The prognostic impact of extracapsular lymph node involvement in rectal cancer patients: Implications for staging and adjuvant treatment strategies.

Limited data suggest that extracapsular lymph node involvement (LNI) has a negative prognostic impact in gastrointestinal malignancies. The aim of this study was to assess the prevalence and prognostic impact of LNI in patients with primary resected rectal cancer. Between 1997 and 2007, 243 rectal cancer patients underwent surgical therapy without neoadjuvant treatment at our Department. Of these, 12 (5%) patients received transanal endoscopic microsurgery and were not included for further analyses. In the remaining patients, a (low) anterior resection was performed in 79% and an abdominoperineal rectal amputation in 21%. The total number of analyzed lymph nodes and the number of metastatic lymph nodes with/without extracapsular LNI were determined and the prognostic impact of LNI was assessed. The median number of analyzed lymph nodes was 14. In total, 59% of patients were node-negative, 18% of patients were node-positive without extracapsular LNI and 23% of patients were node-positive with extracapsular LNI. A positive lymph node status with extracapsular LNI was significantly correlated with a poorer T-, N- and M-category, grading and more frequent lymphatic vessel infiltration compared with node-negative or node-positive without extracapsular LNI patients (p<0.001). The overall 5-year survival rate of node-negative patients was 75%, for node-positive without extracapsular LNI patients 69% and for node-positive with extracapsular LNI patients 36% (p<0.001). By multivariate analysis, the N-category with extracapsular LNI was characterized as an independent prognostic factor. Extracapsular lymph node involvement reveals an independent negative prognostic impact in patients with rectal cancer undergoing surgical therapy. Staging systems for rectal cancer should include the implementation of extracapsular lymph node involvement.

Prognostic impact of nodal micrometastasis in early esophageal cancer.

INTRODUCTION: Nodal micrometastasis is a negative prognosticator for esophageal cancer. There is a trend toward endoscopic resection for early cancer of the esophagus without lymphadenectomy. Frequency and prognostic impact of nodal micrometastasis in early cancer of the esophagus have not been investigated so far. PATIENTS AND METHODS: This study includes 69 patients with a pT1-stage cancer of the esophagus (SCC: n = 26, AC: n = 43), who underwent transthoracic en-bloc esophagectomy with D2-lympadenectomy between 1996 and 2004. On routine histopathological analysis 48 patients were diagnosed as pN0. Lymph nodes (n = 1344) of these patients were further examined for the presence of isolated tumor cells with the monoclonal anti-epithelial antibody AE1/AE3. RESULTS: In lymph nodes of 7 (14.6%) out of 48 pN0-patients a positive staining for AE1/AE3 as a sign for nodal micrometastasis was found. In these patients the tumor has infiltrated the submucosal layer. In patients with tumors restricted to mucosal layer (n = 20) no nodal micrometastasis was present. 5-year survival of pN0-patients with nodal micrometastasis was inferior compared to pN0-patients (57% vs. 82%; p = 0.002). CONCLUSION: Almost 15% of patients with pT1 N0 M0 carcinoma of the esophagus and only those with submucosal infiltration show nodal micrometastasis. It has a significant negative impact on survival already in early esophageal cancer.

[Value of distal gastrectomy as a remedial operation for failed fundoplication]. / Stellenwert der distalen Magenresektion mit Rekonstruktion nach Roux-Y zur Behandlung des Refluxrezidivs nach Fundoplikatio.

BACKGROUND: Failure of conventional antireflux surgery is a challenging problem. This study aims at defining the role of distal gastrectomy with Roux-en-Y diversion in the treatment of failed fundoplication. MATERIAL AND METHODS: This report reviews the indications and results of 26 patients who underwent revisional antireflux surgery in our department. Distal gastrectomy and Roux-en-Y reconstruction were performed in 6 patients (group a), refundoplication in 15 (group b), and re-hiatoplasty in 5 patients (group c). RESULTS: Group a patients had the longest history (p = 0.001) and the highest number of previous operative procedures (p = 0.001). In contrast, hospital stay was longer and postoperative morbidity was higher after distal gastrectomy (p = n. s.). At follow-up, symptom improvement was achieved most reliably after distal gastrectomy (groups a-c: 100%, 78.6%, and 60% of patients; p = n. s.). CONCLUSION: Distal gastrectomy with Roux-en-Y diversion is a safe and reliable surgical option for selected patients after failed fundoplication. Distal gastrectomy with Roux-en-Y diversion is a reliable surgical option for selected patients after failed fundoplication. Despite a higher morbidity, this procedure represents an important addition to the surgical armamentarium, particularly in patients with a history of multiple previous interventions.

Lymph node size and metastatic infiltration in adenocarcinoma of the pancreatic head.

BACKGROUND: Preoperative lymph node staging of pancreatic cancer by CT relies on the premise that malignant lymph nodes are larger than benign nodes. In imaging procedures lymph nodes >1 cm in size are regarded as metastatic nodes. The extend of lymphadenectomy and potential application of neoadjuvant therapy regimens could be dependent on this evaluation. PATIENTS AND METHODS: In a morphometric study regional lymph nodes from 52 patients with pancreatic cancer were analyzed. The lymph nodes were counted, the largest diameter of each node was measured, and each node was analyzed for metastatic involvement by histopathological examination. The frequency of metastatic involvement was calculated and correlated with lymph node size. RESULTS: A total of 636 lymph nodes were present in the 52 specimens examined for this study (12.2 lymph nodes per patient). Eleven patients had a pN0 status, whereas 41 patients had lymph nodes that were positive for cancer. Five-hundred-twenty (82%) lymph nodes were tumor-free, while 116 (18%) showed metastatic involvement on histopathologic examination. The mean (±SD) diameter of the nonmetastatic nodes was 4.3 mm, whereas infiltrated nodes had a diameter of 5.7 mm (p = 0.001). Seventy-eight (67%) of the infiltrated lymph nodes and 433 (83%) of the nonmetastatic nodes were ≤5 mm in diameter. Of 11 pN0 patients, 5 (45%) patients had at least one lymph node ≥10 mm, in contrast only 12 (29%) out of 41 pN1 patients had one lymph node ≥10 mm. CONCLUSION: Lymph node size is not a reliable parameter for the evaluation of metastatic involvement in patients with pancreatic cancer.

Clinicopathologic and prognostic factors of young and elderly patients with esophageal adenocarcinoma: is there really a difference?

Evidence suggests a significant difference in the incidence, presentation, and outcome of young and elderly patients with esophageal adenocarcinoma. We aimed to compare clinicopathologic and prognostic factors of young and elderly patients with esophageal adenocarcinoma at a surgical department in Europe. From 1996 to 2006, 223 patients with a resectable esophageal adenocarcinoma were analyzed and divided in three groups: (i) patients 70 years (n = 52). Clinicopathological and prognostic factors were compared between these groups. The total number of patients with esophageal adenocarcinoma increased significantly. Although the total number of patients

Survivin mRNA in peripheral blood is frequently detected and significantly decreased following resection of gastrointestinal cancers.

BACKGROUND AND OBJECTIVES: We evaluated if mRNA expression of survivin, an inhibitor of apoptosis, can be used to detect circulating tumor cells in peripheral blood of patients with various gastrointestinal cancers and if they decrease following complete surgical resection. METHODS: Blood samples from 40 gastrointestinal cancer patients were analyzed prior and following surgical resection by direct quantitative real-time reverse transcriptase-PCR (RT-PCR) assays. RESULTS: Survivin mRNA expression was pre-operatively detected in 35 of 40 cancer patients (88%). Post-operative survivin levels were significantly lower than pre-operative levels in 59% of resected patients and were non-detectable in 38% (Wilcoxon rank test: P < 0.04). CONCLUSIONS: This is the first report showing that direct quantitative real-time RT-PCR analysis of survivin mRNA expression in peripheral blood of patients with gastrointestinal cancers is technically feasible. Survivin mRNA levels fall significantly following complete resection and might become a molecular marker for the completeness of surgical resection.

Multiple giant leiomyomas of the esophagus and stomach.

Leiomyomas are rare esophageal disorders, although among the benign esophageal neoplasms, they are the most common. Multiple leiomyomas are distinguished from esophageal leiomyomatosis, an extremely rare condition, which is associated with Alport syndrome, showing deletions and rearrangements of the COL4A5/COL4A6 gene. There are only a few reports of diffuse multilocular lesions. A 19-year-old man presented with upper gastrointestinal bleeding and diffuse abdominal pain. On endoscopy multiple nodules covered with intact mucosa were present, the largest tumor arising from the gastro-esophageal border infiltrating the cardia. Barium swallow demonstrated narrowing of the middle and lower esophagus with the upper third of the stomach filled by the tumor. Thorax and abdominal CT scans revealed infiltration of almost the total aboral esophagus by the tumor with compression of left and right bronchi. The infiltration reached the whole lesser curvature of the stomach. Endosonography showed multiple encapsulated nodules. Due to the extended tumor growth with infiltration of the upper third of the stomach, a total esophago-gastrectomy with reconstruction by colon interposition was performed. On histopathological examination multiple esophageal leiomyomas with infiltration of the proximal third of the stomach was shown. Immunohistochemically the tumor stained positive for desmin and sm-actin and negative for CD34 and c-kit. Genetic analysis ruled out a deletion of the COL4A5/COL4A6 locus on chromosome X that is linked with Alport syndrome-diffuse leiomyomatosis. Extended mutations in the COL4A5 gene, associated with Alport syndrome, to the COL4A6 gene, are required for the development of leiomyomatosis. In young patients with diffuse multinodular infiltration by encapsulated tumors, esophageal leiomyomatosis should be considered. If the proximal third of the stomach is infiltrated by the tumor an extended resection is necessary. Reconstruction procedures include colon interposition.

High rate of lymph-node metastasis in submucosal esophageal squamous-cell carcinomas and adenocarcinomas.

BACKGROUND AND STUDY AIMS: The application of endoscopic mucosectomy in early esophageal cancer is limited by the presence of lymph-node metastasis. The aim of this prospective study was to analyze the rate of lymph-node involvement relative to the depth of mucosal or submucosal tumor penetration, comparing squamous-cell carcinomas and adenocarcinomas. PATIENTS AND METHODS: A total of 60 patients with pT1 esophageal cancer--24 with squamous-cell carcinomas (SCCs) and 36 with adenocarcinomas--were treated with transthoracic en-bloc esophagectomy with two-field lymphadenectomy (n = 50) or transhiatal esophageal resection (n = 10). An average of 30 lymph nodes were examined, and the following characteristics were evaluated: histology, mucosal infiltration, depth of submucosal wall infiltration in three thirds (sm1, sm2, sm3), grading, resection category, ratio of metastatic to resected lymph nodes, and locations of metastatic nodes. RESULTS: The rates of lymph-node metastasis were 0% for the 16 mucosal carcinomas and 45% for the 44 submucosal carcinomas (P < 0.01). There were no significant differences in the extent of lymph-node involvement between submucosal adenocarcinomas (41%) and submucosal SCCs (50%). Sm1 carcinomas were associated with a lower rate of lymph-node metastasis (SCCs 33%, adenocarcinomas 22%) than sm3 carcinomas (SCCs 69%, adenocarcinomas 78%). Two patients (9%) with submucosal SCCs and five patients (23%) with submucosal adenocarcinomas were classified as having stage pM1 lymph. The average lymph-node ratio in patients with pN1 was 0.13 for adenocarcinomas and 0.1 for SCCs (difference not significant). In the multivariate analysis, the parameters mucosal vs. submucosal (P < 0.01) and G1/G2 vs. G3 (P < 0.05) showed a significant impact in relation to metastatic lymph nodes. CONCLUSIONS: The most important factor for predicting lymph-node metastasis in early esophageal cancer is the presence of submucosal infiltration. Early adenocarcinomas and SCCs do not differ with regard to their rate of lymphatic involvement. The rate of lymph-node metastasis increases with the depth of submucosal infiltration, but metastases can already occur in sm1 lesions. Submucosal infiltration is a contraindication for endoscopic mucosectomy. Limited surgical procedures without adequate lymphadenectomy do not appear to be appropriate in the treatment of patients with submucosal esophageal carcinomas.

Klatskin tumors and Klatskin mimicking lesions of the biliary tree.

AIM: We report on the preoperative capability of imaging modalities and clinical assessment to differentiate between Klatskin tumors and Klatskin mimicking lesions of the biliary tree. Adenocarcinomas of the hepatic ducts (Klatskin tumors) mimic benign fibrosing cholangitis. Extensive resections carry a substantial risk but offer the only chance for cure in patients with a Klatskin tumor. METHODS: Thirty-three consecutive patients who underwent resection for suspicion of a malignant tumor of the hepatic hilum were reviewed. All patients underwent preoperative ultrasonography, computed tomography, ERCP and angiography. The patients were divided into a group of true Klatskin tumors and a group of benign Klatskin mimicking lesions. RESULTS: Twenty-seven of the resected specimens were malignant tumors, and six lesions showed only fibrosing cholangitis. Preoperative clinical presentation and imaging modalities were very similar between Klatskin tumors and fibrosing cholangitis. CONCLUSIONS: Management of obstruction of the liver hilum is dictated by the suspicion of malignancy. Complete removal of the tumor remains the therapeutic aim but clinical presentation and imaging modalities cannot help to differentiate between Klatskin tumors and Klatskin mimicking lesions prior to surgery.

[Candida infection in hip alloarthroplasty]. / Candidainfektion nach Alloarthroplastik der Hüfte.

A 46-year-old polytoxicomanic patient underwent a total hip replacement for necrosis of the femoral head. The patient suffered additionally from chronic pancreatitis with insulin-dependent diabetes and polyneuropathy. Three weeks later he developed a deep wound infection followed by surgical revision. The infection persisted despite further revision operations and systemically and locally applied antibiotics. After removal of the prosthesis,microbiology revealed Staphylococcus aureus, enterococcus,and Candida parapsilosis. Five additional revision operations, application of suction-irrigation drainage, and systemically administered antibiotics could not stop the infectious process. The patient was transferred to our institution 3 months after primary surgery. The joint defect was filled with a PMMA Palacos spacer. This time biopsies were only positive for Candida albicans. After 12 days of antifungal therapy with fluconazole,microbiological biopsies were sterile. The spacer was removed and femoral extension applied. After 4 weeks of further antifungal therapy, a revision prosthesis was implanted. Until now no signs of infection have appeared.

Undifferentiated carcinoma of the pancreas: analysis of intermediate filament profile and Ki-ras mutations provides evidence of a ductal origin.

Undifferentiated carcinomas and osteoclast-like giant cell tumours of the pancreas commonly contain foci of neoplastic ductal glands. To test the hypothesis that undifferentiated carcinomas and osteoclast-like giant cell tumours have a ductal origin, the immunocytochemical cytokeratin pattern and the frequency and type of Ki-ras mutations at colon 12 were studied in a series of 17 undifferentiated carcinomas and two osteoclast-like giant cell tumours. The cytokeratin features of undifferentiated carcinomas and osteoclast-like giant cell tumours were compared with those found in 10 ductal adenocarcinomas, 20 acinar cell carcinomas, 25 neuroendocrine tumours, and 15 solid-pseudopapillary tumours. All undifferentiated carcinomas and osteoclast-like giant cell tumours stained with at least one cytokeratin antibody, and 13/19 of them with antibodies against cytokeratins 7, 8, 18, and 19. The latter cytokeratins were expressed in all ductal adenocarcinomas, but only in 15/20 acinar cell carcinomas, 2/25 neuroendocrine tumours, and 1/15 solid-pseudopapillary tumours. In addition to cytokeratin, 15/19 undifferentiated carcinomas/osteoclast-like giant cell tumours were positive for vimentin. Ki-ras mutations at codon 12 were found in 10 undifferentiated carcinomas and one osteoclast-like giant cell tumour from which DNA could be successfully amplified. The Ki-ras mutation patterns were analysed in six tumours and corresponded to those typical of ductal adenocarcinomas. In tumours with ductal and anaplastic components, both components revealed identical mutation patterns. From these findings, it is concluded that both undifferentiated carcinomas and osteoclast-like giant cell tumours belong to the pancreatic tumours that show a ductal phenotype. Since undifferentiated carcinomas and osteoclast-like giant cell tumours share the same cytokeratin and Ki-ras features, they are probably derived from the same cell lineage.

Expression and prognostic significance of HLA class I, ICAM-1, and tumor-infiltrating lymphocytes in esophageal cancer.

Most solid malignancies show some degree of lymphoid infiltration suggesting a specific immunologic host vs. tumor reaction. Tumor-infiltrating lymphocytes (i.e., CD3 + T-lymphocyte subsets), the human leukocyte antigen (HLA) class I molecules, and the intercellular adhesion molecule-1 (ICAM-1) are key factors involved in T-cell-mediated immune surveillance. The present study was designed to assess the expression pattern of intratumoral lymphocyte infiltrates and their relationship to HLA class I and ICAM-1 expression with regard to primary esophageal carcinoma and to evaluate their prognostic influence. Representative samples of primary tumors were obtained from 55 patients who had undergone radical en bloc esophagectomy. Frozen sections of these tumors were stained with monoclonal antibodies directed against CD3 for the assessment of tumor-infiltrating lymphocytes, HLA class I, and ICAM-1. The mean postoperative observation period was 19.5 months (range 5 to 45 months). Lymphocyte infiltration was absent in four tumors (8%), whereas 31 tumors (64%) showed moderate and 13 (27%) showed strong infiltration. HLA class I expression was deficient in 24 tumors (45%). Coexpression of HLA class I and ICAM-1 was significantly associated with lymphocyte infiltration of the tumor. Kaplan-Meier analyses revealed a significant beneficial influence on relapse-free survival for patients with lymphocyte infiltration of primary tumors compared to those with no lymphocyte infiltration of tumors (median 4 months vs. 18 months; P <0.002) and for HLA class I+ tumors compared to HLA class I- tumors (median survival >18 months vs. 7 months; P = 0.0081). The present data support the hypothesis that T-cell-mediated immunity may influence the fate of patients with esophageal cancer.

Photosensitization of uroporphyrin augments the ultraviolet A-induced synthesis of matrix metalloproteinases in human dermal fibroblasts.

Porphyria cutanea tarda is characterized by severe connective tissue damage in sun-exposed skin. The regulated synthesis and degradation of the extracellular matrix by various matrix metalloproteinases (MMPs) determine its amount and composition within the skin. In this study, we therefore asked whether long-wave ultraviolet irradiation (340-450 nm) in conjunction with uroporphyrin I could modulate the synthesis of MMPs with substrate specificities for dermal (collagens I, III, V; proteoglycans) and basement membrane components (collagens IV, VII; fibronectin; laminin) and whether synthesis of the counteracting tissue inhibitor of metalloproteinases is also affected. After irradiation of uroporphyrin-pretreated fibroblasts, specific mRNAs of MMP-1 and MMP-3 increased concomitantly up to 2.7-fold compared with ultraviolet-irradiated cells and up to 10-fold compared with mock-irradiated or uroporphyrin I-treated controls. In contrast, mRNA levels of tissue inhibitor of metalloproteinases remained unaltered. Similar results were obtained by immunoprecipitation. Gelatin and casein zymography revealed increased proteolytic activity of MMP-2 and MMP-3 in blister fluids of patients with porphyria cutanea tarda, indicating that similar events may occur in vivo. Using deuterium oxide as enhancer and sodium azide as quencher of singlet oxygen, we could increase or reduce MMP synthesis, suggesting that singlet oxygen is the major intermediate in the upregulation of MMPs after irradiation of uroporphyrin-pretreated fibroblasts. Taken together, our results show that ultraviolet irradiation alone, and to a greater extent in conjunction with uroporphyrin I, results in an unbalanced synthesis of MMPs that may contribute to the destruction of the dermis and basement membrane, leading to blistering and accelerated photoaging in porphyria cutanea tarda patients.

[Surgical correction of bile duct injuries after laparoscopic cholecystectomy]. / Operative Korrektur von Gallengangsverletzungen nach laparoskopischer Cholezystektomie.

The rate of iatrogenic bile duct lesions has raised up to 3.5% after the introduction of laparoscopic cholecystectomy. Lesions that can not be managed endoscopically require surgical intervention. In this study 12 patients that presented with iatrogenic bile duct lesions following laparoscopic cholecystectomy and underwent reconstructive surgery at our institution are included. In nine patients a hepaticojejunostomy was performed, whereas two patients underwent end-to-end anastomosis. In one patient the lesion was oversewn. There were no complications postoperatively. After a median follow-up of 24,5 months (SD +/- 8 months) all patients are without symptoms. However, in two patients a postoperative endoscopic stenting for 4 months was necessary for bouginage. Reconstructive surgery, mainly hepaticojejunostomy in bile duct lesions is a safe and efficacious treatment of endoscopic treatment failure.

Fibrin-glue-coated collagen fleece in lung surgery--experimental comparison with infrared coagulation and clinical experience.

Diffuse parenchymal bleeding and major air leaks still present a challenge to the thoracic surgeon. This study was therefore designed to evaluate efficacy and handling of fibrin-glue-coated collagen fleece, to address these problems. In an experimental part defects were produced in lungs of troll pigs to compare the use of the fleece with infrared coagulation. Immediate airtightness and postoperative adhesions were evaluated. Scores were designed to evaluate quality and extension of the adhesions. In a clinical study parenchymal resection sites were sealed with fibrin-glue-coated collagen fleece in 52 patients. No patient suffered from postoperative bleeding. In three cases air leaks were still present on the third postoperative day, representing a 5.8% failure rate. 92.3% of the patients showed neither postoperative hemorrhage nor prolonged air leaks. A fixed combination of collagen fleece and fibrin glue consequently can be considered as a valuable tool in thoracic surgery.

UVA irradiation stimulates the synthesis of various matrix-metalloproteinases (MMPs) in cultured human fibroblasts.

UVA irradiation leads to photoaging including clinical features such as wrinkle formation, reduced recoil capacity and blister formation of the skin. Besides synthesis of the extracellular matrix, its regulated degradation by various matrix-metalloproteinases (MMPs) determines the amount and the composition of the extracellular matrix within the dermis and the basement membrane of the dermo-epidermal junction. In this study we therefore ascertained whether UV irradiation could modulate the synthesis of MMPs with substrate specificities for dermal (collagen I, III, V) and basement membrane compounds (collagen IV, VII, proteoglycans, laminin) and whether synthesis of the counteracting tissue inhibitor of metalloproteinases (TIMP-1) was also affected. Following UVA irradiation specific mRNAs of MMPs 1, 2 and 3 were induced concomitantly up to 5-fold compared to mock irradiated controls. In contrast, TIMP-1 mRNA levels remained unaltered. Immunoprecipitation indicated that after UVA irradiation synthesis and secretion of MMPs 1, 2 and 3 into the supernatant increased. Taken together, our data show that UVA irradiation coordinately induced MMPs 1, 2 and 3 implying similar mechanisms in their regulatory pathways, while TIMP-1 synthesis was not altered. Hence, unbalanced synthesis of MMPs potentially contributes to the dissolution of dermal and basement membrane compounds finally leading to blister formation and cutaneous photoaging.

Iodination of mono- and heteroclonal immunoglobulin G with lactoperoxidase and chloramine T.

The difference in the reactivity of tyrosine and histidine residues in mono- and heteroclonal IgG protein toward enzyme catalyzed and chemical iodination has been studied. One heteroclonal and four monoclonal IgG proteins were iodinated using lactoperoxidase or chloramine T. The ratio of the degrees of substitution of the light and the heavy chains varied from IgG to IgG. One of the monoclonal IgG proteins, IgG-Dam, could only be modified in the gamma-chain. The lack of reactivity was attributed to steric hindrance and other local peculiarities. This interpretation is supported by spectrophotometric titration studies.