Randomized controlled trial of ultrasonic dissection versus standard surgical technique in open left hemicolectomy or total gastrectomy.

BACKGROUND: Ultrasonic dissection devices have been designed for use in open surgery but it is not certain how they compare with standard surgical techniques. METHODS: This was a multicentre randomized controlled trial comparing ultrasonic dissection with the traditional surgical technique for haemostasis and dissection during left hemicolectomy and total gastrectomy. The primary endpoint was duration of operation; secondary endpoints were blood loss and other intraoperative parameters, and patient outcomes. Performance of the two techniques was rated by surgeons and assistants on a ten-point Likert scale. RESULTS: The analysis included 100 patients in the ultrasonic and 101 in the conventional dissection group. Patient demographics, and clinical and tumour-related parameters were similar in the two groups. There was no significant difference in duration of operation (mean 170 and 178 min in ultrasonic and conventional groups respectively; P = 0·405). Nor were there significant differences in intraoperative blood loss (median 350 and 400 ml respectively; P = 0·882), other intraoperative parameters, oncological or functional outcome. The ultrasonic dissector device was rated one point higher than conventional techniques by the surgeons. CONCLUSION: Use of the ultrasonic dissector in open total gastrectomy and hemicolectomy had no impact on the overall operating time or other endpoints studied. Surgeons preferred the ultrasonic device for dissection.

[Ischemic anastomotic bowel perforation during treatment with bevacizumab 10 months after surgery]. / Ischämische Anastomosenperforation im Bereich einer Ileotransversostomie unter Therapie mit Bevacizumab.

BACKGROUND: Bevacizumab (Avastin) is a monoclonal antibody against vascular endothelial growth factor (VEGF) receptor that has demonstrated increased overall survival when added to standard chemotherapy regimens in patients with metastatic colorectal cancer. Gastrointestinal perforation is a known risk factor of unknown etiology associated with the use of bevacizumab. OBJECTIVE: We report a 61-year-old woman with adenocarcinoma of the colon ascendens who underwent hemicolectomy and adjuvant chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin. Eight months after the operation, we started therapy with bevacizumab combined with irinotecan, 5-fluorouracil, and leucovorin due to disease progression. Two months after completion of this therapy, ischemic anastomotic bowel perforation occurred and a resection of the anastomosis was performed. Because of anastomotic insufficiency 8 days later, a further revision had to be done and the terminal ileum and the colon were brought out through a stoma. DISCUSSION: This case is unusual because the time interval between the primary operation and the application of bevacizumab is regarded as safe with regard to the risk of perforation. An ischemic genesis of the perforation was considered on the basis of the histopathological workup. In case of perforations during therapy with bevacizumab, a safe surgical approach should be preferred, i.e., a transient stoma instead of a primary reconstruction of the bowel passage.

[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.

Predictors of overall and recurrence-free survival after neoadjuvant chemotherapy for gastroesophageal adenocarcinoma: Pooled analysis of individual patient data (IPD) from randomized controlled trials (RCTs).

BACKGROUND: Neoadjuvant chemotherapy improves prognosis of patients with locally advanced gastroesophageal adenocarcinoma. The aim of this study was to identify predictors for postoperative survival following neoadjuvant therapy. These could be useful in deciding about postoperative continuation of chemotherapy. METHODS: This meta-analysis used IPD from RCTs comparing neoadjuvant chemotherapy with surgery alone for gastroesophageal adenocarcinoma. Trials providing IPD on age, sex, performance status, pT/N stage, resection status, overall and recurrence-free survival were included. Survival was calculated in the entire study population and subgroups stratified by supposed predictors and compared using the log-rank test. Multivariable Cox models were used to identify independent survival predictors. RESULTS: Four RCTs providing IPD from 553 patients fulfilled the inclusion criteria. (y)pT and (y)pN stage and resection status strongly predicted postoperative survival both after neoadjuvant therapy and surgery alone. Patients with R1 resection after neoadjuvant therapy survived longer than those with R1 resection after surgery alone. Patients with stage pN0 after surgery alone had better prognosis than those with ypN0 after neoadjuvant therapy. Patients with stage ypT3/4 after neoadjuvant therapy survived longer than those with stage pT3/4 after surgery alone. Multivariable regression identified resection status and (y)pN stage as predictors of survival in both groups. (y)pT stage predicted survival only after surgery alone. CONCLUSION: After neoadjuvant therapy for gastroesophageal adenocarcinoma, survival is determined by the same factors as after surgery alone. However, ypT stage is not an independent predictor. These results can facilitate the decision about postoperative continuation of chemotherapy in pretreated patients.

Highly specific tumor binding of a 213Bi-labeled monoclonal antibody against mutant E-cadherin suggests its usefulness for locoregional alpha-radioimmunotherapy of diffuse-type gastric cancer.

A monoclonal antibody (E-cadherin delta 9-1) directed against a characteristic E-cadherin mutation (in-frame deletion of exon 9), found in diffuse-type gastric cancer but not in any normal tissue, was conjugated with the high linear energy transfer alpha-emitter 213Bi and tested for its binding specificity in s.c. and i.p. nude mice tumor models. After intratumoral application in s.c. tumors expressing mutant E-cadherin, the 213Bi-labeled antibody was specifically retained at the injection site as shown by autoradiography. After injection into the peritoneal cavity, uptake in small i.p. tumor nodules expressing mutant E-cadherin was 17-fold higher than in tumor nodules expressing wild-type E-cadherin (62% injected dose/g versus 3.7% injected dose/g). 78% of the total activity in the ascites fluid was bound to free tumor cells expressing mutant E-cadherin, whereas in control cells, binding was only 18%. The selective binding of the 213Bi-labeled, mutation-specific monoclonal antibody E-cadherin delta 9-1 suggests that it will be successful for alpha-radioimmunotherapy of disseminated tumors after locoregional application.

The European Organization for Research and Treatment for Cancer (EORTC) strategy for quality assurance in surgical clinical research: Assessment of the past and moving towards the future.

AIMS: Quality assurance (QA) in a surgical trial must be planned and implemented from study development to completion. Elements of quality must be consistently described in a protocols, case report forms (CRFs) and reported in publications. The purpose of this review was to evaluate the most common surgical parameters and how consistently they were described in EORTC study documents where surgery was included. This was the preliminary step in mapping out the challenges of developing a surgical QA strategy in EORTC. METHODS: A systematic review of EORTC surgical protocols from 1980 to 2013 was performed. Two independent reviewers selected and reviewed the protocols. Data extraction was done using a questionnaire developed by EORTC QA committee. The results were compared across the time period. RESULTS: The most common quality parameters described in protocols were surgical technique, definition of resectability, surgical margins and methods of assessing adverse events using the Common Terminology Criteria for Adverse Event (CTCAE). However, these were not consistently reported in publications. A general improvement in the method of protocol development was observed since year 2000 after standardization measures by EORTC. A new surgical chapter template has been proposed. CONCLUSION: There is a need to consistently define and report surgical parameters from protocol development to publication as a first step to QA. A standard surgical chapter in the EORTC protocol template can help address this need. A framework to consistently implement QA for future surgical trials is needed and the rationale for this is described in this review.

Survival benefit and additional value of preoperative chemoradiotherapy in resectable gastric and gastro-oesophageal junction cancer: a direct and adjusted indirect comparison meta-analysis.

Several phase I/II studies of chemoradiotherapy for gastric cancer have reported promising results, but the significance of preoperative radiotherapy in addition to chemotherapy has not been proven. In this study, a systematic literature search was performed to capture survival and postoperative morbidity and mortality data in randomised clinical studies comparing preoperative (chemo)radiotherapy or chemotherapy versus surgery alone, or preoperative chemoradiotherapy versus chemotherapy for gastric and/or gastro-oesophageal junction (GOJ) cancer. Hazard ratios (HRs) for overall mortality were extracted from the original studies, individual patient data provided from the principal investigators of eligible studies or the earlier published meta-analysis. The incidences of postoperative morbidities and mortalities were also analysed. In total 18 studies were eligible and data were available from 14 of these. The meta-analysis on overall survival yielded HRs of 0.75 (95% CI 0.65-0.86, P < 0.001) for preoperative (chemo)radiotherapy and 0.83 (95% CI 0.67-1.01, P = 0.065) for preoperative chemotherapy when compared to surgery alone. Direct comparison between preoperative chemoradiotherapy and chemotherapy resulted in an HR of 0.71 (95% CI 0.45-1.12, P = 0.146). Combination of direct and adjusted indirect comparisons yielded an HR of 0.86 (95% CI 0.69-1.07, P = 0.171). No statistically significant differences were seen in the risk for postoperative morbidity or mortality between preoperative treatments and surgery alone, or preoperative (chemo)radiotherapy and chemotherapy. Preoperative (chemo)radiotherapy for gastric and GOJ cancer showed significant survival benefit over surgery alone. In comparisons between preoperative chemotherapy and (chemo)radiotherapy, there is a trend towards improved survival when adding radiotherapy, without increased postoperative morbidity or mortality.

Loss of immunohistochemical E-cadherin expression in colon cancer is not due to structural gene alterations.

E-cadherin, a transmembrane cell adhesion molecule, has been observed to have an altered pattern of immunoreactivity in several types of carcinomas. In lobular breast cancer, loss of immunoreactivity has been shown to be due either to out-of-frame deletions or to nonsense mutations of the E-cadherin gene. We analysed 29 cases of completely resected colon carcinoma with immunohistochemistry using the HEC-D1 antibody. Normal protein expression similar to that in the adjacent nonmalignant mucosa was seen in 6 cases, whereas 23 tumours had reduced or absent E-cadherin expression. In the 8 cases with no expression of E-cadherin revealed by immunohistochemistry, the entire E-cadherin cDNA sequence was analysed. In these cases, sequence analysis failed to reveal any cDNA mutations despite the negative immunohistochemistry. Possible explanations for this discrepancy include regulatory defects in the E-cadherin promoter, abnormalities at the translation or protein processing levels and mutations in other parts of the gene that were not investigated by the cDNA analysis (e.g. intronic sequences), which could play a role in causing abnormal processing of the E-cadherin protein.

Rapid detection of mutated E-cadherin in peritoneal lavage specimens from patients with diffuse-type gastric carcinoma.

Tumor cells in abdominal lavage specimens from patients with gastric carcinoma strongly predict subsequent peritoneal metastasis and poor prognosis. Reverse transcription (RT)-polymerase chain reaction (PCR) detection of wild-type E-cadherin has been claimed to be superior to conventional cytology for the detection of patients who subsequently develop peritoneal metastases. The present study tested this hypothesis and determined whether or not the detection of mutated, tumor-specific E-cadherin messenger RNA in abdominal lavage specimens serve as a useful diagnostic tool. Preoperative lavage specimens from 52 patients with diffuse-type gastric carcinoma and from 5 patients with benign disease were analyzed by conventional cytology and by RT-PCR for amplification of E-cadherin. Tumor cells were detected by cytology in 8 (15.3%) of the 52 patients with gastric cancer. The E-cadherin was detected in all 57 samples by RT-PCR. Two of these had abnormal E-cadherin amplification products confirmed to be mutations by direct sequencing, which were identical in the primary tumors. These findings suggest that the detection of wild-type E-cadherin is not sufficiently tumor specific. Also, for diffuse gastric carcinomas with confirmed E-cadherin mutations, detection of mutant E-cadherin by RT-PCR is a potentially valuable method for tumor cell detection in lavage specimens.

A phase II trial of paclitaxel in the treatment of recurrent or metastatic soft tissue sarcomas or bone sarcomas.

The study aimed to determine the activity and toxicity of taxol in the treatment of recurrent or metastatic soft tissue sarcomas or osteosarcomas. The major findings are that five patients had stable disease after two cycles of chemotherapy but two of these patients were subsequently removed from the study at their own request. The other three patients progressed after an additional two cycles of chemotherapy. Seven patients progressed during the first two cycles and were removed from the study. One patient completed only one cycle of therapy and was deemed inevaluable for study response. There were eight episodes of grade 3 or 4 neutropenia and two episodes of grade 3 thrombocytopenia. One patient experienced grade 3 neurological toxicity and one patient grade 3 mucositis. Two patients are currently alive with progressing disease and one patient is alive with no evidence of disease after undergoing surgery and radiotherapy. The principal conclusions are that Paclitaxel is ineffective in treating recurrent or metastatic soft tissue sarcoma and osteosarcoma. Treatment at this dose is quite myelosuppressive, but toxicity is generally manageable. Further study of this agent is not justified in this setting.

Sequential and/or concurrent hypofractionated radiotherapy and concurrent chemotherapy in neoadjuvant treatment of advanced adenocarcinoma of the pancreas. Outcome and patterns of failure.

BACKGROUND/AIMS: To investigate treatment outcome and patterns of failure of sequential chemotherapy (CHT) and/or concurrent hypofractionated radiotherapy (RT) and CHT followed by surgery in locally advanced non-metastatic pancreatic adenocarcinoma. METHODOLOGY: Seven patients with locally advanced but marginal resectable tumors (close contact but no signs of infiltration of the mesenteric vessels and/or vena portae) were treated with hypofractionated RT (5x3 Gy per week) and concurrent continuous infusion (300 mg/sqm/24 h, 7 days per week) of 5-fluorouracil (FU). Ten patients with locally advanced disease with radiologically suspected infiltration of the mesenteric vessels and/or v. portae were treated with 2 cycles of Cisplatin (75 mg/sqm) and Gemcitabine (2x1250 mg/sqm), and patients without tumor progression received the same concurrent RT/CHT as group 1. Four weeks after RT/CHT radical pancreatectomy was planned for patients with stable disease or remission. RESULTS: Toxicity was low in both groups, with no CTC grade 4 toxicity. In group 1, RT/CHT was completed in all patients. There was no radiological remission, but stable disease in 5 out of 7 patients. All 5 patients underwent resection of the primary tumor with a R0-resection in 3 patients. In group 2, 8 patients completed CHT and RT/CHT treatment as planned. There were 3 with partial remission. Operation was done in 4 patients, but only one R0 resection was achieved. The median survival time for all 17 patients is 13 months, with 1- and 2-year survival being 53% and 18%, respectively. Local progression was observed in 9, peritoneal seeding in 7 and distant metastasis (mostly liver and lung) in 8 patients. CONCLUSIONS: The neoadjuvant therapy could be administered with low toxicity. Results of this study warrant further investigation aiming at optimal tailoring in of this treatment approach in these two subgroups of patients.

[Therapeutic modalities and prognosis]. / Therapiemodalitäten und Prognose.

The individual prognosis of a patient with gastrointestinal cancer is determined by a number of clinical and biological factors. The most relevant prognostic factors are those that can be influenced by the surgeon himself. The completeness of tumor resection, the so-called residual tumor status on the level of the primary tumor in all three dimensions and on the level of the lymphatic drainge is the outstanding factor with an independent influence on the survival of the patient. In addition, the principles of blood-saving preparation with avoidance of blood transfutions, the consideration of no-touch isolation and the complication-free postoperative course have been shown to be independent prognostic factors that can be influenced by the surgeon. There is clear evidence that the hospital volume and the experience of the surgeons, expressed by the number of cases (caseload) in a specific field, has a strong impact on the outcome of a surgical treatment in gastrointestinal cancer patients. To optimize the prognosis of a patient with gastrointestinal cancer one should consider all therapy-related prognostic factors, and therapeutic modalities should be scheduled after a consensus conference (tumor board) of all therapeutic fields involved in the treatment of cancer.

[Intestinal pouches: gastric reconstruction]. / Intestinale Pouches: Magenersatz.

Reconstruction of the intestinal passage after a total gastrectomy is usually based on a direct esophagojejunostomy with end-to-side implantation of the afferent loop. The second principle of reconstruction is based on preservation of the duodenal passage. Long-term problems such as weight loss and malnutrition are further considerations that lead to the concept that gastric reconstruction should have the form of a reservoir. In addition to the construction of the reservoir itself, the clinical concern of avoiding gastroesophageal reflux is a further requirement for the choice of reconstruction type. Diversion of the duodenal content via a Roux-en-Y end-to-side anastomosis is considered to be the standard procedure. Interposition of a sufficiently long duodenal loop with maintenance of the duodenal passage also has the effect of preventing duodenal reflux. A theoretical advantage of this procedure is the linking of the motility of the duodenum with that of the interposed segment with improved synchronization of the aboral nutrient passage. When one considers complicated reconstructive procedures, the present literature suggests construction of a pouch is definitely functionally superior to the simple esophagojejunostomy. Whether the duodenal passage should be maintained or whether a Roux-Y technique should be used is a question that is still open for discussion.

[Treatment of gastric cancer beyond current guideline: state of the art]. / Therapie des Magenkarzinoms über die aktuelle Leitlinie hinaus: Eine Bestandsaufnahme.

The majority of recommendations in the current S3 guideline on the diagnosis and treatment of gastric carcinoma are based on good clinical practice and lack supporting randomized studies. With the development of endoscopic resection and multimodal treatment concepts, pretherapeutic tumor staging has gained in importance. However, the accuracy of present imaging modalities is still limited with a tendency towards overstaging of locally advanced tumors. Extended lymph node dissection cannot be recommended in cases with advanced lymph node involvement. In cardiac cancer retroperitoneal lymphatic spread to the left renal vein is an early event and should thus not be classified as stage IV disease. In cases of intra-abdominal gastrectomy a pouch reconstruction should be considered in cases with a good overall prognosis. Subgroup analyses indicate a differential therapeutic effect of the established perioperative chemotherapy depending on the location of the primary tumor. There is also good evidence for an additional beneficial effect of radiotherapy in combination with chemotherapy.

[The new TNM classification of tumors of the esophagogastric junction. Surgical consequences]. / Die neue TNM-Klassifikation der Tumoren des ösophagogastralen Übergangs. Chirurgische Konsequenzen.

The new International Union Against Cancer (UICC) classification in its seventh version has been out since January 2010. It included some important changes for the classification of esophageal and gastric carcinomas compared to the sixth version. For esophageal carcinomas this means a more detailed subdivision of the T and N stages which should, together with the newly introduced prognostic grouping (separate for squamous cell carcinoma and adenocarcinoma) enable a more precise and individualized prediction of prognosis. Another innovation is that positive lymph nodes in the esophageal drainage area, including celiac axis nodes and paraesophageal lymph nodes in the neck, are classified as regional lymph node metastases rather than distant metastatic spread, irrespective of tumor location. Hereby the lymphadenectomy specimen should include ≥ 6 lymph nodes (LN). The most controversial improvement is that adenocarcinomas of the esophagogastric junction (AEG) are all classified as esophageal carcinomas. This should acknowledge the similar prognosis of AEGs and esophageal carcinomas, which is worse compared to gastric carcinomas in other locations. Regarding the classification of gastric carcinomas the T-stages were redefined and lymph node staging (N-stage) was refined to allow for a better prediction of prognosis. The lymphadenectomy specimen after gastrectomy should hereby include ≥ 16 LNs. As the primary aim of the UICC classification is a preferably accurate prognosis prediction, the impact on a surgeon's therapeutic decision is low. For decisions regarding the type of resection the endoscopic AEG classification with the aim of R0 resections is still the instrument of choice. The value of the UICC classification is that it enables sophisticated comparisons between different treatment regimens and strategies.

[Lymphadenectomy for malignancies of the upper gastrointestinal tract]. / Lymphadenektomie bei Malignomen des oberen Gastrointestinaltraktes.

Studies from specialized and high volume centers revealed an improved overall survival for patients subjected to extended lymphadenectomy. The drawbacks of radical lymph node dissection seem to be represented in higher rates of morbidity and mortality and thus are correlated to the surgical expertise of the respective institution. Especially patients in the early stages of metastatic lymph node spread benefit from extended and more radical lymphadenectomy. In a retrospective analysis of this institution's own patients, a pN0 category pT stage and the amount of retrieved lymph nodes have been found to be independent prognostic factors. In patients with up to six positive nodes (pN1) pT stage, the number of retrieved nodes, the number of positive nodes and R stage are correlated to survival prognosis. If more than six nodes are invaded only the amount of metastatic nodes and R stage are relevant prognostic factors. It will be of upmost interest to compare these data with analyses from regional and national cancer registers for gastric and esophageal cancer. As so far no reliable procedure for preoperative determination of lymphatic spread exists, the recommendations by the respective research organizations will have to be adopted until further notice, which is D2 lymphadenectomy for locally advanced gastric cancer and 2-field lymphadenectomy for patients with advanced esophageal cancer.Due to higher complication rates for patients subjected to radical lymphadenectomy, it is recommended that these procedures be performed in specialized high volume centers with corresponding surgical experience.

[Impact of clinical trials for surgery]. / Bedeutung klinischer Studien für die Chirurgie.

Clinical trials play a key role in patient care, academic education and research in surgery. Without valid studies the practice of evidence-based medicine is limited. Surgery is supported through funding by the German Ministry of Education and Research to establish an infrastructure for clinical trials. So far seven universities have worked together in a network since 2007 and successfully obtained funding for six large randomized trials from a program existing since 2004. Until now 2,249 patients have been randomized within 11 trials and 910 patients have been treated at local hospitals without academic responsibilities. An increase in the interest in clinical trials in daily practice has resulted through the certification of hospitals for special treatment that specifies that at least 5% of all patients are included in clinical trials.