrificed at 3, 4, and 5 months. Pathological evaluation was performed with HE staining. RESULTS: Overall mortality was 17%. However, mortality within the first ten animals was 30%. Reasons were technical problems with the anastomosis, opening of the pleural cavity, or bleeding events. All animals had a severe esophagitis regardless of the time. Intestinal metaplasia could be found in 60% of the animals after 4 months and esophageal adenocarcinoma in 55% after 5 months. One animal showed multiple lung metastases. CONCLUSION: After a certain learning curve esophagojejunostomy is feasible in mice with an acceptable mortality rate and leads to esophageal adenocarcinoma.

The diagnostic challenge of mediastinal sarcoidosis accompanying esophageal cancer.

The primary staging of an oesophageal cancer can be difficult, if accompanied by sarcoidosis. In these patients endosonography, CT and PET may not be sufficient for staging purposes concerning lymph node and distant metastases. In these special cases operative biopsies of enlarged lymph nodes and unclear pulmonary nodules have to be obtained. In connection with the radiographic examinations the histopathological results of the biopsies contribute to further precise staging and help to decide on a curative versus a palliative therapy concept.

Pancreatic resection for metastatic renal cell carcinoma: a single center experience and review of the literature.

Renal cell carcinoma (RCC) is one of the few tumour types metastatic to the pancreas. In order to evaluate the outcome following resection of pancreatic metastases of RCC a retrospective review of surgical patients was performed. The initial histopathological staging, disease-free interval, surgical outcome and survival were evaluated. The median interval between nephrectomy and pancreatic resection was 9 years. Six out of the ten patients preoperatively presented with severe complaints caused by the pancreatic metastasis, such as pain, chronic pancreatitis, jaundice and gastrointestinal bleeding. Severe postoperative complications only occurred in two patients, who presented in a deteriorated condition preoperatively. The median follow-up was 56 months, in 3 patients more than 5 years. Although the spontaneous course of RCC metastases can be favourable, the complete resection of pancreatic metastases for patients in good physical condition is suggested if possible. Moreover, good palliation of symptoms in patients with long-term survival can be achieved.

Preventively enteral application of immunoglobulin enriched colostrums milk can modulate postoperative inflammatory response.

Several studies demonstrated acute inflammatory response following traumatic injury. Inflammatory response during surgical interventions was verified by a significant increase of endotoxin plasma levels and a decrease of the endotoxin neutralizing capacity (ENC). However, the incidence of elevated endotoxin levels was significantly higher (89%) than detected bacterial translocation (35%). Thus parts or products of Gram-negative bacteria seem to translocate more easily into the blood circulation than whole bacteria. Along with the bacterial translocation, the inflammatory response correlated directly with the severity of the surgical intervention. In comparison after major and minor surgery Interleukin-6 (IL-6) and C-reactive protein (CRP) was also significantly different. Similar effects in mediator release were shown during endovascular stent graft placement and open surgery in infrarenal aortic aneurysm. Open surgery demonstrated a significant stronger endotoxin translocation and a decrease of ENC. Strategies to prevent translocation seem to be sensible. Colostrum is the first milk produced by the mammary glands within the first days after birth. It contains a complex system of immune factors and has a long history of use in traditional medicine. Placebo-controlled studies verified that prophylactic oral application of immunoglobulin-enriched colostrum milk preparation diminishes perioperative endotoxemia, prevents reduction of ENC and reduces postoperative CRP-levels, suggesting a stabilization of the gut barrier. This effect may be caused by immunoglobulin transportation by the neonatal receptor FcRn of the mucosal epithelium.In conclusion, there is an association of perioperative endotoxemia and the subsequent increase in mediators of the acute phase reaction in surgical patients. A prophylactic oral application of colostrum milk is likely to stabilize the gut barrier i.e. reduces the influx of lipopolysaccharides arising from Gram-negative bacterial pathogens and inhibits enterogenic endotoxemia. This appears to be a major mechanism underlying the therapeutic effect in patients at risk for Gram-negative septic shock.

Differentiated surgical treatment of rectovaginal fistulae.

OBJECTIVE: Rectovaginal fistulae (RVF) are a serious and debilitating problem for patients and a challenge for the treating surgeons. We present our experiences in the surgical treatment of these patients. METHODS: Study population consisted of 22 consecutive patients (range 26-70 years) with RVF treated in our department between 2003 and 2009. 13 RVF were observed after colorectal or gynaecological surgery, 3 occurred after radiotherapy, 2 due to tumour infiltration, 4 because of local inflammation (3x diverticultis, 1x ulcus simplex recti). The RVF was classified in all patients before treatment as either 'low' or 'high'. RESULTS: Local procedures (transvaginal excision, preanal repair) as initial treatment were performed in 9 patients with low fistula. In 13 cases with high fistula an abdominal approach was performed to close the fistula. A recurrence was observed in 8/22 cases (36%), which were treated by a gracilis flap (n=2), a bulbospongiosus composite (n=1), a second abdominal approach (n=4), and a re-local excision (n=1). Ultimatively, in 19 cases the defect healed but in 3 patients the RVF persisted. CONCLUSIONS: Most important predictor of healing/failure is etiology followed by localization and recurrence of the RVF. Local (preanal, transvaginal) procedures are suitable for low RVF, whereas abdominal surgery is necessary in high RVF. In recurrent RVF, muscle flaps are promising procedures.

The simultaneous expression of both ephrin B3 receptor and E-cadherin in Barrett`s adenocarcinoma is associated with favorable clinical staging.

BACKGROUND: In intestinal epithelium, tyrosine kinase receptor Ephrin B3 (Eph B3) maintains the architecture of the crypt-villus axis by repulsive interaction with its ligand ephrin-B1. While loss of Eph B3 is linked to colorectal cancer initiation, overexpression of Eph B3 in cancer cell lines inhibits growth and induces functional changes with decreased mesenchymal and increased epithelial markers. In order to study this tumor suppressor activity of Eph B3 in esophageal adenocarcinoma we analyzed the simultaneous expression of Eph B3 and E-cadherin in both the healthy esophagus and in Barrett's carcinoma. METHODS: Simultaneous expression of Eph B3 and E-cadherin was investigated in samples from 141 patients with Barrett's carcinoma and from 20 healthy esophagi using immunhistology and quantitative PCR. Results from healthy squamous epithelium, Barrett's metaplasia and staging-specific esophageal adenocarcinoma were correlated. RESULTS: A significantly reduced E-cadherin mRNA expression could be detected in adenocarcinoma compared to dysplasia. The immunhistological activity of E-cadherin and Eph B3 was reduced in adenocarcinoma compared to dysplasia or healthy esophageal mucosa. The intracellular E-cadherin distribution changed significantly from the cytoplasm to the membrane, when the Eph receptor was simultaneously expressed. Simultaneous expression of E-cadherin and Eph B3 showed a significant inverse correlation to tumor stage. CONCLUSIONS: We present novel evidence of the tumor suppressor activity of Eph B3 in esophageal adenocarcinoma possibly due to the impact on redistribution of cellular E-cadherin to the membrane. Our results suggest that this effect might play a role in the dysplasia-adenocarcinoma sequence, the infiltrative growth pattern and the development of lymph node metastases.

Down-regulation of CDH1 is associated with expression of SNAI1 in colorectal adenomas.

INTRODUCTION: Down-regulation of E-cadherin (CDH1) and epithelial-mesenchymal transition (EMT) are considered critical events for invasion and metastasis of colorectal carcinoma. Here we tested whether the important regulators of E-cadherin expression SNAI1 and TWIST1 are already detectable in human colorectal adenomas. METHODS: RNA was extracted from a set of randomly selected formalin-fixed and paraffin-embedded (FFPE) colorectal adenomas (n = 41) and normal colon mucosa (n = 10). Subsequently mRNA expression of CDH1, CDH2, SNAI1 and TWIST1 was analysed by quantitative RT-PCR analysis. CDH1 as well as SNAI1 protein expression were assessed by immunohistochemistry (IHC). RESULTS: SNAI1 mRNA was expressed in 78% (n = 32/41), TWIST1 mRNA in 41% (n = 17/41) and CDH2 mRNA in 41% (n = 17/41) of the colorectal adenoma tissue, while normal colon mucosa was negative for these transcription factors. We found a significant correlation between reduced CDH1 and the presence of SNAI1 mRNA expression and for combined SNAI1 and TWIST1 mRNA expression, respectively. A correlation between CDH2 mRNA expression and reduced CDH1 expression was not observed. We confirmed the relationship between SNAI1 expression and reduced E-cadherin expression on the protein level via IHC. CONCLUSION: Our data show that SNAI1 and Twist1 are already expressed in benign precursor lesions of colorectal cancer and that SNAI1 expression was significantly correlated with lower expression of CDH1. Whether these findings reflect true EMT and/or are a sign of a more aggressive biology need to be investigated in further studies.

The amount of neoadjuvant chemotherapy for Barrett's carcinoma does not correlate with long-term survival.

INTRODUCTION: Several studies have proven an ameliorated prognosis after a neoadjuvant therapy for locally advanced Barrett's carcinoma in case of response. The necessary amount of neoadjuvant chemotherapy within a multimodal therapy concept with following oesophageal resection has never been evaluated so far. METHODS: The clinical course of 122 patients with Barrett's carcinoma, who all underwent a neoadjuvant chemotherapy with cisplatin, five fluorouracil and leucovorin and following oesophagectomy, was reviewed. The pretherapeutic clinical and postoperative histopathological staging, histopathological response, clinical course, recurrence rates and long-term survival were retrospectively analysed and compared to the data of 30 patients, who were included in the same multimodal therapy concept, but who had to cease the chemotherapy early because of toxicity. RESULTS: Postoperative pathological staging showed that the response rate correlates with the N and R status. The responding patients benefit from longer survival. Comparing the two subgroups, we could not find a significant difference in response rate, tumour staging, resection rate, long-term survival or pattern of recurrent disease. However, postoperative morbidity and mortality did not correlate with severe chemotherapy-induced toxicity. CONCLUSIONS: This is the first study on the necessary number of chemotherapy cycles in terms of a neoadjuvant therapy for Barrett's carcinoma. We could show a similar downstaging effect, a good histopathological response and a comparable ameliorated long-term survival of patients with one compared to patients with three chemotherapy cycles. A biological selection seems to determine the course of the disease already at this early stage.

Neoadjuvant chemotherapy in Barrett's carcinoma - prognosis and response prediction.

In spite of endoscopic surveillance programs, 90% of patients initially presenting with Barrett's carcinoma have locally advanced disease. In these patients, preoperative chemotherapy increases the chance of a curative resection in responding patients. Unfortunately, response occurs in only 50% of patients after chemotherapy with cisplatin, 5-fluorouracil and leucovorin. Response prediction seems to be possible by measuring metabolic activity by positron emission tomography (PET) scan. Differentiation of responders from non-responders even before starting chemotherapy might be possible using microarray technology and immunhistology in tumour biopsies. A pattern of at least two-fold differentially regulated genes comparing responding and non-responding oesophageal adenocarcinomas was identified. The strongest difference can be seen for tumour necrosis factor, polyribonucleotide nucleotidyltransferase and the ephrin-B3-receptor. In conclusion, our experience suggests that it may be possible to characterize patients responding to chemotherapy by PET two weeks after starting the chemotherapy or even before treatment using customized microarray analysis.

Interleukin-10 and -12 predict chemotherapy-associated toxicity in esophageal adenocarcinoma.

INTRODUCTION: Chemotherapy-associated mucositis often prevents completion of an entire chemotherapy cycle. The underlying pathophysiology of chemotherapy-associated mucositis has not been well established. The individual immunologic predisposition of patients seems to play an important role. METHODS: One hundred fifty-six patients with locally advanced or metastatic esophageal adenocarcinoma received neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and leucovorin followed by resection. Before the neoadjuvant therapy, monocytes were isolated from blood samples and were stimulated with lipopolysaccharide and interferon. An enzyme-linked immunosorbent assay was used to measure interleukin (IL)-10 and -12 levels and correlated with patients' clinical course. RESULTS: Twenty-two patients (14,1%) developed grade III to IV mucositis (according to the NCI-Common toxicity criteria scales) within the neoadjuvant chemotherapy. Pretherapeutic low IL-10 (<24.1 pg/ml) and high IL-12 (>5500 pg/ml) levels were significantly associated with mucositis causing a therapy interruption or even cessation. Patients with high IL-10 (>43.6 pg/ml) and low IL-12 (<4408.5 pg/ml) levels had an uneventful neoadjuvant chemotherapy. CONCLUSIONS: Pretherapeutic individual monocyte function is correlated with the development and the grade of chemotherapy induced mucositis. This knowledge might help us in predicting the grade of mucositis and in understanding the genesis regarding the association to pro- and anti-inflammatory effects of monocyte cytokines.

Microarray-based response prediction in esophageal adenocarcinoma.

PURPOSE: In locally advanced (uT(3), N(+)) adenocarcinomas of the esophagus, neoadjuvant chemotherapy improves patient outcome. However, only a subgroup of patients responds. Therefore, in the present study, we evaluated whether the response to neoadjuvant chemotherapy can be predicted by a pretreatment tumor biopsy analysis. EXPERIMENTAL DESIGN: Biopsies of 47 patients with locally advanced (uT(3), N(+)) adenocarcinoma of the esophagus were obtained during primary staging. All patients underwent neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and leucovorin and subsequent resection of the esophagus. Biopsies were used for microarray analysis. The predominance of tumor cells within the specimens was >70%. Affymetrix U133 plus 2.0 gene chips with 54675 probe sets were used. A statistical comparison of patients responding to chemotherapy versus nonresponding patients was done. All patients were examined with immunohistology against Ephrin B3 receptor and Ki-67. RESULTS: A total of 86 genes were at least 2-fold differentially regulated comparing responding with nonresponding adenocarcinomas of the esophagus. The predominant genes encoded for the regulation of the cell cycle, transduction, translation, cell-cell interaction, cytoskeleton, and the signal transduction. The strongest difference was seen for the Ephrin B3 receptor. This result could be confirmed by immunhistology. A statistical significant correlation between the Ephrin B3 receptor, chemotherapy response, pathologic staging, and grading could be shown. CONCLUSIONS: There were significant differences in the gene profile between patients with adenocarcinoma of the esophagus responding to neoadjuvant chemotherapy compared with nonresponding patients. This suggests that it could be possible to characterize patients responding to chemotherapy even before starting the treatment using customized microarray analysis.

Results of a multimodal therapy in patients with stage IV Barrett's adenocarcinoma.

BACKGROUND: Locally advanced and metastatic Barrett's carcinomas account for the majority of this tumor entity at the time of diagnosis. Many studies have shown that a multimodal therapy concept consisting of neoadjuvant chemotherapy followed by resection can result in improved long-term survival in patients responding to chemotherapy. The benefit of a multimodal therapy concept in patients with stage IV disease remains unclear. METHODS: A total of 178 patients with Barrett's carcinoma who underwent multimodal therapy with resection of the tumor were reviewed. The pathological staging and the clinical course of patients with metastatic disease, who were treated equally, were compared to patients with locally advanced tumors. RESULTS: As expected, postoperative pathological staging showed that patients with metastatic disease have a more advanced T- and N-status. Moreover, the histopathological response according to Becker showed a chemoresistence in 84% of cases with metastatic disease, whereas 54% of patients with locally advanced carcinomas had a good response rate. Overall survival was poor, with 9 months in the metastatic group. CONCLUSIONS: This is the first study to compare the outcome of a modern multimodal therapy concept in patients with metastatic Barrett's carcinoma in comparison to patients with the locally advanced form of the disease. There are profound differences in the two groups with regard to survival time and response rates. Because of the poor outcome to date, multimodal therapy with resection of the tumor in stage IV disease cannot be recommended.