Prognostic value of histopathological regression in 850 neoadjuvantly treated oesophagogastric adenocarcinomas.

BACKGROUND: Recently, histopathological tumour regression, prevalence of signet ring cells, and localisation were reported as prognostic factors in neoadjuvantly treated oesophagogastric (junctional and gastric) cancer. This exploratory retrospective study analyses independent prognostic factors within a large patient cohort after preoperative chemotherapy including clinical and histopathological factors. METHODS: In all, 850 patients presenting with oesophagogastric cancer staged cT3/4 Nany cM0/x were treated with neoadjuvant chemotherapy followed by resection in two academic centres. Patient data were documented in a prospective database and retrospectively analysed. RESULTS: Of all factors prognostic on univariate analysis, only clinical response, complications, ypTNM stage, and R category were independently prognostic (P<0.01) on multivariate analysis. Tumour localisation and signet ring cells were independently prognostic only when investigator-dependent clinical response evaluation was excluded from the multivariate model. Histopathological tumour regression correlates with tumour grading, Laurén classification, clinical response, ypT, ypN, and R categories but was not identified as an independent prognostic factor. Within R0-resected patients only surgical complications and ypTNM stage were independent prognostic factors. CONCLUSIONS: Only established prognostic factors like ypTNM stage, R category, and complications were identified as independent prognostic factors in resected patients after neoadjuvant chemotherapy. In contrast, histopathological tumour regression was not found as an independent prognostic marker.

Limited resection and free jejunal graft interposition for squamous cell carcinoma of the cervical oesophagus.

BACKGROUND: Therapeutic strategies for cervical oesophageal squamous cell carcinoma (SCC) are controversial. Treatment options range from definitive radiotherapy to multimodal treatment. Outcome after limited resection and reconstruction with a free jejunal graft interposition was evaluated retrospectively. METHODS: Patients with clinical T1-4 Nx M0 tumours treated between 1986 and 2006 were included. RESULTS: Of 109 patients, 94 underwent preoperative chemoradiotherapy and 15 had a primary resection. Complete or partial preservation of the larynx was achieved in 93 patients (85.3 per cent). Minor and major complications occurred in 74.3 per cent, with 44.0 per cent of all patients having more than one complication. Reoperation was necessary in 29.4 per cent. The 30-day mortality rate was 1.8 per cent, and the in-hospital mortality rate 2.8 per cent. The complete R0 resection rate was 72.5 per cent. Median overall survival was 34.3 months; 1-, 3- and 5-year survival rates were 83.8, 47.0 and 47.0 per cent respectively. Survival was not influenced by complications (P = 0.401) or reoperation (P = 0.428). CONCLUSION: Despite high complication and reoperation rates, the mortality rate was low, even after preoperative chemoradiation. This complex surgical strategy is a treatment option for cervical SCC in oncological centres with an infrastructure providing multidisciplinary management.

[The relationship between German university hospitals and medical schools. Cooperation model versus integration model]. / Das Verhältnis von Klinikum und Fakultät. Kooperations- versus Integrationsmodell.

The relationship between German university hospitals and medical schools is mainly based on the cooperation model; in a few cases the integration model is applied. Both models bear characteristic advantages and disadvantages; in the cooperation model, e.g., processes might be slowed down by a multitude of regulatory mechanisms. The integration model supports a close connection of the medical school and university hospital. Currently, legislation concerning university medicine in Germany shows a trend to increase the influence of the government and the university president within the balance of power. Therefore, the cooperation model is still favored. In order that university hospitals remain sustainable for the future, especially in terms of research, site-specific solutions have to be developed and legitimated.

Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial.

Oxaliplatin and 5-fluorouracil have a significant activity in locally advanced oesophageal squamous cell cancer (OSCC). However, their optimal dosage and efficacy when combined with concurrent radiotherapy as neoadjuvant treatment are unknown. This non-randomised, phase I/II study aimed to define the maximum tolerated dose (MTD) and assessed the histopathological tumour response rate to neoadjuvant oxaliplatin in weekly escalating doses (40, 45, 50 mg m(-2)) and continuous infusional 5-fluorouracil (CI-5FU; 225 mg m(-2)) plus concurrent radiotherapy. Patients had resectable OSCC. Resection was scheduled for 4-6 weeks after chemoradiotherapy. During phase I (dose escalation; n=19), weekly oxaliplatin 45 mg m(-2) plus CI-5FU 225 mg m(-2) was established as the MTD and was the recommended dosage for phase II. Oesophageal mucositis was the dose-limiting toxicity at higher doses. During phase II, histopathological responses (<10% residual tumour cells within the specimen) were observed in 10 of 16 patients (63%; 95% confidence interval: 39-82%). Overall, 16 of the 25 patients (64%) who underwent resection had a histopathological response; tumour-free resection (R0) was achieved in 80%. Neoadjuvant weekly oxaliplatin 45 mg m(-2) plus CI-5FU 225 mg m(-2) with concurrent radiotherapy provides promising histological response rates and R0 resection rates in locally advanced OSCC.

Predictors of response and survival for neoadjuvant treated patients with esophageal adenocarcinoma.

Mainly patients with advanced esophageal adenocarcinoma who respond to neoadjuvant chemotherapy show a significant survival benefit after resection. Therefore, prediction of response before treatment is desirable. The aim of this study was to assess genetic predictors of response and survival for patients with esophageal adenocarcinoma prior to neoadjuvant therapy. Thirty-two patients with advanced esophageal adenocarcinoma who underwent neoadjuvant therapy with resection of their tumor were analyzed for thymidylate synthase (TS), excision repair cross complementing (ERCC1) and Gluthatione S-transferase (GSTP-1) mRNA levels prior to the treatment. These results were analyzed in regards of response and survival. In total, 18 patients responded to this protocol. Seventeen of those did show a gene expression level at or below the respective median of at least one gene. This had a profound impact on survival, demonstrating an increase in survival for patients who have TS, ERCC1, or GSTP-1 mRNA level at or below the median. These results demonstrate a potential predictive value of a gene expression profile available prior to therapy. These data have to be confirmed by a larger prospective trial.

Expression of prostaglandin E synthase in Barrett's cancer.

Expression of prostaglandin E synthase (PGES) - an enzyme of the prostaglandin biosynthetic pathway with suspected impact on carcinogenesis--was studied in Barrett's cancer to determine its pathogenetic role and prognostic impact in this entity. Expression analysis of PGES was performed on mRNA level (quantitative reverse transcription polymerase chain rection [RT-PCR]) in a large surgical series of 123 primary resected adenocarcinomas of the distal esophagus (Barrett's cancer). Gene expression results were correlated with clinical parameters, overall survival and expression levels of previously analyzed target genes of the cyclooxygenase (COX) pathway (COX-1, COX-2) and mediators of angiogenesis (vascular endothelial growth factor [VEGF]-A) and lymphangiogenesis [VEGF-C]. Expression of PGES was demonstrated in all 123 tumors (100%) on mRNA level (quantitative RT-PCR). Relative mRNA expression levels were highly variable between different cases. Gene expression showed a strong positive correlation with both COX isoforms (COX-1: r = 0.502, P < 0.001; COX-2: r = 0.679, P < 0.001), with the angiogenetic VEGF-A (r = 0.583, P < 0.001) and with the lymphangiogentic VEGF-C (r = 0.465, P < 0.001). PGES mRNA expression showed no significant correlation with clinicopathologic parameters (i.e. pTNM categories, UICC stage, survival). Variable overexpression of PGES seems to be potentially implicated in Barrett's carcinogenesis. Gene expression of PGES is strongly correlated with other mediators of the prostaglandin biosynthetic pathway, that is both COX isoforms (COX-1 and COX-2). However, no impact on patients' outcome in relation to PGES expression was found.

[Therapy of mediastinitis in patients with esophageal cancer]. / Therapie der Mediastinitis am Beispiel des Osophaguskarzinoms.

Mediastinitis caused by anastomotic leaks is the most severe complication after esophagectomy and the major source of morbidity and mortality. It is characterized by local intrathoracic reactions (mediastinitis) and systemic extrathoracic reactions (sepsis). Consequently the therapeutic concepts are clearly defined. To achieve successful management, early diagnostic work-up is mandatory in every disturbance of the normal postoperative course. This includes direct endoscopic inspection of the anastomosis to evaluate the vitality of the anastomosed organs and the size of the leak. According to location and clinical classifications of the leak, the spectrum of therapeutic options ranges from simple drainage procedures, endoscopic interventions, and stent implantation to reoperation or discontinuity resection. In any case the treatment goals must be immediate and sufficient drainage of the leakage and hindrance of further contamination across the leakage by gastrointestinal content. Also mandatory is the early initiation of supportive systemic strategies according to pathophysiologic principles of sepsis. The fundamental requirements for successful management are therefore aggressive local intervention and application of new concepts in sepsis therapy.

[Rare occurrence of fulminant acid burn of the esophagus]. / Seltene Ursache einer fulminanten Säureverätzung des Osophagus.

Peptic ulcer due to Zollinger-Ellison syndrome is a rare entity. In this case report a 55-year-old man had a medical history of esophageal reflux, vomiting, and diarrhea for 10 years. Despite continuous medication with a proton pump inhibitor, no complete recovery from symptoms was achieved. A diagnosis of gastrinoma was at first not considered. After discontinuation of the proton pump inhibitor for only a few days, the strong stimulation of the gastrinoma led to fulminant hydrochloric acid burn of the distal esophagus with iatrogenic or spontaneous perforation at the esophagogastral junction. We describe the operative treatment as a two-stage reconstruction with colon interposition and resection of the primary tumor in the duodenum.

Management of early esophageal cancer.

In early esophageal cancer, squamous cell cancer and early adenocarcinoma must be managed differently because they have different origins, pathogenesis. and clinical characteristics. The current treatment options vary widely, from extended resection with lymphadenectomy to endoscopic mucosectomy or ablation. None of these treatment options can be recommended universally. Instead, an individualized strategy should be based on the depth of tumor infiltration into the mucosa or submucosa, the presence or absence of lymph node metastases, the multicentricity of tumor growth, the length of the segment of intestinal metaplasia, and comorbidities of the patient. Endoscopic mucosectomy may be sufficient in a subset of patients who have m1 or m2 squamous cell carcinoma and in patients who have isolated foci of high-grade intraepithelial neoplasia or mucosal cancer. Surgical resection is the treatment of choice for carcinomas invading the submucosal and multicentric tumors. Limited resection with jejunal interposition provides an effective treatment option for patients who have early esophageal adenocarcinoma. The onset of lymph node involvement is later in patients who have early adenocarcinoma than in patients who have squamous cell cancer, probably because chronic injury and repair mechanisms obliterate the otherwise abundant lymph vessels.

[Esophageal carcinoma]. / Osophaguskarzinom.

Esophageal cancer is more than ever a surgical problem. Modern diagnostic procedures facilitate individual staging, and risk analysis is important for adequate patient selection. Using both allows an individualized indication. Under multimodal therapeutic protocols, neoadjuvant treatment can best be evaluated and is recommended in locally advanced tumors: RCTx in SCC, and CTx in Barrett cancer. Here the Ivor-Lewis procedure is the surgical method of choice. Postoperative complications are always possible, but the management now is standardized and has largely decreased mortality.

[R1 resection in the surgery of upper gastrointestinal tumors: relevance and therapeutic consequences]. / R1-Resektion in der Chirurgie des oberen Gastrointestinaltrakts: Bedeutung und therapeutische Konsequenzen.

Microscopically involved tumor margins are an important problem in the surgery of locally advanced esophageal and gastric carcinomas. We conducted a systematic review of the literature and a specific analysis of our own patient database. This article summarizes current knowledge of the incidence and prognosis of R1 resections in upper gastrointestinal cancers. Preoperative strategies for reducing the rate of R1 resections are presented, and the surgical options in case of R1 resection are discussed.

[Lymphadenectomy with tumors of the upper gastrointestinal tract]. / Lymphadenektomie bei Tumoren des oberen Gastrointestinaltraktes.

In surgical therapy for upper gastrointestinal cancer, adequate lymphadenectomy together with R0 resection of the primary tumour is one of the most important prognostic factors which can be influenced by the surgeon. Recommendations for localization- and stage-adapted lymphadenectomy can be made according to histopathologic and anatomic investigations of the patient collectives of large centres. After neoadjuvant radiochemotherapy in cancer of the cervical oesophagus, the absence of lymph nodes on the resected specimen seems to be of less prognostic value. In squamous cell cancer of the suprabifurcal oesophagus, radical lymphadenectomy is recommended. Despite significant morbidity, in specialized centres this procedure yields good results with low mortality. For infrabifurcal oesophageal cancer, two-field lymphadenectomy during the so-called Ivor-Lewis operation is the method of choice. Locally advanced Barrett carcinoma is also an indication for classic two-field lymphadenectomy together with abdominothoracic oesophagectomy and creation of a stomach tube with intrathoracic anastomosis. The lymphadenectomy should however include the area of retroperitoneal lymphatic drainage at the pedicle of the left kidney. Submucosal cancer in this area can be treated with luminal limited resection of the oesophagogastric junction with adequate lymphadenectomy. Adenocarcinoma of the cardia and subcardial gastric cancer including the cardia both require lymphadenectomy analogous to that performed in gastric cancer, with special attention paid to the retroperitoneal lymphatic drainage towards the left kidney pedicle. For therapy of gastric cancer, a systematic D2 lymphadenectomy should always be performed.

Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study.

AIMS: To correlate immunohistochemical expression patterns and prognosis in oesophageal adenocarcinoma. METHODS: The expression of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor (EGFR) was studied in a series of 137 primarily resected oesophageal adenocarcinoma samples. The expression analysis on protein level was performed on routine paraffin wax-embedded material, with immunohistochemical staining of the samples, assembled on a tissue microarray. The results were correlated with clinicopathological features (pT, pN and G) and survival. RESULTS: 22 (16%) tumours showed an overexpression of the c-erbB-2 oncoprotein. Expression of EGFR was observed in 72 (55%) cases, accumulation of p53 in 68 (52%) cases and of cyclin D1 in 102 (77%) cases. Loss of p16INK4A expression was observed in 101 (76%) cases and low expression of p27KIP1 in 91 (71%) cases. Expression of these proteins did not correlate with tumour stage, grade, Lauren's or World Health Organization classification or lymph node status. On univariate survival analysis, more advanced tumour stage (p = 0.002), lymph node involvement (p = 0.003), high tumour grade (p = 0.017) and lack of EGFR expression (p = 0.034) were found to be associated with poorer survival. On multiple regression analysis, only tumour stage (p = 0.03) and lymph node involvement (p = 0.004) were shown to have an association with the survival of the patient. CONCLUSION: The immunohistochemical expression of c-erbB-2 oncoprotein, cylin D1, p16INK4A, p27KIP1, p53 and EGFR in most oesophageal adenocarcinomas suggests their implication in the pathogenesis of this entity. None of the molecular markers assessed, however, was of prognostic value. Identification of any marker superior to or even approaching the prognostic value of conventional histopathological markers (pT and pN) was therefore not possible.

Preferred location for the development of esophageal adenocarcinoma within a segment of intestinal metaplasia.

BACKGROUND: Barrett's metaplasia is the predominant precursor for the development of esophageal adenocarcinoma. This precancerous lesion has become the focus of various surveillance programs aimed at detecting earlier and therefore potentially curable lesions. However, sampling error by missing invasive cancer lesions is a common problem. This study aimed to identify preferred locations within a segment of Barrett's mucosa for the development of esophageal adenocarcinoma. METHODS: The study group consisted of 213 patients with histologically proven esophageal adenocarcinoma. Of those, there were 134 cases of early cancer and 79 cases of locally advanced lesions. These patients received neoadjuvant chemotherapy. The frequency of intestinal metaplasia and the location of the tumor occurrence within the segment of intestinal metaplasia were assessed. RESULTS: Intestinal metaplasia was found in 83% of the early lesions and in 98% of the advanced tumors after neoadjuvant chemotherapy. In 82.2% of the cases, the tumor was located at the distal margin of the intestinal metaplasia in patients with early tumor manifestations. The remaining tumor mass after neoadjuvant therapy also was located predominantly at the distal margin of the segment of intestinal metaplasia (85% of the cases). CONCLUSIONS: The results demonstrate that almost all adenocarcinomas of the esophagus are based on the development of a segment of intestinal metaplasia. The distal margin of Barrett's mucosa seems to be the most vulnerable location for the development of invasive cancer.

Adenocarcinoma of the esophago-gastric junction.

BACKGROUND: The border between the esophagus and stomach gives rise to many discrepancies in the current literature regarding the etiology, classification and surgical treatment of adenocarcinoma arising at the esophago-gastric junction. We have consequently used the AEG-criteria (adenocarcinoma of the esophago-gastric junction) for classification and have based the selection of the surgical approach on the anatomic topographic subclassification. METHODS: In the following we report an analysis of a large and homogeneously classified population of 1602 consecutive patients with adenocarcinoma of the esophago-gastric junction, with an emphasis on the surgical approach, the pattern of lymphatic spread, the outcome after surgical treatment and the prognostic factors. Demographic data, morphologic and histopathologic tumor characteristics, and long-term survival rates were compared among the three tumor subclassifiations. RESULTS: The study confirms the marked differences in sex distribution, associated specialized intestinal metaplasia in the esophagus, tumor grading, tumor growth pattern, lymphatic spread, and stage between the three tumor entities. The degree of resection and lymph node status were the dominating independent prognostic factors by multivariate analysis. The data show no significant differences of long-term survival after abdomino-thoracic esophagectomy and extended total gastrectomy in these patients. CONCLUSION: The classification of adenocarcinomas of the esophago-gastric junction in three types, AEG type I, type II and type III shows marked differences between the tumor entities and is recommended for selection of a proper surgical approach. Complete tumor resection and adequate lymphadenectomy are associated with good long-term prognosis. Better surgical management and standardized procedures will improve the outcome also of patients who need to undergo more radical surgery, i.e. abdomino-thoracic esophagectomy.

Immunocytochemical detection of disseminated tumor cells in the bone marrow of patients with esophageal carcinoma.

BACKGROUND: Approximately half of the patients diagnosed with localized esophageal cancer die of metastatic disease within the first 2 years following tumor resection. The development of monoclonal antibodies (MAbs) directed against epithelial cell-associated and tumor antigens has enabled the detection of single disseminated tumor cells in secondary organs. PURPOSE: We used MAbs directed against epithelial cell antigens (i.e., cytokeratins) to determine the proportion of patients with esophageal cancer who display isolated tumor cells in their bone marrow. In addition, we evaluated the prognostic significance of a finding of bone marrow tumor cells in patients with esophageal cancer whose tumors were completely resected. METHODS: Prior to the initiation of treatment, bone marrow was aspirated from both sides of the upper iliac crests of 90 patients with squamous cell carcinoma of the esophagus. Bone marrow was also obtained from a population of 30 individuals who had not been diagnosed with cancer. Tumor cells in cytologic bone marrow preparations were detected by use of an assay that employed the MAbs CK2 (directed against cytokeratin 18), KL1 (directed against a 56,000-kd pan-cytokeratin component), and A45-B/B3 (directed against an epitope common to cytokeratins 8, 18, and 19) plus the alkaline phosphatase anti-alkaline phosphatasestaining method. Bone marrow biopsies, for conventional histologic examination with Giemsa staining, were performed on 62 patients. The Kaplan-Meier method and the logrank test were used to assess disease-free and overall survival according to the presence or absence of tumor cells in the bone marrow of 42 patients with completely resected tumors. Reported P values are two-sided. RESULTS: Cytokeratin-positive tumor cells were detected in the bone marrow of 37 (41.1%) of the 90 total patients. The number of tumor cells detected per 10(5) mononuclear bone marrow cells ranged from one to 82. No significant differences in the numbers of disseminated tumor cells were noted for patients diagnosed with tumors at different stages. Only two (3.2%) of 62 bone marrow specimens examined after Giemsa staining showed morphologically identifiable tumor cells. Tumor cells were not detected in the bone marrow of patients who had not been diagnosed with cancer. After a median follow-up of 15.5 months (range, 6-33 months), 15 (79.0%) of 19 patients with completely resected tumors and tumor cells in their bone marrow had relapses compared with three (13.0%) of 23 patients with completely resected tumors and no tumor cells in their bone marrow (P = .019, logrank test). Patients with completely resected tumors and tumor cells in their bone marrow had significantly shorter overall survival than corresponding patients without tumor cells in their bone marrow (P = .036, logrank test). CONCLUSIONS AND IMPLICATIONS: Dissemination of esophageal cancer cells to the bone marrow is more frequent than expected from the rare occurrence of overt skeletal metastases. In general, the presence of tumor cells in the bone marrow may be an indicator of the disseminatory potential of individual tumors.

[Response prediction--early response evaluation. Consequences for surgical oncology]. / Response-Vorhersage--frühe Response-Evaluation. Konsequenzen für die chirurgische Onkologie.

Response to perioperative chemotherapy or chemoradiation can hardly be predicted on the basis of molecular marker analyses. In contrast, by means of metabolic and molecular imaging using positron emission tomography, response can be assessed as early as 14 days after the start chemotherapy for many tumors. There is no doubt that the prognosis of patients with surgically resected tumors is much better in the case of a response to chemotherapy or chemoradiation. Important consequences can be deduced from this regarding the indications for perioperative therapies, the radicality of surgery or the surgical indications per se. In the following, we delineate the current knowledge on response prediction and early response evaluation in selected tumor entities and draw possible conclusions for clinical practice and future clinical studies.

[Procedures of temporary wall closure in abdominal trauma and sepsis]. / Verfahren zum temporären Bauchdeckenverschluss bei Trauma und Sepsis.

Temporary abdominal closure methods differ mainly between vacuum-assisted and conventional approaches. Each method has its indications. Vacuum-assisted methods seem to be superior especially for trauma indications--in terms of lethality, the possibility of secondary closure during primary hospital stay, and frequency of enterocutaneous fistulas. Skin-only closure might be used as a short-term application (e.g. when damage control closure is needed), and the Bogota bag silo gives space to protruding bowels in pending or manifest abdominal compartment syndrome. Temporary fascial mesh closure enables repetitive laparotomies through the mesh, thus sparing the fascia. For that reason it is to be preferred, especially for its good practicability in clinical situations and on mission abroad.

[Penetrating injuries to the pelvis]. / Penetrierende Beckenverletzung.

As criminality and weapon use increase, general and military surgeons are increasingly confronted with penetrating pelvic injuries both at home and on peacekeeping missions. Penetrating injuries to the iliac vascular axis are associated with considerable mortality, and thus the majority of these emergency patients arrive in a state of deep hypovolemic shock. Concomitant bowel injuries are present in one of five cases, resulting in contamination of the damaged area. Surgical options are simple lateral repair, ligation of the veins, temporary shunt insertion, and prosthetic graft interposition in the injured artery. In extremis ligation of the common or external iliac artery may be the only option to save the patient's life. Surgeons must be aware that damage control surgery and related methods may be needed early on to enable patient survival.

[Curative vs palliative strategies in locoregional recurrence of gastrointestinal malignancies]. / Therapeutische Strategien bei lokoregionalen Rezidiven gastrointestinaler. Tumoren Palliation oder Kuration?

Locoregional recurrence is a relevant problem in surgical oncology. Intraluminal local relapse only occurs when the primary resection is carried through with inappropriate safety margins. If possible, a second surgical resection with wider margins is the treatment of choice. When the primary resection was appropriately done, extraluminal relapse in the original tumor bed indicates the primary tumor was already in an advanced stage. The indication for a second resection must be considered carefully. A realistic prospect of long-term tumor control exists only when the second resection yields tumor-free margins and is combined with chemo- and radiotherapy. There is usually no curative treatment option for recurrences in the draining lymph node region, the so-called fourth dimension.