The VACStent trial: combined treatment of esophageal leaks by covered stent and endoscopic vacuum therapy.

BACKGROUND: Endoscopic treatment of esophageal leaks, mostly by covered stents or endoscopic vacuum therapy (EVT), has largely improved the clinical outcome in the last decade. However, both techniques suffer from significant limitations. Covered stents are hampered by a high rate of migration and missing functional drainage, whereas endoluminal EVT devices are limited by obstruction of the GI tract. The new design of the VACStent makes it a fully covered stent within a polyurethane sponge cylinder, allowing EVT while stent passage is still open. Initial clinical applications have demonstrated the fundamental concept of the VACStent. METHOD: A prospective multicenter open-label study was performed with the primary endpoint safe practicality, complete leak coverage, and effective suction-treatment of esophageal leaks. Secondary endpoints were prevention of septic conditions, successful leak healing, and complications, in particular stent-migration, local erosions and bleeding. RESULTS: Fifteen patients with different, mostly postoperative anastomotic leaks were enrolled in three centers. A total of 41 VACStents were implanted. The mean number of VACStents per patient was 2.7, with a mean duration of VACStent treatment of 15 days. The primary endpoint was met in all VACStent applications (41/41 implants), resulting in a leak healing rate of 80% (12/15 patients). Septic episodes were prevented in 93% (14/15 patients) and there was no mortality. There were no severe device-related adverse events (SADE) nor significant local bleeding or erosion. Minor stent-dislocation and migration, respectively, was observed in 7%. Oral intake of liquids or food was documented in 87% (13/15 patients). One anastomotic stenosis was seen during follow-up. CONCLUSIONS: VACStent treatment is a safe and effective treatment in esophageal leaks which can be covered by the sponge cylinder. Its application was described as easy and resembling that of conventional GI stents, with an impressive clinical success rate comparable to EVT outcomes. The VACStent offers a new option for clinical treatment of critical situations in esophageal perforations and anastomotic sutureline failures.

Training or non-surgical factors-what determines a good surgical performance? A randomised controlled trial.

BACKGROUND: Acquiring laparoscopic skills is a necessity for every young surgeon. Whether it is a talent or a non-surgical skill that determines the surgical performance of an endoscopic operation has been discussed for years. In other disciplines aptitude testing has become the norm. Airlines, for example, have implemented assessments to test the natural aptitude of future pilots to predict their performance later on. In the medical field, especially surgery, there are no similar comparable tests implemented or even available. This study investigates the influence of potential factors that may predict the successful performance of a complex laparoscopic operation, such as the surgeon's age, gender or learning method. METHODS: This study focussed 70 surgical trainees. It was designed as a secondary analysis of data derived from a 2 × 2 factorial randomised controlled trial of practical training and/or multimedia training (four groups) in an experimental exercise. Both before and then after the training sessions, the participating trainees performed a laparoscopic cholecystectomy in a pelvitrainer. Surgical performance was then evaluated using a modified objective structured assessment of technical skills (OSATS). Participants were classified as 'Skilled' (high score in the pre-test), 'Good Learner' (increase from pre- to post-test) or 'Others' based on the OSATS results. Based on the results of the recorded performance, the training methods as well as non-surgical skills were eventually evaluated in a univariate and in a multivariate analysis. RESULTS: In the pre-training performance 11 candidates were categorised as 'Skilled' (15.7%), 35 participants as 'Good Learners' (50.0%) and 24 participants were classified as 'Others'. The univariate analysis showed that the age, a residency in visceral surgery, and participation in a multimedia training were significantly associated with this grouping. Multivariate analyses revealed that residency in visceral surgery was the most predictive factor for the 'Skilled' participants (p = 0.059), and multimedia training was most predictive for the 'Good Learner' (p = 0.006). Participants in the group of 'Others' who were neither 'Skilled' nor improved in the training phase were younger (p = 0.011) and did not receive multimedia (p < 0.001) or practical (p = 0.025) training. CONCLUSION: The type of learning method has been shown to be the most effective factor to improve laparoscopic skills, with multimedia training proving to be more effective than practical training.

Is the transnasal access for esophagogastroduodenoscopy in routine use equal to the transoral route? A prospective, randomized trial.

BACKGROUND AND STUDY AIMS: Routine esophagogastroduodenoscopy (EGD) is increasingly performed without sedation. Transoral (TO) and transnasal (TN) EGD offer different patient comfort and complications. PATIENTS AND METHODS: For a controlled, randomized, clinical trial comparing TN-EGD with TO-EGD without sedation, patients were assigned to TN-EGD using a thin endoscope (group 1, 93 patients), or TO-EGD using a standard endoscope (group 2, 90 patients). Physician-rated procedural time and complications as well as patient-rated side effects and preferences were compared. In group 3, patients (118) who had previously undergone TO-EGD, now underwent TN-EGD. RESULTS: Between group 1 and 2 there was no significant difference for procedural time. Nausea (p = 0.047) and epistaxis (p < 0.001) were significantly more frequent for TN-EGD. Conversion rate from TN- to TO-EGD was low with 4.3 %. For TN-EGD, patients' tolerance was better (p < 0.001), gagging was less (p < 0.001). In case of a future EGD, patients who know both procedures (group 3), strongly vote for TN-EGD (80 %). All groups vote against sedation for future procedures (90 %/90 %/89 %). CONCLUSIONS: Epistaxis can be relevant after TN-EGD, but can mostly be managed conservatively. TN-EGD is superior to TO-EGD regarding subjective and objective gagging as well as procedural tolerance. Patients who experienced both access routes, prefer TN-EGD. TN-EGD without sedation should be aspired for patient comfort and is recommended for routine use.

Clinical implantation of 92 VACStents in the upper gastrointestinal tract of 50 patients-applicability and safety analysis of an innovative endoscopic concept.

Introduction: Endoscopic vacuum therapy (EVT) has emerged as a promising treatment option for upper gastrointestinal wall defects, offering benefits such as evacuation of secretions and removal of wound debris by suction, and reduction and healing of wound cavities to improve clinical outcomes. In contrast, covered stents have a high rate of migration and lack functional drainage, while endoluminal EVT devices obstruct the GI tract. The VACStent is a novel device that combines the benefits of EVT and stent placement. Its design features a fully covered Nitinol-stent within a polyurethane sponge cylinder, enabling EVT while maintaining stent patency. Methods: This study analyzes the pooled data from three different prospective study cohorts to assess the safe practicality of VACStent placement, complete leak coverage, and effective suction-treatment of esophageal leaks. By pooling the data, the study aims to provide a broader base for analysis. Results: In total, trans-nasal derivation of the catheter, suction and drainage of secretion via vacuum pump were performed without any adversity. In the pooled study cohort of 92 VACStent applications, the mean stent indwelling time was 5.2 days (range 2-8 days) without any dislocation of the device. Removal of the VACStent was done without complication, in one case the sponge was lost but subsequently fully preserved. Minor local erosions and bleeding and one subsequent hemostasis were recorded unfrequently during withdrawal of the device (5.4%, 5/92) but no perforation or pressure ulcer. Despite a high heterogeneity regarding primary disease and pretreatments a cure rate of 76% (38/50 patients) could be achieved. Discussion: In summary, insertion and release procedure was regarded as easy and simple with a low potential of dislocation. The VACStent was well tolerated by the patient while keeping the drainage function of the sponge achieving directly a wound closure by continuous suction and improving the healing process. The implantation of the VACStent provides a promising new procedure for improved clinical treatment in various indications of the upper gastrointestinal wall, which should be validated in larger clinical studies.Clinical Trial Registration: Identifier [DRKS00016048 and NCT04884334].

Deterioration in quality of life (QoL) in patients with malignant ascites: results from a phase II/III study comparing paracentesis plus catumaxomab with paracentesis alone.

BACKGROUND: Malignant ascites (MA) is associated with poor prognosis and limited palliative therapeutic options. Therefore, quality of life (QoL) assessment is of particular importance to demonstrate new treatment value. Following the demonstration of the superiority of catumaxomab and paracentesis over paracentesis on puncture-free survival, this analysis aimed at comparing deterioration in QoL between both the treatment options. PATIENTS AND METHODS: In a randomised, multicentre, phase II/III study of patients with MA due to epithelial cell adhesion molecule (EpCAM) positive cancer, the QoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items (EORTC QLQ-C30) questionnaire at screening, 1, 3 and 7 months after treatment and in the case of re-puncture on the day of paracentesis. Time to first deterioration in QoL was defined as a decrease in the QoL score of at least five points and compared between the catumaxomab (n=160) and control (n=85) groups using the log-rank test and Cox proportional hazards models adjusted for baseline score, country and primary tumour type. RESULTS: Deterioration in QoL scores appeared more rapidly in the control than in the catumaxomab group (median 19-26 days versus 47-49 days). The difference in time to deterioration in QoL between the groups was statistically significant for all scores (P<0.01). The hazard ratios ranged from 0.08 to 0.24 (P<0.01). CONCLUSIONS: Treatment with catumaxomab delayed deterioration in QoL in patients with MA. Compared with paracentesis alone, catumaxomab enabled patients to benefit from better QoL for a prolonged survival period.

Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer.

It is unclear whether disseminated tumour cells detected in bone marrow in early stages of solid cancers indicate a subclinical systemic disease component determining the patient's fate or simply represent mainly irrelevant shed cells. Moreover, characteristics differentiating high and low metastatic potential of disseminated tumour cells are not defined. We performed repeated serial bone marrow biopsies during follow-up in operated gastric cancer patients. Most patients with later tumour relapse revealed either an increase or a constantly high number of tumour cells. In contrast, in patients without recurrence, either clearance of tumour cells or negative or low cell counts were seen. Urokinase plasminogen activator (uPA)-receptor expression on disseminated tumour cells was significantly correlated with increasing tumour cell counts and clinical prognosis. These results demonstrate a systemic component in early solid cancer, indicated by early systemically disseminated tumour cells, which may predict individual disease development.

Laparoscopic extraperitoneal rectal cancer surgery: the clinical practice guidelines of the European Association for Endoscopic Surgery (EAES).

BACKGROUND: The laparoscopic approach is increasingly applied in colorectal surgery. Although laparoscopic surgery in colon cancer has been proved to be safe and feasible with equivalent long-term oncological outcome compared to open surgery, safety and long-term oncological outcome of laparoscopic surgery for rectal cancer remain controversial. Laparoscopic rectal cancer surgery might be efficacious, but indications and limitations are not clearly defined. Therefore, the European Association for Endoscopic Surgery (EAES) has developed this clinical practice guideline. METHODS: An international expert panel was invited to appraise the current literature and to develop evidence-based recommendations. The expert panel constituted for a consensus development conference in May 2010. Thereafter, the recommendations were presented at the annual congress of the EAES in Geneva in June 2010 in a plenary session. A second consensus process (Delphi process) of the recommendations with the explanatory text was necessary due to the changes after the consensus conference. RESULTS: Laparoscopic surgery for extraperitoneal (mid- and low-) rectal cancer is feasible and widely accepted. The laparoscopic approach must offer the same quality of surgical specimen as in open surgery. Short-term outcomes such as bowel function, surgical-site infections, pain and hospital stay are slightly improved with the laparoscopic approach. Laparoscopic resection of rectal cancer is not inferior to the open in terms of disease-free survival, overall survival or local recurrence. Laparoscopic pelvic dissection may impair genitourinary and sexual function after rectal resection, like in open surgery. CONCLUSIONS: Laparoscopic surgery for mid- and low-rectal cancer can be recommended under optimal conditions. Still, most level 1 evidence is for colon cancer surgery rather than rectal cancer. Upcoming results from large randomised trials are awaited to strengthen the evidence for improved short-term results and equal long-term results in comparison with the open approach.

[Modern didactics in surgical education--between demand and reality]. / Moderne Didaktik in der chirurgischen Weiterbildung--zwischen Anspruch und Wirklichkeit.

Surgical residency contains an inadequate amount of hands-on training in the operating room and time constraints further make this type of education on the floor unlikely. Due to these deficits in residency training, private surgical courses outside of the established residency programmes are in high demand. Therefore, surgical residents must spend their own resources and time in addition to their residency training in order to receive adequate clinical exposure. Didactic approaches like problem-based learning have begun to influence our modern education. These novel education approaches along with visualisation training, video-based presentations, and multimedia-based training can be useful adjuncts to traditional surgical training.

BIOLAP: biological versus synthetic mesh in laparo-endoscopic inguinal hernia repair: study protocol for a randomized, multicenter, self-controlled clinical trial.

BACKGROUND: Inguinal hernia repair is one of the most common surgical operations globally; more than 20 million groin herniae are repaired annually worldwide. Recurrence after an inguinal hernia operation is a considerable clinical problem. Another remaining problem after hernia surgery is the occurrence of chronic pain. Up to now, the use of synthetic meshes is the standard procedure, but there is increasing evidence that biological meshes could be advantageous concerning the occurrence of chronic pain due to different postoperative remodeling, without the disadvantages of a life-long implant. We hypothesize that the use of a biological mesh reduces postoperative pain without being inferior in terms of recurrence rate compared with a synthetic mesh. METHODS/DESIGN: The trial compares possible the advantages of biological matrices to synthetic meshes in laparo-endoscopic inguinal hernia repair. Four hundred and ninety-six patients with primary bilateral inguinal herniae in 20 German hernia centers will be enrolled. Biological mesh is used for one of the bilateral herniae, the other side will be operated on with a synthetic mesh. Randomization will preset which side is repaired with which material and trial participants will not be informed about the location of each mesh type. The primary endpoints will be intensity of postoperative local pain and the incidence of recurrent hernia after 2 years. DISCUSSION: There is no reasonably sized trial that assesses the use of biological meshes in laparo-endoscopic inguinal hernia repair. Our self-controlled trial design allows a direct comparison of the two meshes with very few confounding factors as well as minimizing the exclusion criteria. As we compare CE-certified medical devices in their designated indication the medical risk is not different compared to routine clinical care. Due to the common nature of bilateral inguinal hernia, a high recruitment rate is achievable. Because guidelines for hernia repair have stressed the need for reliable data on the already frequent use of biological meshes, we can expect our trial to have a direct implication on hernia-repair standards. TRIAL REGISTRATION: German Clinical Trials Register, ID: DRKS00010178 . Registered on 16.June.2016. BIOLAP underwent full external peer review as part of the funding process with the German Research Foundation.

Liver transplantation for hilar cholangiocarcinoma: a German survey.

BACKGROUND: The present study reports a German survey addressing outcomes in nonselected historical series of liver transplantation (OLT) for hilar cholangiocarcinoma (HL). PATIENTS AND METHODS: We sent to all 25 German transplant centers performing OLT a survey that addressed (1) the number of OLTs for HL and the period during which they were performed; (2) the incidence of HL diagnosed prior to OLT/rate of incidental HL (for example, in primary sclerosing cholangitis); (3) tumor stages according to Union Internationale Centre le Cancer; (4) patient survival; and (5) tumor recurrence rate. RESULTS: Eighty percent of centers responded, reporting 47 patients who were transplanted for HL. Tumors were classified as pT2 (25%), pT3 (73%), or pT4 (2%). HL was diagnosed incidentally in 10% of cases. A primary diagnosis of PSC was observed in 16% of patients. Overall median survival was 35.5 months. When in-hospital mortality (n = 12) was excluded, the median survival was 45.4 months, corresponding to 3- and 5-year survival rates of 42% and 31%, versus 31% and 22% when in-hospital mortality was included. HL recurred in 34% of cases. Three- and 5-year survivals for the 15 patients transplanted since 1998 was 57% and 48%, respectively. Median survival ranged from 20 to 42 months based on the time period (P = .014). CONCLUSIONS: The acceptable overall survival, the improved results after careful patient selection since 1998, and the encouraging outcomes from recent studies all suggest that OLT may be a potential treatment for selected cases of HL. Prospective multicenter randomized studies with strict selection criteria and multimodal treatments seem necessary.

What is the evidence for the use of biologic or biosynthetic meshes in abdominal wall reconstruction?

INTRODUCTION: Although many surgeons have adopted the use of biologic and biosynthetic meshes in complex abdominal wall hernia repair, others have questioned the use of these products. Criticism is addressed in several review articles on the poor standard of studies reporting on the use of biologic meshes for different abdominal wall repairs. The aim of this consensus review is to conduct an evidence-based analysis of the efficacy of biologic and biosynthetic meshes in predefined clinical situations. METHODS: A European working group, "BioMesh Study Group", composed of invited surgeons with a special interest in surgical meshes, formulated key questions, and forwarded them for processing in subgroups. In January 2016, a workshop was held in Berlin where the findings were presented, discussed, and voted on for consensus. Findings were set out in writing by the subgroups followed by consensus being reached. For the review, 114 studies and background analyses were used. RESULTS: The cumulative data regarding biologic mesh under contaminated conditions do not support the claim that it is better than synthetic mesh. Biologic mesh use should be avoided when bridging is needed. In inguinal hernia repair biologic and biosynthetic meshes do not have a clear advantage over the synthetic meshes. For prevention of incisional or parastomal hernias, there is no evidence to support the use of biologic/biosynthetic meshes. In complex abdominal wall hernia repairs (incarcerated hernia, parastomal hernia, infected mesh, open abdomen, enterocutaneous fistula, and component separation technique), biologic and biosynthetic meshes do not provide a superior alternative to synthetic meshes. CONCLUSION: The routine use of biologic and biosynthetic meshes cannot be recommended.

Immunotherapy of peritoneal carcinomatosis.

Intraperitoneal immunotherapy actually is a promising concept for treatment of peritoneal carcinomatosis for several reasons: The use of specifically engineered therapy in terms of antibodies or stimulated T lymphocytes against epithelial tumour antigens offers an elegant way to attack tumours on the peritoneal surface, as peritoneal cells have a mesenchymal origin. This is especially true for modern multimodal treatment concepts, were local compartment treatment together with systemic chemotherapy and (if possible) surgical tumour removal will be individually combined.

Urokinase plasminogen activator receptor (uPA-R): one potential characteristic of metastatic phenotypes in minimal residual tumor disease.

Evidence of dynamic development of cytokeratin (CK) 18-positive disseminated tumor cells in bone marrow of curatively resected cancer patients has implicated a subclinical minimal residual disease as a biologically relevant component in solid cancer. However, differentiation between irrelevant shed cells and those cells potentially capable of causing later recurrence has not yet been made. In parallel, accumulating data show functional association of the urokinase plasminogen activator (uPA) system and the membranous uPA receptor (uPA-R) with the capacity of a tumor cell for invasion and metastasis. The present study was designed to find descriptive evidence in vivo concerning whether uPA-R could be one potential characteristic for metastatically relevant phenotypes of disseminated tumor cells. An immunocytochemical double staining for uPA-R and CK18 (immunogold/alkaline phosphatase anti-alkaline phosphatase) was performed on perioperative and follow-up bone marrow aspirations of 78 curatively resected gastric cancer patients, if positive tumor cell status had been shown previously with the single alkaline phosphatase anti-alkaline phosphatase method. Bone marrow cells (10(6)) were examined in each assay. Postoperative qualitative and quantitative development of uPA-R-expressing disseminated tumor cells was followed in relation to uPA-R-negative cells and correlated with later clinical relapse. Double staining could be performed perioperatively or in follow-up, or both, in 58 of 78 patients. Expression of uPA-R on perioperatively disseminated tumor cells significantly correlated with later quantitative increases of tumor cells (P = 0.0009). Overall median tumor cell numbers with uPA-R expression significantly increased during follow-up from a median value of 5.5 to 10.0 in 10(6) cells (P = 0.008), and the mean relative percentage of uPA-R-positive, compared with uPA-R-negative, disseminated tumor cells also increased, from 47.9% at surgery to 68.6% in follow-up (P < 0.001). This was mainly due to patients with later tumor relapse (increase from 63.9 to 80.7%, P = 0.001). Patients without relapse showed slight increases at lower percentage levels (5.7% at surgery, 7.4% in follow-up). Differences for relapsing patients were significant (surgery, P = 0.006; follow-up, P < 0.001). Our results suggest from an in vivo model that uPA-R may be one antigen that enables identification and follow-up observations of metastatically relevant phenotypes of disseminated tumor cells, differentiating their individual potential for causing relapse.

E-cadherin expression in primary and metastatic gastric cancer: down-regulation correlates with cellular dedifferentiation and glandular disintegration.

Expression of the epithelial cell adhesion molecule E-cadherin in primary and metastatic gastric carcinoma was examined using immunohistochemical analyses. Compared to normal mucosa, 92% of the primary tumors (n = 60) showed reduced E-cadherin expression, suggesting that down-regulation of this cell adhesion molecule is a common early event in gastric tumorigenesis. No significant correlation was found between E-cadherin expression and tumor diameter, lymphatic vessel invasion, Borrmann classification, lymph node status, or manifest metastases. Although advanced tumors (tumor stage 3/4) showed a loss of E-cadherin-positive cells (< or = 50% cells/lesion, P = 0.0168), the most significant correlation was observed between low E-cadherin expression and cellular dedifferentiation (grading 3/4, P = 0.0001) and disintegration of tissue architecture (Lauren and WHO classifications, P = 0.0001). Low E-cadherin expression (< or = 50% cells/lesion) was associated with tumor recurrence (P = 0.0013) and mortality (P = 0.0246). E-cadherin expression in metastatic lesions (n = 58) also correlated with the degree of glandular differentiation (P = 0.0001). Significant correlation (rs = 0.686) was observed between E-cadherin expression in primary and metastatic lesions from individual patients (n = 39). However, while metastases derived from E-cadherin-negative tumors remained negative, those originating from E-cadherin-positive tumors frequently demonstrated increased levels of expression. Evaluation of multiple metastases in 11 patients revealed uniformly strong E-cadherin expression in liver metastases, suggesting a possible regulatory role of the microenvironment.

c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems.

PURPOSE: The c-erbB-2 gene (encoding the protein p185) is overexpressed in diverse human cancers and has been implicated to be of prognostic value in gastric cancer. Recent studies suggest a role of p185 in tumor progression by specifically promoting the invasive capacity of tumor cells. Therefore, the present study was conducted with the following three objectives: (1) to support the prognostic value of c-erbB-2 in gastric cancer in a large prospective series using a monoclonal antibody and a highly sensitive immunohistochemical method; (2) to determine the association of c-erbB-2 expression with the expression of invasion-related genes; and (3) to perform the first overall multivariate analysis including c-erbB-2 and the invasion-related tumor-associated protease systems. PATIENTS AND METHODS: In a consecutive prospective series of 203 gastric cancer patients (median follow-up, 42 months), expression of c-erbB-2 and a panel of tumor-associated proteases and inhibitors by tumor cells were evaluated semiquantitatively (score 0 to 3) and analyzed for correlation (chi(2) test, Bonferroni-corrected). Kaplan-Meier survival analysis and multivariate Cox analysis were performed to determine the relative prognostic impact of c-erbB-2 and the invasion-related parameters. RESULTS: Kaplan-Meier analysis (log-rank statistics) revealed a significant association of increasing expression of c-erbB-2 with shorter disease-free (P =. 0023) and overall survival (P =.0160). High amounts of p185 were significantly associated with a high expression of urokinase-type plasminogen activator (uPA) (P <.010), uPA-receptor (P =.030), type-1 plasminogen activator inhibitor (PAI) (P <.010), type-2 PAI (P =.021), cathepsin D (P =.036), matrix metalloproteinase-2 (P =. 024), alpha-1-antichymotrypsin (P =.025), and alpha-2-macroglobulin (P =.017). Multivariate analysis considering these proteases/protease inhibitors, in addition to alpha-1-antitrypsin, tissue plasminogen activator, plasminogen, alpha-2-antiplasmin, and antithrombin III, and established prognostic parameters revealed that, in addition to surgical curability, pT stage, pN stage, and PAI-1, c-erbB-2 is an independent prognostic factor for overall survival of curatively resected patients (n = 139; P =.049; relative risk, 1.54; 95% confidence interval, 1.08 to 1.67) and all patients (P =.028; relative risk 1.33; 95% CI, 1.28 to 1.38). CONCLUSION: c-erbB-2 is confirmed as a new independent, functional prognostic parameter for overall survival in gastric cancer, even when a panel of invasion-related factors, including the strong prognostic parameter PAI-1, are considered. The significant correlation of p185 with several tumor-associated proteases supports the hypothesis that c-erbB-2 is a promoter of invasion and metastasis. This strongly suggests that c-erbB-2 may be a promising target for anti-invasive therapy in gastric cancer.

Blood transfusion-modulated tumor recurrence: first results of a randomized study of autologous versus allogeneic blood transfusion in colorectal cancer surgery.

PURPOSE: Allogeneic blood transfusions have reportedly been associated with a poor prognosis in patients with curatively resected cancer. To control for immunosuppression induced by a speculatively causal allogeneic blood transfusion, we designed a randomized study in which the control group received autologous blood transfusions not related to any condition of immunosuppression. PATIENTS AND METHODS: One hundred twenty patients with potentially curative resectable colorectal cancer and the capability to predeposit autologous blood were randomly selected to receive either standard allogeneic blood transfusion or predeposited autologous blood. RESULTS: In curatively resected cancer patients, the number who needed allogeneic blood transfusions was reduced from 60% in the allogeneic blood group to 33% in the autologous blood group (P = .009). After a median follow-up duration of 22 months (range, 8 to 48) tumor recurrence was observed in 28.9% of the allogeneic blood group and 16.7% of the autologous blood group. Life-table analysis established a tendency toward a shorter tumor-free survival for the allogeneic blood group (log-rank P = .11). The problem with this analysis was the strong association of allogeneic blood transfusions with tumor recurrence, which interfered in 33% of patients in the autologous blood group who required additional allogeneic blood transfusions. Multivariate analysis of established risk factors for tumor recurrence and surgery-related variables reflecting potential immunosuppressive conditions showed that only pT stage (relative risk, 6.61; 95% confidence interval [CI], 1.82 to 23.99; P = .004), pN stage (relative risk, 8.39; 95% CI, 3.15 to 22.33; P < .001), and the need for allogeneic blood (relative risk, 6.18; 95% CI, 2.20 to 17.37; P < .001) were independent predictors of tumor recurrence. Subgroup analysis of patients who received a transfusion of < or = 2 U blood found a significantly higher risk of tumor recurrence in the allogeneic blood group (relative risk, 5.16; 95% CI, 1.13 to 23.62; P = .034), which was reduced to borderline significance (relative risk, 3.54; 95% CI, 0.76 to 16.51; P = .107) by adjustment for tumor (T) and node (N) stage. CONCLUSION: As indicated by these first results, the blood transfusion modality has a significant effect on tumor recurrence after surgical treatment of colorectal cancer. A change in the practice of blood transfusion might thus potentially surpass the impact of any recent adjuvant treatment strategies.

Tumor-associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activator system.

PURPOSE: The significance of tumor-associated proteolysis as reflected by parameters of the urokinase-type plasminogen activator (uPA) system for prognosis in cancer patients has been proposed because of evidence for its central role in basic mechanisms of invasion and metastasis. The aim of the present study was to evaluate whether the expression of the uPA parameters might be of clinical value in gastric cancer as a tumor/biologically defined risk factor. PATIENTS AND METHODS: In a consecutive series of 203 patients resected for primary gastric cancer, the expression of uPA, uPA-receptor (uPA-R), plasminogen activator inhibitor (PAI)-1, and PAI-2 was determined immunohistochemically. The results were classified semiquantitatively (0 to 3). Patients were followed-up prospectively for a median of 31 months (range, 9 to 56 months). Disease-free and overall survival were analyzed according to Kaplan-Meier and with univariate and multivariate Cox analyses in relation to conventional prognostic factors. RESULTS: Univariate analyses revealed a highly significant inverse correlation of uPA, uPA-R, and PAI-1 expression with survival time (P = .0008, P = .0002, and P = .0002, respectively), whereas PAI-2 demonstrated only a weak correlation. In multivariate analyses, PAI-1 was an independent and strong prognostic factor (P = .005; relative risk, 1.47 per staining degree; 95% confidence interval [CI], 1.31 to 1.64). In pT1/2 tumors and in Laurén's diffuse and mixed types, uPA, uPA-R, and PAI-1 added significant prognostic information. PAI-1 was also associated with survival in the subgroup of lymph node-positive patients. CONCLUSION: PAI-1, uPA, and uPA-R are new functional risk factors reflecting clinical prognosis. In particular, PAI-1 is a new independent variable for the identification of patients at high risk after tumor resection. Our results support the hypothesis that the uPA system probably is of general importance for prognosis of patients with malignant disease, indicating an individual tumor's capacity for invasion and metastasis.

Prognostic significance of bone marrow micrometastases in patients with gastric cancer.

BACKGROUND: Monoclonal antibodies (mabs) against components of the cytoskeleton such as cytokeratins allow single disseminated epithelial carcinoma cells to be detected in the bone marrow. The aim of this study was to examine the prognostic relevance of these cells in patients with gastric cancer and to evaluate by multivariate analysis their predictive value compared with conventional risk factors. PATIENTS AND METHODS: A total of 1 x 10(6) cells from bone marrow aspirates were screened immunoctochemically for the presence and absolute number of disseminated tumor cells using mab CK2 to cytokeratin component no. 18. Patients were monitored prospectively for 30.6 +/- 15.2 months. RESULTS: Between one and 122 CK2-positive cells per 1 million mononuclear bone marrow cells were present in 95 of 180 patients (53%). A similar prevalence of 51% was found in curatively operated patients (55 of 109). Comparison with conventional prognostic risk factors showed a correlation of cell dissemination with pathohistologic tumor (pT) stage (P = .07) and Bormann classification (P = .022). Tumor-cell content in the bone marrow predicted disease-free and overall survival in curatively resected patients (P = .007 and P = .049, respectively). Multivariate analysis, which included established risk factors, showed that extent of tumor-cell dissemination was an independent prognostic parameter for disease-free survival in T1/2 tumors (P = .014; relative risk [RR], 1.84; 95% confidence interval [CI], 1.35 to 2.52), in intestinal type carcinomas according to Laurén (P = .008; RR, 1.62; 95% CI, 1.23 to 2.12), and in patients without lymph node involvement (P = .004; RR, 2.43; 95% CI, 1.22 to 4.82). CONCLUSION: Presence of disseminated tumor cells in bone marrow is indicative of systemic disease even in early-stage gastric cancer. The extent of tumor-cell presence in bone marrow correlates with prognosis in curatively resected patients. Therefore, a positive bone marrow finding may be a selection criteria for adjuvant treatment because of minimal residual tumor load.