Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study).

BACKGROUND: Initially, unresectable colorectal liver metastases can be resected after response to chemotherapy. While cetuximab has been shown to increase response and resection rates, the survival outcome for this conversion strategy needs further evaluation. PATIENTS AND METHODS: Patients with technically unresectable and/or ≥5 liver metastases were treated with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated with regard to resectability every 2 months. Tumour response and secondary resection data have been reported previously. A final analysis of overall survival (OS) and progression-free survival (PFS) was carried out in December 2012. RESULTS: Between December 2004 and March 2008, 56 patients were randomised to arm A, 55 to arm B. The median OS was 35.7 [95% confidence interval (CI) 27.2-44.2] months [arm A: 35.8 (95% CI 28.1-43.6), arm B: 29.0 (95% CI 16.0-41.9) months, HR 1.03 (95% CI 0.66-1.61), P = 0.9]. The median PFS was 10.8 (95% CI 9.3-12.2) months [arm A: 11.2 (95% CI 7.2-15.3), arm B: 10.5 (95% CI 8.9-12.2) months, HR 1.18 (95% CI 0.79-1.74), P = 0.4]. Patients who underwent R0 resection (n = 36) achieved a better median OS [53.9 (95% CI 35.9-71.9) months] than those who did not [21.9 (95% CI 17.1-26.7) months, P < 0.001]. The median disease-free survival for R0 resected patients was 9.9 (95% CI 5.8-14.0) months, and the 5-year OS rate was 46.2% (95% CI 29.5% to 62.9%). CONCLUSIONS: This study confirms a favourable long-term survival for patients with initially sub-optimal or unresectable colorectal liver metastases who respond to conversion therapy and undergo secondary resection. Both FOLFOX/FOLFIRI plus cetuximab, appear to be appropriate regimens for 'conversion' treatment in patients with K-RAS codon 12/13/61 wild-type tumours. Thus, liver surgery can be considered curative or alternatively as an additional 'line of therapy' in those patients who are not cured. CLINICAL TRIAL NUMBER: NCT00153998, www.clinicaltrials.gov.

The influence of downstream arterial perfusion parameters on doppler pulsatility index and resistance index in an in-vitro perfusion model.

BACKGROUND: To investigate in vitro how downstream perfusion parameters influence pulsatility index (PI), resistance index (RI) and their constituting Doppler velocities. MATERIALS AND METHODS: We analyzed the influence of resistance, compliance, reflection coefficient and input impedance on PI and RI in an in-vitro model of arterial flow. RESULTS: The nominators of PI and RI were determined by resistance. The numerators were determined by compliance and by the reflection coefficient. There were close relationships of PI and RI with resistance under the condition of constant compliance, but not when compliance was variable. CONCLUSION: PI and RI consist of velocity terms which are independently influenced by different parameters of impedance: compliance, reflection coefficient and resistance. These findings explain the contradictory results reported for the relationship between the indices and peripheral resistance in studies where compliance and reflection effects were not considered.

Matrix metalloproteinase 2 polymorphisms in a caucasian population with abdominal aortic aneurysm.

BACKGROUND: The formation of sporadic abdominal aortic aneurysm (AAA) is explained by remodeling of the extracellular matrix (ECM) and breakdown of structural components of the vascular wall. Matrix metalloproteinase 2 (MMP2) is one of the principal matrix-degrading proteases and is known to play a major role in the remodeling of the extracellular matrix in arterial vessels. Increased MMP2 expression in the extracellular matrix of the walls of AAAs has been shown in several studies. To investigate the possible impact of genetic variants of the MMP2 gene in the etiology of AAA, we conducted this case-control study. PATIENTS AND METHODS: We analyzed MMP2 single-nucleotide polymorphisms (SNPs) in 51 patients with AAA and 48 controls. Differences in genotype and allele frequencies of identified polymorphisms were determined after sequencing the entire coding region and three selected parts of the promoter. RESULTS: Eighteen polymorphisms were identified, 6 of which are newly described, with 3 located in the introns (c.IVS1+31C>G, c.IVS7-18G>A, c.IVS10+26C>T) and 3 located in the coding region (c.124G>A, c.1368C>T, c.1860C>T). There were no statistically significant differences in genotype or allele frequencies between the two groups. CONCLUSIONS: Our analysis of the entire coding region and three parts of the promoter of the MMP2 gene failed to show an association between genetic polymorphisms and AAA, suggesting that variations in the MMP2 gene do not contribute to the development of AAA.

Quality of life and long-term results after ruptured abdominal aortic aneurysm.

OBJECTIVES: Quality of life as an endpoint of surgery and the long-term prognosis for patients who have survived surgery for a ruptured abdominal aortic aneurysm (RAAA) is not well-documented. PATIENTS AND METHODS: The records of all patients from 1993 to 2000 who underwent resection of RAAA were reviewed. Survival data were calculated from direct contact with the patients or follow-up records. All patients who were alive at the time of our study were invited to participate in follow-up investigations. They received the internationally comparable WHO-QOL-BREF-test. RESULTS: In a period of 7 years, 80 patients underwent surgery for RAAA. The average follow-up time was 5.1 years (1-7.9 years). Our data show that 51% of our patients died within 6 months postoperatively because of the complications of the aortic rupture (in-hospital mortality 39%). Patients who survived the first 6 months after surgery died for the same reasons as the normal population. However, patients who were younger than 75 at the time of RAAA had a higher relative survival rate than a matched sample of the population. There was no significant difference in the quality of life between the study group and the general population. CONCLUSIONS: RAAA survivors had no difference in long-term survival as compared to the general population and also had very few long-term complications. The WHOQOL-BREF-test suggests that the quality of life of survivors of RAAA is similar to the general population.

Infragenicular polytetrafluoroethylene bypass with tapered versus straight vascular grafts: results from a prospective multicenter cohort study.

Both straight and tapered arterial grafts are commonly used for infragenicular bypass surgery. Opinions vary considerably regarding the use of each type of graft and depend on individual experience, as no trial yet has assessed clinical outcomes comparing both groups. We conducted a prospective, multicenter, cohort study to analyze results for each graft type. From a total of 81 patients, 50 underwent infragenicular bypass surgery with straight PTFE prostheses and 31 with tapered prostheses in a prospective, multicenter trial. Six different centers for vascular surgery took part in the trial. In clinical follow-up at discharge as well as 3, 6, 12, 18, 24, and 36 months after revascularization, various parameters were evaluated comparing patency rates, limb salvage, and major amputation rates. Significant differences were found in limb salvage rates between the two groups. Patients receiving a straight graft fared better in this regard. Further data suggest that short-term primary patency is also improved in straight prostheses. Sixty-four percent of these remained patent after 1 year, while only 50% of tapered prostheses were still patent. No differences between the groups were found for secondary patency. The advantages of straight prostheses seem to be reduction of thrombus formation and intimal hyperplasia. Furthermore, it appears that the surgeons participating in this study prefer the use of straight prostheses. Even though the group of patients that received tapered grafts had slightly more unfavorable preoperative conditions, the data still support the superiority of straight vascular grafts. However, prospective randomized trials are necessary to evaluate the benefit of different bypass designs definitively.

ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma.

Gene expression profiling revealed ADAM9 to be distinctly overexpressed in pancreatic ductal adenocarcinoma (PDAC). We examined the relevance of ADAM9 expression in PDAC diagnosis and prognosis. A total of 59 infiltrating PDACs, 32 specimens from patients with chronic pancreatitis, 11 endocrine tumours and 24 acinar cell carcinomas were immunohistochemically analysed for ADAM9 expression. Staining for ADAM9 was detected in 58 out of 59 (98.3%) PDACs and in two out of 24 (8.3%) acinar cell carcinomas, but not in endocrine tumours. In the non-neoplastic pancreas, whether normal or chronically inflamed, ADAM9 was expressed in centroacinar and intralobular duct cells, but not in interlobular duct cells and their hyperplastic lesions. Pancreatic ductal adenocarcinomas showing cytoplasmic ADAM9 expression correlated with poor tumour differentiation and also with shorter overall survival than in cases showing only an apical membranous staining pattern (P=0.001). Multivariate analysis identified cytoplasmic ADAM9 expression as an independent marker of shortened survival in a set of 42 curatively (R0) resected PDAC (P<0.05, hazard ratio 2.85, 95% confidence interval: 1.21-6.71). The results show that ADAM9 expression distinguishes PDACs from other solid pancreatic tumours. In addition, cytoplasmic ADAM9 overexpression is associated with poor differentiation and shortened survival. Therefore, ADAM9 overexpression might contribute to the aggressiveness of PDACs.

Locally advanced small-bowel adenocarcinoma missed primarily by capsule endoscopy but diagnosed by push enteroscopy.

Wireless-capsule-endoscopy is a new painless method that is able both to visualize the entire small bowel and to detect even small lesions. We report here the case of a patient in whom a locally advanced small-bowel adenocarcinoma was initially missed on capsule endoscopy, but was diagnosed by subsequent push enteroscopy. Capsule endoscopy was carried out in a 47-year-old patient with a history of obscure gastrointestinal bleeding, iron-deficiency anemia, and a lack of symptoms suggestive of stenosis. The capsule imaging revealed angiodysplasias in the jejunum, but no other abnormalities. Push enteroscopy was carried out to allow argon plasma coagulation treatment of the angiodysplasias that had been detected; it revealed a polypoid tumor 20 mm in diameter at 150 cm from the incisors, with the capsule endoscope still located proximal to the tumor and with its optical dome turned towards the push enteroscope. Clinical staging and subsequent surgical resection showed a locally advanced adenocarcinoma (pT4, pN0 (0/7), pMx, G3).[nl]Small-bowel tumors within the reach of push enteroscopy may be missed by capsule endoscopy. Although wireless capsule endoscopy is a major advance in the investigation of the small bowel, well-designed clinical studies still need to define the precise algorithm for diagnostic work-up of suspected small-bowel diseases.

[Early results of esophageal surgery in carcinoma]. / Frühergebnisse der Osophaguschirurgie beim Karzinom.

AIMS: The aim of this study was the evaluation of early results of esophageal resection for cancer including the assessment of pre-operative risk factors and post-operative mortality (risk score developed by Barthels et al. 1998). METHODS: One hundred and eighty one patients with esophageal cancer were operated with curative intention between October 1993 and December 2002. In a prospective analysis were reviewed: patient characteristics, characteristics of the esophageal cancer, part and type of esophageal resection, radicality, complications and mortality. CONCLUSION: In total, a resection of the tumor could be achieved in 143 cases (79.0%). The overall complication rate was 52.5%, mainly cardio-pulmonary complications (25.9%) were seen. The surgical complications were determined by anastomotic leak (12.6%) and recurrent nerve injury (9.1%). Both types of complications were observed significantly more often after esophageal resection with a cervical anastomosis (p = 0.03 and p < 0.01). The hospital mortality was 8.4%. The 30 days mortality was 4.9%. Using a preoperative risk score retro- and prospectively, our data showed a lower mortality in patients with a low risk profile (2.4% and 2.3%) compared to those with a medium risk profile (7.4% and 6.4%). The only patient with a high risk profile died after resection. DISCUSSION AND SUMMARY: The results of this analysis show that resection of esophageal cancer can be accomplished with acceptable morbidity and mortality. However, it has to be taken into account that the increase of pre-operative factors leads to an increase in post-operative mortality.

Intraoperative chemiluminometric assay for simplified localization of parathyroid adenomas during surgery for primary hyperparathyroidism.

Hyperparathyroidism is no longer considered an uncommon endocrinopathy. Between 1994 and 2002, 138 patients underwent neck exploration for primary hyperparathyroidism at the Department for Surgery in the University Hospital of Dresden. Common reasons for operation failure are usually hyperplasia or remnant parathyroid tissue, inadequate parathyroidectomy at initial operation or the occurrence of abnormal hyperfunctioning supernumerary glands. To reduce the operation time, as well as the failure rate that accompanies the incomplete excision of hypersecreting parathyroid tissue, we perform an intraoperative monitoring of parathyroid hormone with an immunochemiluminometric assay (Nichols Advantagetrade mark Intact PTH). With modification of this assay, it was possible to perform the assay in the operating theatre and to attain the hormone values within 10 min. In all cases of successful operation with excision of the adenomatous parathyroid gland the PTH values declined to under 20 percent of the initial intraoperative PTH values. Our results declare the intraoperative parathyroid hormone monitoring as a cost-effective method to control the effect of surgical treatment.

[Results and complications of ruptured abdominal aortic aneurysm repair]. / Ergebnisse und Komplikationen in der Behandlung des rupturierten abdominellen Aortenaneurysmas.

During 1993 to 2000 85 patients were treated for a ruptured abdominal aortic aneurysm. The average age of the patients was 72.4 years (46-90). 71 patients showed an infrarenal rupture and the remaining 14 a suprenal rupture. 76 of 85 cases were covered ruptures. All patients were operated upon. A tube graft was required in 43 cases and 31 needed a bifurcated graft. In further two cases an extraanatomical bypass was necessary due to a mycotic aneurysm. The operation on 11 patients could not be completed and 21 patients died in hospital during the postoperative period. On the other hand, 53 patients survived the rupture of the aneurysm. The mortality rate was 37.6 %. The early non-surgical complications dominated during the postoperative period. Respiratory failure, renal failure and cardiac failure were responsible for the mortality rate. It is unforseeable which patients will survive the emergency operation. Therefore it is always appropriate to attempt the reconstruction of an acutely ruptured AAA.

[The value of colour duplex sonography in the assessment of surgical resectability of pancreatic tumors]. / Farbduplexsonographie zur Beurteilung der Resektabilität von Pankreastumoren.

UNLABELLED: The Value of Colour Duplex Sonography in the Assessment of Surgical Resectability of Pancreatic Tumors. AIM: The aim of this study was to evaluate the assessment by modern colour duplex imaging (CDI) concerning the relation between tumour and vessels including haemodynamic parameters in the main abdominal arteries and the portal system, and to evaluate the influence of these results on surgical decision making. METHOD: From January 1997 to October 1998, 146 patients with a tumour of the pancreas were included in a prospective study. Tumour contact to vessels and to the retroperitoneum, data on the flow in the main abdominal arteries and the portal circulation (regional topography) as well as the detection of liver metastases, enlarged lymph nodes and peritoneal carcinomatosis were defined as representing criteria of resectability. The results were compared with the intraoperative situation and with the definite histological findings. RESULTS: In 57 resectable tumours, the portal system was found to be infiltrated by the tumour up to a length of 1.5 cm. The flow velocity reached between 4 and 53 cm/s (mean flow) and 9 to 105 cm/s (maximum flow). Out of 146 pancreatic tumours, 89 were found as being non-resectable. In these cases, the measured parameters differed depending on the degree of tumour infiltration in to the portal circulation. We measured values from 0 to 96 cm/s (mean flow) and from 0 to 201 cm/s (maximum flow) with loss of breath-dependent modulation. The contact area between tumor and portal vessel was longer than 2 cm. Pathological flow in the main abdominal arteries was only found in 2 of 13 cases. The local situation was assessed correctly in 140 out of 146 cases by CDI (sensitivity of 93.0 %, specificity of 97.8 %, positive predictive value of 96.4 %, negative predictive value of 95.6 %). Regarding the complete oncological status (local situation, metastases, lymph node involvement and peritoneal carcinomatosis), a sensitivity of 82.5 % and a specificity of 92.1 % (positive predictive value of 87.0 %, negative predictive value of 89.1 %) was found. CONCLUSION: Modern CDI can reliably assess the resectability of pancreatic tumours by the evaluation of morphological and haemodynamic parameters. There are still difficulties in the assessment of lymph node involvement as well as in the detection of small liver metastases and of peritoneal carcinomatosis without ascites.

[Radiofrequency ablation of liver tumours]. / Hochfrequenz-Thermoablation bei Lebertumoren.

BACKGROUND: A variety of local treatment modalities exists for the palliative therapy of inoperable primary or secondary liver tumours. In this connection the promising use especially of thermal ablation methods has been reported recently. Numerous procedures and technical terms have been mentioned in this context giving us the opportunity of a review on this subject. METHODS: From the literature of the last five years (Medline/PubMed) including the lists of references physical principles and application techniques, indications and contraindications, possibilities of evaluation and results of high frequency thermotherapy (HFTT) respectively radiofrequency ablation (RFA) were investigated and compared to our own first experiences. Survival and recurrence rates were estimated from the study results. RESULTS: Most authors describe the HF-thermoablative treatment as a technically uncomplicated and relatively low-risk procedure. After a mean follow-up of about 10 months the mean survival rate was about 90 % and tumor recurrence was seen in approximately 30 % of the patients. The main problems occurred in view of the complete registration of all tumors with imaging techniques before RFA and the complete ablation, especially of larger tumours. CONCLUSIONS: In most of the clinical studies RFA promises an advantage of survival and improvement of quality of life compared to the known courses of untreated liver tumours. Therefore this method should be practiced on a larger scale in suitable patients. At the same time its efficacy must be proven by comparative studies.

Liposarcoma of the diaphragm: CT and sonographic appearances.

Malignant tumors arising from the diaphragm are exceedingly rare. We describe the first case, to our knowledge, of a primary diaphragmatic liposarcoma and demonstrate computed tomographic and sonographic findings.

[Acute limb ischemia]. / Akute Extremitätenischämie.

PATHOPHYSIOLOGY: Signs and symptoms of acute limb ischemia follow the pathophysiology of the disease. If embolism--mainly of cardiac origin--hits a previously unaffected vessel, and if the same embolus occludes the anatomically preexisting collateral vessel, complete ischemia will occur. TREATMENT: Only a revascularization procedure without any delay will be able to avert major amputation; however, once the ischemia/reperfusion cascade has been started, the limb is threatened even after successful revascularization. If acute ischemia results from local arterial thrombosis in an atherosclerotic vessel system a sufficient number of collateral vessels may be recruited within a short time period; thus, borderline compensation of the perfusion is achieved in most cases. This situation allows for thorough angiographic evaluation of the whole arterial tree of the affected limb as well as for perioperative risk assessment of the patient. These are the prerequisites for a technically ambitious revascularization procedure which is needed in most of the older patients with significant comorbidity.

Generation of survivin-specific CD8+ T effector cells by dendritic cells pulsed with protein or selected peptides.

The identification of tumor-associated antigens recognized by CD8+ cytotoxic T cells paved the way to new concepts in adjuvant anticancer therapy. However, the number of tumor-associated proteins found to be expressed in the majority of human cancers is still rather limited. Recently, the newly identified apoptosis inhibitor protein survivin has been recognized as a widely occurring tumor-associated protein. In the present study, we demonstrate that survivin is capable of inducing specific CD8+ effector T cells in vitro. T cells from healthy donors were subjected to several cycles of stimulation by autologous dendritic cells (DCs) pulsed with soluble recombinant survivin protein. Activation of CD8+ cytotoxic T cells by survivin-derived peptides cross-presented by DCs was demonstrated by lysis of autologous survivin-expressing B cell transfectants. Using a peptide-motif scoring system, two survivin peptides (ELTLGE-FLKL and TLPPAWQPFL) were predicted and proved to bind to the HLA-A*0201 molecule. Both peptides were shown to induce CD8+ effector T cells when presented on DCs; one peptide could be verified to result from natural intracellular processing of survivin. These findings recommend survivin as a new and widely applicable target for protein- and peptide-based immunotherapy of tumors.

New ELISA for quantitation of human urokinase receptor (CD87) in cancer.

The serine protease urokinase-type plasminogen activator (uPA), its inhibitor (PAI-1), and its receptor (uPAR; CD87) facilitate cancer cell invasion and metastasis. Whereas uPA and PAI-1 antigen levels determined in tumor tissue extracts of breast cancer patients correlate with disease recurrence and overall survival, the prognostic relevance of uPAR is still a matter of debate. We established two new sandwich-type enzyme-linked immunosorbent assay (ELISA) formats (HU/IIIF10-ELISA and HU/HD13-ELISA) using the epitope-defined monoclonal antibody (mAb) IIIF10 or the conformation-dependent mAb HD13.1, a polyclonal chicken antibody (HU277), and recombinant soluble uPAR (CHO-suPAR) as the standard. The lower detection limit of the assays was at 0.16 ng/ml, with a linear dose-response up to 5 ng/ml of uPAR antigen. Both ELISA formats showed good reproducibility and recovery. The intra-assay and the inter-assay variation coefficients were respectively 4.3% and 11.7% (HU/IIIF10-ELISA) and 4.0% and 10.7% (HU/HD13-ELISA). The recovery rate of uPAR in cell lysates spiked with CHO-suPAR was above 82% and 88%, respectively. With these new ELISA formats, uPAR antigen content in breast cancer tissue extracts and tumor cell lysates was determined and compared to a commercially available ELISA (ADI-ELISA). By all of the three uPAR ELISA formats CHO-suPAR and uPAR present in lysates of non-malignant epithelial cells and stimulated monocytes were quantified with similar sensitivity. Interestingly, in breast cancer cell lines of epitheloid origin a higher uPAR antigen content was determined by the HU/IIIF10-ELISA than the HU/HD13- or ADI-ELISA formats. In lysates of fibroblastic breast cancer cell lines similar uPAR values were obtained with the HU/IIIF10- and ADI-ELISA formats, whereas with the HU/HD13-ELISA significantly lower uPAR concentrations were determined. The prognostic relevance of tumor uPAR antigen was evaluated in 199 primary breast cancer patients with a median follow-up of 24 months. uPAR antigen values above the cut-off of 3.33 ng/mg protein as determined by the HU/IIIF10-ELISA were significantly correlated with short disease-free survival (p=0.025). Results obtained by the other two ELISA formats (HU/HD13-ELISA and ADI-ELISA) were not associated with prognosis. Our findings stress the need of well-characterized antibodies, which detect both uPAR of non-malignant and tumor cells, in setting up a uPAR-ELISA useful for assessing breast cancer patient prognosis.

[Therapy of deep leg vein thrombosis. When is surgical therapy indicated?]. / Therapie der tiefen Beinvenenthrombose. Wann ist eine chirurgische Therapie indiziert?

In spite of quite a few clinical trials the benefit of venous thrombectomy is seen controversially. The primary objectives of treating venous thrombosis are survival rate, prevention of pulmonary embolism and of postthrombotic syndrome. We report our experience with 47 patients who underwent venous thrombectomy. The mortality rate was 0%. We did not observe clinically relevant pulmonary embolism. After two years 90% of thrombectomised veins were patent. The mortality rates given in the literature of conservative treatment with heparin and following oral anticoagulation are 0.4 to 1.6%. Fibrinolysis shows mortality rates of 1 to 2.4, and thrombectomy of 3.8%, respectively. Venous thrombectomy is an effective treatment to prevent pulmonary embolism. In our own experience we saw no clinically significant pulmonary event. The danger of embolism rises with the proximity of the venous thrombus. Therefore those patients may have the greatest potential benefit from thrombectomy who present with a mobile inguinal thrombus or a thrombus in the iliac vein. So far there are no statistically sufficient data to support the indication of thrombectomy to prevent a postthrombotic syndrome.