Search

Supplementary Table S4 from Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion

Purpose: Bone marrow is a common homing organ for early disseminated tumor cells (DTC) and their presence can predict the subsequent occurrence of overt metastasis and survival in lung cancer. It is still unclear whether the shedding of DTC from the primary tumor is a random process or a selective release driven by a specific genomic pattern.Experimental Design: DTCs were identified in bone marrow from lung cancer patients by an immunocytochemical cytokeratin assay. Genomic aberrations and expression profiles of the respective primary tumors were assessed by microarrays and fluorescence in situ hybridization analyses. The most significant results were validated on an independent set of primary lung tumors and brain metastases.Results: Combination of DNA copy number profiles (array comparative genomic hybridization) with gene expression profiles identified five chromosomal regions differentiating bone marrow-negative from bone marrow-positive patients (4q12-q32, 10p12-p11, 10q21-q22, 17q21, and 20q11-q13). Copy number changes of 4q12-q32 were the most prominent finding, containing the highest number of differentially expressed genes irrespective of chromosomal size (P = 0.018). Fluorescence in situ hybridization analyses on further primary lung tumor samples confirmed the association between loss of 4q and bone marrow-positive status. In bone marrow-positive patients, 4q was frequently lost (37% versus 7%), whereas gains could be commonly found among bone marrow-negative patients (7% versus 17%). The same loss was also found to be common in brain metastases from both small and non-small cell lung cancer patients (39%).Conclusions: Thus, our data indicate, for the first time, that early hematogenous dissemination of tumor cells might be driven by a specific pattern of genomic changes.

The literature indicates higher recurrence rates for stapled hemorrhoidopexy than for conventional techniques. This could be due to inappropriate patient selection. The aim of this study was to evaluate the short- and long-term outcome after stapled hemorrhoidopexy compared with the Milligan–Morgan procedure in a homogeneous patient population with circumferential third-degree hemorrhoids. One hundred thirty patients were enrolled into a randomized controlled study, of which 122 were clinically evaluated at weeks 1, 2, and 4, and thereafter each year for a minimum of 3 years. Patients completed a questionnaire for symptoms, function, and pain. Pain was assessed using a visual analog scale. Recurrences were determined by anoscopy and self-report. The study was performed at the University Hospital Hamburg. Endpoints were pain, recurrence, bleeding, itching/burning, urinary retention, incontinence symptoms, and prolonged rate of wound healing. The cumulative recurrence rates after 5 years were 18 % (n = 11) in the stapled hemorrhoidopexy group and 23 % (n = 14) in the Milligan–Morgan group (p = 0.65). Patients who underwent stapled hemorrhoidopexy had significantly less postoperative pain with mean VAS scores at week 1: 3.1 vs. 6.2; week 2: 0.5 vs. 3; week 4: 0.05 vs. 0.6 (p

Basal transcription regulation of the epidermal growth factor receptor is dependent upon a CA simple sequence repeat polymorphism in the intron-1 (CA-SSR-1). Here, we evaluate the role of CA-SSR-1 in complete resected esophageal cancer (EC) patients without neoadjuvant or adjuvant treatment. Genomic DNA was extracted from peripheral blood leukocytes of 241 patients. To determine the number of the CA repeats in the CA-SSR-1, DNA was amplified by polymerase chain reaction and sequenced. The results were correlated with clinicopathological parameters and clinical outcome. Three genotypes were defined based on cut-off points for short allele (S) with ≤18 and long allele (L) >18 CA repeats. A steadily increasing risk was evident between LL, SL, and SS genotype for larger tumor size, presence of lymph node metastases, and disseminated tumor cells in bone marrow as well as tumor recurrence (P

Research projects and clinical trials strongly rely on high-quality biospecimens which are provided by biobanks. Since differences in sample processing and storage can strongly affect the outcome of such studies, standardization between biobanks is necessary to guarantee reliable results of large, multicenter studies. The German Cancer Aid Foundation (Deutsche Krebshilfe e.V.) has therefore initiated the priority program "tumor tissue banks" in 2010 by funding four biobank networks focusing on central nervous system tumors, melanomas, breast carcinomas, and colorectal carcinomas. The latter one, the North German Tumor Bank of Colorectal Cancer (ColoNet) is managed by surgeons, pathologists, gastroenterologists, oncologists, scientists, and medical computer scientists.The ColoNet consortium has developed and harmonized standard operating procedures concerning all biobanking aspects. Crucial steps for quality assurance have been implemented and resulted in certification according to DIN EN ISO 9001. A further achievement is the construction of a web-based database for exploring available samples. In addition, common scientific projects have been initiated. Thus, ColoNet's repository will be used for research projects in order to improve early diagnosis, therapy, follow-up, and prognosis of colorectal cancer patients. Apart from the routine sample storage at -170 °C, the tumor banks' unique characteristic is the participation of outpatient clinics and private practices to further expand the sample and clinical data collection.The first 2 years of funding by the German Cancer Aid Foundation have already led to a closer scientific connection between the participating institutions and to a substantial collection of biospecimens obtained under highly standardized conditions.

Duodenal stump insufficiency after surgery for penetrating gastroduodenal ulcer is associated with substantial mortality. “Classical” technique of closing a difficult duodenal stump (Nissen–Bsteh) has, up to now, not been compared with duodenojejunostomy (DJ) in larger patient sets. This also refers to the potential benefit of a gastric and biliary diversion under such conditions. The aim of the present study was to compare classical duodenal closure (CC) with DJ and to evaluate the impact of gastric and biliary diversion on postoperative outcome after surgery for penetrating, high-risk duodenal ulcer in a matched control study. Out of 321 patients, treated for penetrating duodenal ulcer disease, the perioperative outcome of 62 DJ patients was compared with 62 patients undergoing CC matched for age, gender, biliary diversion, and the operating surgeon collective. A total of 70 patients, equally distributed between DJ and CC subsets, received temporary biliary diversion. Overall perioperative mortality was 10.5 %. However, DJ significantly reduced the mortality rate (4.8 %) associated with penetrating duodenal ulcer compared to CC (16.1 %, P

Background and study aims: Endoscopic ultrasonography (EUS) has been shown to be the most accurate test for locoregional staging of upper gastrointestinal tumors; however, recent studies have questioned its accuracy level in daily clinical application. The present retrospective study analyzes the accuracy of EUS in guiding interdisciplinary treatment decisions. Patients and methods: 123 primarily operated patients (63 % men, mean age 61.4 years) were included; only cases with tumor-free resection margins and without evidence of distant metastases were selected. EUS and histopathological findings were compared. Main outcome parameter was the distinction between tumors to be primarily operated (T1 /2N0) and those to be treated by neoadjuvant or perioperative chemotherapy (T3/4, or any N + ), based on an assumed algorithm for treatment stratification. Results: Overall staging accuracy of EUS was 44.7 % for T and 71.5 % for N status irrespective of tumor location. Overstaging was the main problem (44.9 % for T, 42.9 % for N staging). The overall EUS classification was correct in 79.7 % (accuracy), with a sensitivity 91.9 % and specificity 51.4 %; only 19 out of 37 cases with histopathological T1/2N0 were correctly classified by EUS. Positive and negative predictive values of EUS in diagnosing advanced tumor stage for assignment to neoadjuvant therapy were 81.4 % and 73.1 %, respectively. Conclusions: Whereas EUS has a high sensitivity in the diagnosis of locally advanced gastric cancer, endosonographic overstaging of T2 cancers appears to be a frequent problem. EUS stratification between local (T1 /2N0) and advanced (T3/4 or any N + ) tumors would thus result in incorrect assignment to neoadjuvant treatment in half of cases.

There is an assumption that multivisceral resections (MVRs) in patients with a pancreatic malignancy are associated with higher morbidity. The oncologic benefit, however, remains controversial.The aim was to identify risk factors for complications in cases of MVR in patients with pancreatic cancer. Of 1099 patients who underwent major pancreatic resection at our institution between January 1992 and October 2008, a total of 55 were treated with an MVR involving resection of one or more additional organs. This group was compared with 154 patients who had palliative bypass surgery and 303 patients who underwent standard pancreatic head resection.Multivisceral resection patients had an overall higher incidence of major surgical complications (p0.001). In-hospital mortality was comparable in all groups. Median survival after MVR was inferior to that after standard resection but was significantly better than that after palliative bypass. Univariate logistic regression analysis identified concomitant colon, kidney, and liver resections and any intraoperative transfusion as predictors of complications; in the multivariate analysis, only kidney resections and any intraoperative transfusion were confirmed predictors. In contrast, T status, kidney resection, resection of four or more organs, any postoperative transfusion, and intensive care unit stay of2 days were identified as predictors of survival in the univariate Cox regression analysis; in the multivariate analysis, only the T status was confirmed. Median survival after MVR was 16 months, after palliative bypass 6 months, and after standard resection 18 months (p0.001).Multivisceral resections are technically feasible procedures with increased survival when compared to palliative bypass procedures. The incidence of postoperative complications was increased with kidney resection and when intraoperative transfusion was required.

Current available preoperative diagnostic workup is insufficient to differentiate between benign and malignant pancreatic neuroendocrine tumors (PNET). The aim of the present study was to evaluate the potential prognostic role of the promoter GTn repeat polymorphism (GTn) of the heme oxygenase-1 gene in PNET.Tumor, metastasis, corresponding healthy tissue, and peripheral blood leukocyte DNA of 46 patients who underwent surgical resection for PNET were analyzed for GTn by PCR, capillary electrophoresis, and DNA-sequencing. The GTn was correlated to clinicopathologic parameters and clinical outcome.GTn was classified into short (25) and long (≥ 25) alleles and three (SS, SL, and LL) genotypes were defined. There was no difference in GTn genotype among tumor, healthy tissue, metastasis, and peripheral blood leukocyte DNA. The SS and SL genotype displayed significantly more poor differentiated tumors (P = 0.001) and higher tumor recurrence rate (P = 0.0001) compared with LL patients. The LL genotype patients presented predominantly benign PNET (P0.001). The LL genotype had the longest disease-free (P0.001) and overall survival (P = 0.006). Besides the WHO classification the GTn was identified as a strong predictor of tumor recurrence (hazard ratio 3.1, 95% confidence interval 1.3-7.3) in PNET.GTn differentiates between benign and malignant PNET and is a strong predictor of tumor recurrence.

Chronic pancreatitis (CP) is a disease with enormous social and personal impact. It is most commonly caused by the abuse of alcohol combined with nicotine. CP is usually characterised by an inflammatory mass located in the pancreatic head. Its natural course is characterised by persistent or recurrent painful attacks as well as progressive loss of pancreatic function due to fibrosis of the parenchyma with consecutive endocrine and exocrine insufficiency. The only success parameter of any treatment is the effective long-lasting pain relief and improvement in the quality of life. The surgical armamentarium includes simple drainage procedures, resections of different extents or a combination of both. Duodenum-preserving resection of the pancreas offers the best short-term outcome according to trials conducted so far. It has the benefit of combining the highest safety with the highest efficiency. Additionally, the extent of the operation can be adapted to the morphology of the individual patient.

Marx A H, Zielinski M, Kowitz C-M, Dancau A-M, Thieltges S, Simon R, Choschzick M, Yekebas E, Kaifi J T, Mirlacher M, Atanackovic D, Brummendorf T H, Fiedler W, Bokemeyer C, Izbicki J R & Sauter G (2010) Histopathology 57, 418–426 Homogeneous EGFR amplification defines a subset of aggressive Barrett’s adenocarcinomas with poor prognosis Aims: The epidermal growth factor receptor (EGFR) is a tyrosine kinase (TK) involved in the tumour progression of many cancer types and may serve as an important therapeutic target (erlotinib, cetuximab). Heterogeneity of EGFR amplification and expression could represent a major drawback for anti-EGFR therapy. The aim of this study was performed to determine the potential impact of tumour heterogeneity on anti-EGFR therapy in Barrett’s adenocarcinoma (BAC). Methods and results: Tissue microarray (TMA) sections of 112 BAC and 45 lymph node metastases were analysed for EGFR amplification and expression using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). A subset of 20 samples was also sequenced for EGFR exons 18–21 and Kirsten rat sarcoma viral oncogene homologue (KRAS) exons 2–3 mutations. EGFR amplification was seen in seven (6.25%) of 112 interpretable BAC and typically high-level with more than 10–20 EGFR copies per tumour cell (EGFR/centromere 7 ratio >3). EGFR amplification was associated with high pT, pN and poor prognosis (P = 0.0004). Identical EGFR amplification status was found in 29 primary tumours and 29 matched lymph node metastases. Moreover, FISH analysis of three to 16 large sections from all amplified BAC and corresponding lymph node metastases did not reveal any heterogeneity of EGFR amplification. No EGFR mutation but one KRAS mutation was found. Conclusion: The high level and homogeneity of EGFR amplification in primary tumours and metastases suggests the potential therapeutic utility of anti-EGFR drugs in BAC.

BACKGROUND Prostate specific membrane antigen (PSMA) is a suggested target for antibody-based therapy of prostate cancer potentially involved in the regulation of cell migration. This study was undertaken, to gain more insight on the role of PSMA in early prostate cancer and its distribution in various normal tissues. METHODS A total of 1,700 different prostate cancers treated by radical prostatectomy and 612 samples from 76 different normal tissue types were successfully analyzed by immunohistochemistry (IHC) in a tissue microarray (TMA) format. PSMA immunostaining in cancers was also compared with clinical follow-up, preexisting HER2 expression and Ki67 labeling index data. RESULTS PSMA staining was only found in prostate epithelium and expression was higher in cancer cells than in benign tissue. PSMA staining was found in 94.1% of cancers and was significantly associated with tumor stage, high Gleason grade, preoperative PSA, and HER2 expression (P

Functional and clinical long-term outcome after stapled transanal rectal resection (STARR) in patients with an isolated symptomatic rectocele are investigated. Short-term results after 1 year are comparable with the functional outcome even after 5 years. Eighty per cent of the patients were still satisfied. STARR is an alternative procedure to the conventional surgical approaches for patients with an obstructed defecation syndrome and rectocele. Several studies have reported short-term outcome after STARR, but long-term results are still missing. The objective of this study was to evaluate long-term clinical outcome after STARR with a follow-up of 5 years. Twenty patients with only an isolated symptomatic rectocele due to obstructed defecation syndrome were subjected to STARR. Functional and clinical outcome was assessed by Outlet Obstruction Syndrome score (OOS score), Wexner score (WS), and Symptome Severity score (SSS score). Data were prospectively collected over 7 years. The perioperative morbidity after STARR accounted for 20% (n = 4). One patient was subjected to reoperation due to perforation, two postoperative bleedings occurred, and one patient developed an increasing local granulomatous reaction at the stapler line. The median follow-up accounted for 66 months (range 60–84). Sixteen patients (80%) were satisfied with the functional outcome. The median OOS, SSS and WS score improved significantly already after 1 year in these patients and remained stable at 5-year follow-up. In contrast, four patients were classified as treatment failures since the OOS score and the SSS score showed no improvement. At 5-year follow-up, these patients remained symptomatic without improvement in OOS and SSS scores. The STARR procedure is an effective operation in isolated symptomatic rectoceles with regard to relief of the obstructed defecation syndrome. The short-term improvement after STARR predicts long-term outcome in obstructed defecation syndrome caused by a rectocele.

Purpose: Deletions of 8p and gains of 8q belong to the most frequent cytogenetic alterations in prostate cancer. The target genes of these alterations and their biological significance are unknown. Experimental Design: To determine the relationship between chromosome 8 changes, and prostate cancer phenotype and prognosis, a set of 1.954 fully annotated prostate cancers were analyzed in a tissue microarray format by fluorescence in situ hybridization. Results: Both 8p deletions and 8q gains increased in number during different stages of prostate cancer progression. 8p deletions/8q gains were found in 26.1%/4.8% of 1,239 pT2 cancers, 38.5%/9.8% of 379 pT3a cancers, 43.5%/8.9% of 237 pT3b cancers, 40.7%/14.8% of 27 pT4 cancers, 39.1%/34.8% of 23 nodal metastases, 51.9%/33.3% of 27 bone metastases, and 45.5%/59.9% of 22 hormone refractory cancers (P < 0.0001 each). Both 8p deletions and 8q gains were also significantly associated with high Gleason grade and with each other (P < 0.0001 each). In primary tumors, 8p deletions were seen in only 27.3% of 1,882 cancers without 8q gain but in 57.4% of 122 tumors with 8q gain (P < 0.0001). Among cancers treated with radical prostatectomy, 8p deletions (P = 0.003) and 8q gains (P = 0.02) were associated with biochemical tumor recurrence. However, multivariate analysis (including prostate-specific antigen, pT/pN stage, Gleason score, and surgical margin status) did not reveal any statistically independent effect of 8p or 8q alterations on biochemical tumor recurrence. Conclusions: 8p deletions and 8q gains are relatively rare in early stage prostate cancer but often develop during tumor progression. The prognostic effect does not seem to be strong enough to warrant clinical application. Clin Cancer Res; 16(1); 56–64

Microcirculatory disorders play a major part in the pathogenesis of acute pancreatitis. Improvement of microcirculation is hypothesized to open a therapeutic window. The aim of this study was to evaluate the effects of small-volume resuscitation in acute pancreatitis.In rats, acute pancreatitis of graded severity was induced and pancreatic microcirculation was observed in vivo with an epiluminescent microscope. Primary outcome measures were microcirculation, leukocyte adherence, concentration of trypsinogen-activating peptide, amylase activity and histopathologic tissue damage.In necrotizing pancreatitis patients receiving prophylactic intervention with 7.5% hypertonic saline the functional capillary density was 76%. Postcapillary venular leukocyte adherence was 45% of vein cross-section. The median histopathologic damage scored 8 points. In controls, a complete microcirculatory breakdown was observed, and in the group with therapeutic intervention no significant difference was detected. In intermediate pancreatitis, the number of perfused capillaries remained 55.0 versus 23.3% in controls. Leukocyte adherence was 40.0 versus 51.7%. The histopathologic damage scored 6.0 versus 9.0 points. Trypsinogen-activating peptide concentration was reduced to 164 versus 402 nM in controls. In cerulein pancreatitis, the number of perfused capillaries was equally preserved in both groups.Small-volume resuscitation preserves capillary microcirculation and prevents pancreatic injury in intermediate necrotizing pancreatitis.

A pancreatic duct diameter (PDD) ranging from 4 to 5 mm is regarded as “normal”. The “large duct” form of chronic pancreatitis (CP) with a PDD > 7 mm is considered a classical indication for drainage procedures. In contrast, in patients with so-called “small duct pancreatitis” (SDP) with a PDD

Background and Objectives To further improve the screening, diagnosis and therapy of patients with non-small cell lung cancer (NSCLC) additional diagnostic tools are desperately warranted. Aim of this study was to investigate the potential of the DNA methylation of DAPK, MGMT, and GSTPI in serum of patients with NSCLC as a prognostic molecular marker in this disease. Methods Seventy-six patients with NSCLC were included in this study. The analysis of DNA methylation in serum of patients was performed on pre-operative samples. Following DNA isolation and bisulfite-treatment, DNA methylation was analyzed by quantitative-methylation-specific real-time PCR with β-actin as the internal reference gene. Results DNA methylation was detectable with following frequencies: DAPK 68.4%, MGMT 7.9%, GSTPI 0%. There were no associations between DNA methylation status and histology, tumor stage, grading or gender detectable. With a mean follow-up of 19.7 months the median survival was 26.3 months. There were no associations between the status of DNA methylation in patient's serum and prognosis detectable. Conclusion The analysis of DNA methylation in serum of patients with NSCLC by quantitative-methylation-specific real-time PCR is technically feasible. Although our results suggest quantification of DNA methylation in serum not of prognostic significance in this disease, further studies are warranted to determine the future potential of this molecular approach. J. Surg. Oncol. 2009;100:414–417. © 2009 Wiley-Liss, Inc.

Her-2 is the molecular target for antibody-based treatment of breast cancer (trastuzumab). The potential benefit of anti-Her-2 therapy is currently investigated in several other HER-2-amplified cancers including gastric cancer. Although HER-2 amplification occurs in more than 10% of gastric cancers, potential heterogeneity of HER-2 amplification and overexpression could represent a major drawback for anti-Her-2 therapy. To address the potential applicability of trastuzumab in gastric cancer, tissue microarray sections of 166 gastric adenocarcinomas and 69 lymph node metastases were analyzed for Her-2 overexpression and amplification using Food and Drug Administration-approved reagents for immunohistochemistry and fluorescence in situ hybridization. HER-2 amplification was seen in 27 (16%) of 166 gastric adenocarcinomas. Amplification was typically high level with more than 20 HER-2 copies per tumor cell and a HER-2/centromere 17 ratio >3. Amplification was associated with intestinal tumor phenotype but unrelated to survival, grading, pT, pN, or pM. Identical HER-2 status was found in primary tumor and their matched lymph node metastases. Moreover, HER-2 and Topoisomerase IIalpha coamplification analysis of 3 to 16 large sections from 8 Her-2-positive gastric cancers did not reveal any heterogeneity of the amplicon site. The high level of HER-2 amplification in combination with the homogeneity of its expression in primary and metastatic tumors argues for a possible therapeutic utility of trastuzumab in HER-2-amplified gastric adenocarcinomas.

To analyze the impact of pancreatitis-mimicking, concomitant alterations on intraoperative assessment of curative resectability, the anatomical site of irresectability, and outcome after nonintentional R2 resection in pancreatic cancer. Of 1,099 patients subjected to pancreatic resection for cancer, 40 (4%) underwent R2 resection (group A). The site where tumors turned out to be irresectable and the coincident presence of potentially misleading, fibro-desmoplastic alterations were analyzed. Outcome after resection was compared with 40 bypass patients matched for age, gender, histopathology, and use of additive chemotherapy (group B). R2 resection was due to misjudgment regarding resectability in 38 patients (95%) and to uncontrollable hemorrhage in 2 patients (5%). Group A patients had significantly longer operative times (P

Identification of dysplasia in inflammatory bowel disease represents a major challenge for both clinicians and pathologists. Clear diagnosis of dysplasia in inflammatory bowel disease is sometimes not possible with biopsies remaining "indefinite for dysplasia." Recent studies have identified molecular alterations in colitis-associated cancers, including increased protein levels of alpha-methylacyl coenzyme A racemase, p53, p16 and bcl-2. In order to analyze the potential diagnostic use of these parameters in biopsies from inflammatory bowel disease, a tissue microarray was manufactured from colons of 54 patients with inflammatory bowel disease composed of 622 samples with normal mucosa, 78 samples with inflammatory activity, 6 samples with low-grade dysplasia, 12 samples with high-grade dysplasia, and 66 samples with carcinoma. In addition, 69 colonoscopic biopsies from 36 patients with inflammatory bowel disease (28 low-grade dysplasia, 8 high-grade dysplasia, and 33 indefinite for dysplasia) were included in this study. Immunohistochemistry for alpha-methylacyl coenzyme A racemase, p53, p16 and bcl-2 was performed on both tissue microarray and biopsies. p53 and alpha-methylacyl coenzyme A racemase showed the most discriminating results, being positive in most cancers (77.3% and 80.3%) and dysplasias (94.4% and 94.4%) but only rarely in nonneoplastic epithelium (1.6% and 9.4%; P < .001). Through combining the best discriminators, p53 and alpha-methylacyl coenzyme A racemase, a stronger distinction between neoplastic tissues was possible. Of all neoplastic lesions, 75.8% showed a coexpression of alpha-methylacyl coenzyme A racemase and p53, whereas this was found in only 4 of 700 nonneoplastic samples (0.6%). alpha-methylacyl coenzyme A racemase/p53 coexpression was also found in 10 of 33 indefinite for dysplasia biopsies (30.3 %), suggesting a possible neoplastic transformation in these cases. Progression to dysplasia or carcinoma was observed in 3 of 10 p53/alpha-methylacyl coenzyme A racemase-positive, indefinite-for-dysplasia cases, including 1 of 7 cases without and 2 of 3 cases with p53 mutation. It is concluded that combined alpha-methylacyl coenzyme A racemase/p53 analysis may represent a helpful tool to confirm dysplasia in inflammatory bowel disease.

To study the role of loss of heterozygosity (LOH) in serum microsatellite DNA of patients with gastrointestinal stromal tumors (GIST).In GIST, tumor markers from peripheral blood are missing.Seventy-eight patients (59 GIST, 13 leiomyomas, 2 leiomyosarcomas, and 4 schwannomas) underwent resection at our institute between 1985 and 2006. Thirty-three preoperative sera (26 GIST and 7 non-GIST) and 62 postoperative sera (47 GIST and 15 non-GIST) were available and tested for alterations in 12 representative microsatellite loci on chromosomes 22, 17, 13, 9, and 3, using fluorescence-based automated capillary electrophoresis by ABI Prism. Survival was calculated with Kaplan-Meier plots.Seventeen out of 26 GIST patients had a positive preoperative serum LOH score (or =2 LOH, sensitivity 65.4%), and 6 out of 7 non-GIST patients had a negative score (or =1 LOH, specificity 85.7%, P=0.030, Fisher exact test). Serum LOH in GIST were strongly correlated with Fletcher risk groups (P=0.016, chi test). All metastasized GIST (7/7) showedor =2 LOH preoperatively. Postoperative sensitivity and specificity of LOH analysis for prediction of relapse in 47 GIST was 75.0% and 64.1%, respectively. After a median observation time of 51.3 months (95% confidence interval, 39.4-61.4), LOH in serum significantly predicted overall survival (P=0.007, log-rank test).LOH serum analysis in GIST may play a role as a noninvasive, differential diagnostic, prognostic, and monitoring marker in the clinical routine.

To assess the role of immunohistochemically detectable nodal microinvolvement of patients with "curatively" resected esophageal carcinoma.In 73 patients with resectable esophageal carcinoma [squamous cell carcinoma (SCC), n = 45 (61.6%); adenocarcinoma (AC), n = 28 (38.4%)] a total of 2174 lymph nodes (LN) were removed. In each of the 1958 LN classified as negative on conventional histopathology, immunohistochemistry was performed using the anticytokeratin antibody AE1/AE3. To determine the role of the amount of residual tumor load, the patients were grouped according to the percentage of LN affected with micrometastasis (0%,11%, andor =11%).Tumor cells were immunohistochemically detected in 47 LN (2.4%) from 25 (34.2%) patients. Five-year overall survival probability (5-YSP) of 30% in pN(0 )patients with detected occult tumor cells in LN was significantly worse than that in those without nodal microinvolvement (76%, P = 0.021), hereby resembling that of pN1-patients (24%, P = 0.84). Median overall survival in patients with no (0%), low (11%), and high (11%) micrometastatic tumor load was 43, 27, and 11 months, respectively. Substratification according to histological type showed that, in patients with AC, the presence of nodal microinvolvement had a significant impact on 5-YSP (0% versus 65%; P = 0.03), whereas in patients with SCC, differences of 5-YSP were only of borderline significance (24% versus 53%; P = 0.081).Minimal tumor cell load as assessed by the ratio of micrometastatically affected LN is a complementary tool for better risk stratification of patients with esophageal carcinoma.

To investigate the importance of lymph node yield (LNY) and the ratio of afflicted lymph nodes in esophageal carcinoma patients.Between 1992 and 2004, 368 patients with esophageal carcinoma underwent surgery. Esophagectomy with curative intent was performed in 255 patients. Subtotal esophagectomy was performed either by thoracoabdominal (104 patients, 40.8%) or by transhiatal approach (151 patients, 59.2%).According to the LNY, patients were grouped into 3 groups. Twenty-six patients hador =5, 96 had 6 to 18, and 113 hador =19 dissected lymph nodes. In patients with nodal involvement (pN1), no significant overall survival differences were identified when stratifying subgroups according to the LNY. However, LNY had striking prognostic relevance in pN0 patients. The median overall survival was 23 (or =5 LN), 36 (6-18 LN), and 88 months (or =19). Even for patients with tripled LNY than the proposed minimum by the International Union Against Cancer (UICC) (18 LN), the rate of patients with detected lymph node metastases was only 46%, compared with 61% for patients with a LNY ofor =19 (P = 0.002). In pN1 patients classified according to the ratio of afflicted lymph nodes, median overall survival was 27 months in patients with a ratio11%, compared with 15 and 13 months in patients with a ratio of 11% to 33% and33%, respectively (P0.001). Multivariate Cox regression modeling identified ratio as the strongest independent prognostic factor for overall survival in pN1 and the LNY in pN0 patients.The minimal regional LNY of 6 lymph nodes as recommended by the UICC for esophageal carcinoma is far too low to appropriately stage the disease. The LNY and the ratio should be reflected in the next version of the UICC classification.

Background The utility of open lung biopsy (OLB) in mechanically ventilated patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) of unknown origin has been questioned because of its potentially low diagnostic yield and possibly related morbidity. To quantify possible benefits and risks, and especially so for bedside lung biopsy, we reviewed retrospectively our 8-year, single unit experience with this procedure. Methods Mechanically ventilated, critically ill patients with acute respiratory failure of unknown origin who underwent OLB were analyzed in a retrospective, single-center, cohort study in a medical intensive care unit in a university medical center. Measurements and Main Results Twenty-seven patients were analyzed (15 female, 12 male, of mean 48 years [standard deviation, 14]), 67% of whom were immunocompromised. All patients underwent bronchoscopy and bronchoalveolar lavage before OLB. Pa o 2 /Fraction of inspired oxygen at the time of biopsy was 188 ± 109 mm Hg. Biopsies were performed in the operating room on 9 patients and at bedside on 18. A specific diagnosis was obtained in 70% of biopsies. Biopsy results led to alteration in treatment in 81% of patients. Minor complications occurred in 52% of patients and major complications in 7%. The rate of complications did not appear to differ with the location of the procedure (bedside vs operating room). No deaths were attributed to the procedure. Conclusions Bedside OLB can be performed safely in selected, mechanically ventilated, critically ill patients with ALI or ARDS. Our results support the concept that lung biopsy often leads to management alterations in patients where a standardized diagnostic workup failed to yield a definitive diagnosis.

Background: Transcriptional activity of the heme oxygenase-1 gene (HMOX-1) is modulated by a GTn-repeat promoter polymorphism. The long GTn-repeat allele has been previously reported to be associated with increased risk of oral squamous cell carcinoma (OSCC) in male areca chewer and short GTn-repeat allele has been proposed to have protective properties in OSCC patients. The aim of the present study was to correlate the GTn-repeat genotypes with clinicopathological characteristics along with clinical outcome of non-areca chewer OSCC patients. Methods: DNA of 99 patients that underwent complete surgical resection of OSCC was analyzed for GTn-repeat polymorphism in the HMOX-1 promoter by polymerase chain reaction, capillary electrophoresis and DNA sequencing. Results: Seven SS (7.1%), 51 SL (51.5%) and 41 LL (41.4%) genotypes were found. In a total of 14 (14.1%) patients, tumor recurrence (TR) was observed. There was no TR in the SS allele carriers. In SL carriers three and in LL 11 TR occurred (P = 0.009, chi-squared test). Mean relapse-free survival was 109.2 months in SL allele carriers compared with 72.3 months in LL allele carriers (P = 0.01, log-rank test). Multivariate Cox regression modeling identified GTn-repeat genotype as an independent prognostic factor (P = 0.03; relative risk (RR) 4.1; 95% CI 1.1–14.6). Conclusion: Presence of S allele was associated with a lower TR rate and better relapse-free survival in OSCC patients. HMOX-1 promoter polymorphism might be considered as a potential prognostic marker in OSCC patients.

Background: To assess in-hospital complication rates and survival duration after en bloc vascular resection (VR) for infiltration of pancreatic malignancies in major vessels. Methods: Between 1994 and 2005, 585 patients underwent potentially curative pancreatic resection without adjuvant chemotherapy. Four hundred forty-nine patients (77%) underwent standard oncologic resection (VR−), whereas 136 (23%) received VR (VR+). For calculation of in-hospital morbidity and mortality rates, all 136 patients who underwent VR were considered. In contrast, for survival analysis, only pancreatic adenocarcinoma patients (n = 100) were included. Results: One hundred twenty-eight VR+ patients underwent portal or superior mesenteric vein resection and 13 hepatic artery (HA) or superior mesenteric artery (SMA) resection. In 5 patients, synchronous VR addressing both the mesenterico-portal axis and either the HA or SMA was performed. In-hospital morbidity and mortality rates of VR− patients (39.7%/4.0%) nearly equaled that of VR+ patients (40.3%/3.7%). From the 100 patients with pancreatic adenocarcinoma, histopathology confirmed “true” vascular invasion in 77 patients. Twenty-three patients had peritumoral inflammation, mimicking tumor invasion. Median survival was 15 months (11.2–18.8) in patients with histopathologic proven vascular invasion and 16 months (14.0–17.9) in those without (P = 0.86). Two-year survival probabilities were 36% (without) versus 34% (with vascular invasion; P = 0.9). Among VR+ patients with histopathologically evidenced vascular invasion, 19 survived longer than 30 months, and 6 were still alive 5 years after surgery. Multivariate modeling identified nodal involvement (N1) and poor grading (G3) as the only predictors of decreased survival. Evidence of vascular invasion had no adverse impact on survival. Conclusion: Postoperative morbidity and mortality rates after en bloc VR are comparable with “standard” pancreatectomy procedures. Median survival of 15 months in patients with vascular invasion is superior to that of patients who undergo palliative therapy and nearly equals that of patients who are not in need for VR.

Pancreatic ductal adenocarcinoma is the fifth leading cause of death among all malignancies, leading to approximately 40,000 deaths each year in Europe. The annual incidence rate for all types of pancreatic cancer is approximately nine new cases per 100,000 people, ranking it as the 11th among all cancers. Stage, grade and resection margin status are currently accepted as the most accurate pathologic variables predicting survival. All classification systems fail prognostically to distinguish between different stages. Even in patients with seemingly early tumours (T1, N0), the likelihood of relapse is high. This reflects the shortcomings of the pathologic staging to sufficiently discriminate patients with a high risk to develop tumour recurrence from those that carry a lower risk.On the other hand, none of the currently used systems includes or takes into consideration the role of disseminated tumour cells neither in the lymph nodes nor in the bone marrow. Occult residual tumour disease is suggested when either bone marrow or lymph nodes, from which tumour relapse may originate, are affected by micrometastatic lesions undetectable by conventional histopathology. For detection, antibodies against tumour-associated targets can be used to detect individual epithelial tumour cells both in lymph nodes and in bone marrow. The clinical significance of these immunohistochemical analyses is still controversial. Various monoclonal antibodies are still in use for micrometastatic detection, thus contributing to the incongruity of data and validity of results. These assays have been rarely used in patients with pancreatic carcinoma.The presence or absence of lymph-node metastases can predict the likelihood of survival for most, if not all, patients with pancreatic ductal adenocancer and the likelihood that metastases will develop at distant sites.

Background Reinsertion of the distal common bile duct (CBD) into the pancreatic resection cavity during duodenum-preserving pancreatic head excision (DPPHE) may be an alternative option to Whipple resection or bilioenteric anastomosis when chronic pancreatitis is associated with CBD stenosis. Methods Outcome in 82 patients with chronic pancreatitis who underwent DPPHE with CBD reinsertion was compared with that in 432 who had DPPHE without reinsertion and 50 who had a Whipple procedure or pylorus-preserving pancreatoduodenectomy (PPPD). Results There were no deaths after DPPHE with CBD reinsertion, compared with four (0·9 per cent) after DPPHE without reinsertion and three (6 per cent) after classical resection. Overall morbidity rates were 30, 28·9 and 36 per cent respectively. Fifteen patients (18 per cent) who had DPPHE with CBD reinsertion developed a stricture at the reinsertion site, compared with a long-term stricture rate of 2·3 per cent (ten patients) after DPPHE without CBD reinsertion and 4 per cent (two patients) after PPPD/Whipple resection. Conclusion Although associated with a high incidence of anastomotic stricture, reinsertion of the CBD into the resection cavity as part of DPPHE can be used to preserve duodenal passage and offers an alternative to extended resection for chronic pancreatitis.

L1 is a cell adhesion molecule expressed at the invasive front of colorectal tumors with an important role in metastasis. The aim of the present study was to determine L1 protein expression in a large cohort of colorectal cancer patients and its impact on early metastatic spread and survival. A total of 375 patients that underwent surgical treatment for colorectal cancer were chosen retrospectively. A tissue microarray was constructed of 576 tissue samples from these patients and analyzed by immunohistochemistry with a monoclonal antibody against human L1 (UJ127). Lymph node and bone marrow micrometastasis were assessed with monoclonal antibodies Ber-EP4 and pancytokeratin A45-B/B3, respectively. Associations between L1 expression and lymph node, bone marrow micrometastasis and survival were investigated with Fisher's, log-rank test and Cox multivariate analysis. All statistical tests were two-sided. L1 was detected in a subset of 48 (13%) of 375 patients examined. Analysis of L1 expression and survival revealed a significantly worse outcome for L1-positive patients by log-rank test (P

Background and study aims Endoscopic ultrasonography (EUS) is generally established as the most sensitive diagnostic tool for the assessment of locoregional tumor stage in esophageal carcinoma. It therefore has a crucial impact on the decision whether patients should undergo surgery as primary treatment or should receive neoadjuvant therapy. This study retrospectively evaluates the accuracy of EUS in tumor and nodal staging of prospectively evaluated patients with esophageal carcinoma in relation to tumor type, tumor grading, tumor site, and the influence of dilation. Patients and methods All 214 patients included in the study underwent surgery without neoadjuvant therapy and had tumor-free resection margins with no evidence of distant metastasis. EUS investigations were done at our Department of Interdisciplinary Endoscopy. EUS results were compared with the pathological findings. Results EUS correctly identified T status in 141 patients (65.9 %). The sensitivity and specificity in relation to T status were 68.1 % and 98.2 % respectively for T1, 40.9 % and 83.4 % for T2, 84.3 % and 64.6 % for T3, and 14.3 % and 98.8 % for T4. The overall diagnostic accuracy of EUS in relation to N status was 64.5 % (n = 138); sensitivity and specificity for the diagnosis of N1 were 93.8 % and 20 %, respectively. Sixty-eight (80 %) of 85 pN0-staged tumors were overstaged as uN1. Dilation had a significant influence on the accuracy of EUS staging in advanced tumors ( P = 0.02), whereas tumor grading impacted on EUS staging in early tumors ( P = 0.01). Tumor site and tumor type did not show any influence. Conclusions Endosonographic staging of esophageal carcinoma is still unsatisfactory. An improvement in staging accuracy may be achieved by adding fine-needle aspiration biopsy (FNA) to EUS, because FNA improves N-stage accuracy, but it has no bearing on T-stage accuracy.

To evaluate surgical strategies for neuroendocrine pancreatic tumors (NEPT) in the light of the new WHO classification from 2004 and to draw conclusions for future surgical concepts.: The extent of surgical resection in primary and recurrent NEPT is unclear.Between 1987 and 2004, 62 patients with sporadic NEPT were treated at our institution and sections from biopsy and resection specimen were histopathologically reclassified. Clinical presentation, surgery, metastases, and pattern of recurrence were related to survival.Fifteen well-differentiated tumors (WDT, 24%), 39 low-grade carcinomas (LGC, 63%), and 8 high-grade carcinomas (HGC, 13%) were identified. Median observation time was 30.5 months; 48 of 62 patients (78%) were surgically resected, and in 45 patients R0/R1 status was achieved. Overall 2- and 5-year survival in the latter group was 80% and 64%, respectively. Retrospective WHO classification revealed that organ-preserving segmental resections had been performed in 10 LGC and 1 HGC. These patients showed equal outcome as radically resected counterparts (n = 19). Liver and other organ metastases were present in 19 of 62 patients (31%), and resection was accomplished in 7 of 19 patients, which conferred better overall survival (P = 0.026, log-rank test); 21 of 45 R0/R1-resected patients (47%) suffered from recurrence, and reoperation was accomplished in 9 patients, which resulted in better overall survival (P = 0.066).Organ-preserving resections offer sufficient local control in LGC; therefore, radical resections do not seem to be justified. On the other hand, radical resection is indicated even in metastasized patients or in case of loco-regional recurrence. The silent and slow course of the disease facilitates long-term surgical control.

Midkine (MK), a heparin-binding growth factor, has an important role in cancer progression. The outcome of patients with gastrointestinal stromal tumors (GISTs) is correlated with tumor size and mitotic count. The aim of this study was to determine MK expression in GISTs. Midkine was detected in 31 (55%) of 57 surgically resected GISTs by immunohistochemistry with a rabbit antibody against MK and peroxidase method. A significant worse outcome of MK-positive patients was found (P

To compare radio(chemo)therapy with 41.4–50.4 Gy (moderate dose, MD-RCT) plus resection versus radio(chemo)therapy with 59.4–66.6 Gy (higher dose, HD-RCT) alone for outcome in stage III esophageal cancer, and to investigate potential prognostic factors including preradiotherapy (pre-RT) hemoglobin. 148 patients with stage III esophageal cancer, treated with MD-RCT plus resection (n = 41) or HD-RCT alone (n = 107), were retrospectively evaluated for age, gender, performance status, tumor location, tumor length, stage, histology, grading, number of chemotherapy courses, pre-RT hemoglobin, resection, overall survival (OS), metastases-free survival (MFS), and locoregional control (LC). On univariate analysis, MD-RCT plus resection resulted in better 2-year OS (57% vs. 25%; p = 0.049), 2-year MFS (71% vs. 39%; p = 0.041), and 2-year LC (76% vs. 39%; p = 0.003). On multivariate analysis, results maintained significance for LC (p = 0.021). According to multivariate analysis, pre-RT hemoglobin was associated with OS (p = 0.003), MFS (p = 0.043), and LC (p = 0.041), tumor length with OS (p = 0.002) and MFS (p = 0.017), and the number of chemotherapy courses with OS (p = 0.008). Complications were more frequent in the MD-RCT-plus-surgery group (p < 0.001). Acute (p = 0.47) and late toxicity (p = 0.86) were similar in both groups. In patients receiving surgery, R0 resection was superior to R1/2 resection for OS (p < 0.001), MFS (p = 0.030), and LC (p < 0.001). MD-RCT plus R0 resection was also superior to HD-RCT alone. MD-RCT plus resection resulted in better LC than HD-RCT alone. If R0 resection is possible, MD-RCT plus resection appears preferable, as it results in better outcome. If only R1/2 resection can be performed, HD-RCT alone appears preferable regarding outcome and the greater morbidity associated with resection.

Local esophagoplasty is indicated for patients with short esophageal strictures when endoscopic therapies including bougienage and balloon dilatation are not effective.

The heterogeneity of patient population and of symptoms as well as poor understanding of the pathophysiology in patients with CP are obstacles in the effectiveness of patient treatment. The symptom triad of chronic pancreatitis includes exocrine and endocrine pancreatic insufficiency and, representing the most important surgical indication, recurrent episodes of pain, which brings patients to their physicians and causes addiction to analgesics. In the past, 2 major reasons have been addressed advocating conservative treatment. The “historical” “burn-out” theory, advocating that pain will eventually subside as a consequence of the self-limiting pathophysiology of pancreatitis-related pain,1 has been challenged by more recent series, which report persistence of pain for more than 10 years.2 The second, emphasizing high morbidity and mortality rates associated with pancreatic operations, has become more or less obsolete as a result of significant progress in surgical and interventional techniques, especially in high-volume pancreatic centers. Therefore, conservative “watchful waiting” is nowadays hardly acceptable, especially if pancreatic pain has a morphologic basis. Therapeutic options in conservative, interventional (endosonography-guided celiac plexus blockade), and surgical treatment of CP (including thoracoscopic splanchnicectomy) are mainly addressing pain relief. Based on the various hypotheses of pain origin in CP,3,4 (ductal) drainage and resection have become the 2 major principles for surgical treatment. Both options are combined in the principle of duodenum-preserving pancreatic head resection and its various modifications.5–8 Apart from morphologic changes involving the glandular parenchyma, 2 anatomic variants of chronic pancreatitis can be distinguished with regard to the diameter of the main pancreatic duct, which is normally 4 to 5 mm.9 The large duct form, defined as main ductal diameter of >7 mm,10 has been considered the classic domain of drainage procedures.11–13 This so-called “large-duct chronic pancreatitis” is the typical feature of ductal irregularities presented by patients suffering from chronic pancreatitis (CP). Although conclusive, the argumentation that ductal dilatation causes ductal hypertension, hereby leading to pain, lacks evidence. An extremely rare form of CP has been termed small duct pancreatitis, defined as main ductal diameter of ≤3 mm.9 This condition has been regarded as the domain of resectional procedures of various extents.14–19 Even total pancreatectomy as ultima ratio has been suggested. The therapeutic algorithm from the American Gastroenterological Association (AGA) in 1998, does not consider the option of draining procedures for these patients.20 To maintain as much pancreatic tissue as possible and to lower the risk of postoperative exocrine and endocrine pancreatic dysfunction, our group devised, in a previous study, a surgical technique of an organ-sparing operation, which consisted in a longitudinal V-shaped excision of the anterior aspect of the pancreas.21 Based now on more than 10 years of follow-up, here we report on long-term results regarding pain relief, improvement of quality of life, as well as exocrine and endocrine pancreatic functions in patients with SDP.

Background EUS-guided pancreatic pseudocyst and abscess drainage ideally requires the insertion of both a transmural stent and nasocystic catheter to ensure continuous irrigation and effective drainage. Sequential stent and nasocystic catheter insertion may be time consuming because of the difficulty in recannulating the pseudocyst after the initial stent placement. Objective Our purpose was to describe a novel one-step simultaneous double-wire technique that facilitates effective pancreatic pseudocyst and abscess drainage. Design To solve the problem of recannulating the pseudocyst cavity after the initial transmural stent placement, we developed a prototype 3-layer puncture kit that allows the simultaneous insertion of 2 guidewires at the initial puncture in one step. This puncture kit consists of a 22-gauge needle used for FNA, a 6F inner polytetrafluoroethylene (Teflon) catheter, and an outer 8.5F Teflon catheter. Setting Tertiary referral center. Patients Eight consecutive patients were treated. Interventions With use of a therapeutic linear echoendoscope and the assembled kit with the needle protruding out distally, the pseudocyst cavity was punctured by using electrocautery. The needle and the inner catheter were then withdrawn, leaving the outer catheter within the cavity. The size of this outer catheter permitted the simultaneous insertion of two 0.035-inch guidewires. Sequential insertion of a transmural stent and nasocystic catheter was then performed without a need for recannulation of the pseudocyst or abscess cavity. Main Outcome Measurements Successful endoscopic drainage. Results All patients were successfully treated without complications. Mean procedural time was 32.5 minutes (range 25-45 minutes). Conclusions With this novel technique, establishing an irrigation system for the treatment of pancreatic pseudocysts and abscesses becomes easier, faster, and safer.

Background Adenocarcinoma of the esophago-gastric junction (EGJ) potentially spreads to abdominal and mediastinal lymph nodes. Methods Eighty-five patients with type I and II EGJ cancer underwent curative esophagectomy or esophago-gastrectomy and radical abdominal and mediastinal lymphadenectomy. Microinvolvement was detected with the mAb Ber-Ep4 in all histopathologically free lymph nodes. Results In type I tumors (n = 40), lower mediastinal lymph nodes were positive in 24% and among type II tumors (n = 45) in 10% of patients. Ber-Ep4+ cells in apparently free lymph nodes were found in 49% of patients. On inclusion of Ber-Ep4+ nodes, positive mediastinal lymph node staging was rising to 40 and 33% in type I and II patients, respectively. After a median observation time of 27.1 months, 37 of 85 patients (43.5%) had died of tumor disease. Kaplan–Meier analysis revealed a significant impact of nodal microinvolvement on disease-specific survival for type I and type II tumors (P = 0.016 and P

Purpose The appropriate surgery for curable squamous cell cancer (SCC) of the esophagus is discussed controversially. Patients and Methods Transthoracic esophagectomy (TTE) with radical en-bloc-lymphadenectomy was performed in 79/120 patients (66%). Due to severe comorbidity, 41/120 patients (34%) underwent less traumatizing transhiatal esophagectomy. Lymph nodes were stained using mAb BER-Ep4. Results pN0 status was found in 54 patients (45%) and pN1 status in 66 patients (55%). In the pN0 subgroup, 30 out of 54 patients (55.6%) had occult tumor cells in lymph nodes detected with BER-Ep4. pN1 patients had additional BER-Ep4 positive cells in histopathologically negative lymph nodes in 41 out of 66 patients (59.2%). Median disease-specific survival was 31.4 and 16.8 months for the transthoracic and transhiatal groups, respectively (P = 0.129). pN0 patients lived longer after transthoracic resection (P = 0.0349), and in the subgroup without lymph node micrometastases this effect was even stronger (P = 0.025). In contrast, in pN0 patients with nodal microinvolvement, TTE did not entail a survival benefit when compared with the transhiatal group (P = 0.333). Conclusion TTE results in improved outcome in the absence of lymph node micrometastases. Poor survival in patients with lymphatic micro-dissemination indicates systemic disease and the need for adjuvant treatment. J. Surg. Oncol. 2006;93:541–549. © 2006 Wiley-Liss, Inc.

BACKGROUND The chemokine and bone marrow-homing receptor CXCR4 has been implicated in metastatic dissemination of various cancers. We investigated CXCR4 expression in esophageal cancer specimens and its association with survival, lymph node microinvolvement, and bone marrow micrometastasis. METHODS We analyzed frozen tumor specimens from 136 patients with completely resected esophageal cancer for CXCR4 expression by immunohistochemistry. Lymph node microinvolvement and bone marrow micrometastasis were assessed by immunohistochemistry with monoclonal antibodies Ber-EP4 (against epithelial cell adhesion molecule) and pancytokeratin A45-B/B3 (against several cytokeratins), respectively. Associations between CXCR4 expression and clinicopathologic features, including tumor stage, histologic grade, lymph node metastasis and microinvolvement, bone marrow micrometastasis, and survival, were investigated with Fisher's test, log-rank test, and Cox multivariable analysis. All statistical tests were two-sided. RESULTS CXCR4 protein was expressed in 75 (55%) of 136 esophageal tumors examined. CXCR4 expression was statistically significantly associated with reduced median overall and disease-specific survival, compared with CXCR4 nonexpression (P < .001; log-rank test). The median overall survival of patients with CXCR4-positive tumors was 20 months and with CXCR4-negative tumors, 76 months (difference = 56 months, 95% confidence interval [CI] = 4 to 108 months; P < .001). The median disease-specific survival of patients with CXCR4-positive tumors was 25 months and with CXCR4-negative tumors was 97 months (difference = 72 months, 95% CI = 34 to 110 months; P < .001). CXCR4 expression was statistically significantly associated with increased lymph node microinvolvement (P < .001) and with increased bone marrow micrometastasis (P < .001). In multivariable analysis, CXCR4 expression, compared with its nonexpression, was identified as the independent variable that was most strongly associated with reduced disease-specific survival (relative risk [RR] of death = 2.03, 95% CI = 1.20 to 3.41; P = .008) and overall survival (RR of death = 2.18, 95% CI = 1.33 to 3.59; P = .002). CONCLUSION CXCR4 expression was associated with poor clinical outcome in esophageal cancer patients. CXCR4 may have a role in early metastatic spread because its expression was associated with micrometastases to both the lymph nodes and bone marrow. Thus, CXCR4 should be explored further as a target for adjuvant therapy for micrometastatic disease.

BACKGROUND It has been suggested that hemoglobin levels of 12–14 g/dL are optimal for tumor oxygenation, radiosensitivity, and prognosis. In this prospective study, the authors evaluated the effectiveness of epoetin-α to maintain hemoglobin levels at 12–14 g/dL during radiotherapy (RT) for patients with UICC Stage III esophageal carcinoma, and they examined the impact of erythropoetin on overall survival (OS), metastatic-free survival (MFS), and local control (LC). METHODS Sixty patients who received RT between March, 2001 and September, 2004, were included in this prospective, nonrandomized study. Thirty patients received epoetin-α (150 IU/kg 3 times per week) during RT (Group A), and 30 patients did not receive epoetin-α (Group B). Epoetin-α was started at hemoglobin levels < 13 g/dL and was stopped at hemoglobin levels ≥ 14 g/dL. Hemoglobin was measured before RT and once weekly during RT. RESULTS Both patient groups were balanced for age, gender, performance status, tumor location/length, histology, grading, tumor classification, lymph node status, chemotherapy, treatment (45–50.4 grays [Gy] plus resection vs. 45.0–50.4 Gy vs. 59.4–66.0 Gy), and hemoglobin level before RT. In 20 of 30 patients (67%) from Group A and in 3 of 30 patients (10%) from Group B, ≥ 60% of hemoglobin levels during RT were 12–14 g/dL (P = 0.003). The median change in hemoglobin was + 0.4 g/dL per week in Group A and − 0.4 g/dL per week in Group B. LC was significantly better in Group A (66% vs. 38% at 1 year, respectively; P = 0.012), a trend was observed for OS (59% vs. 33%, respectively; P = 0.08), and MFS did not differ significantly (43% vs. 38%, respectively; P = 0.34). No epoetin-α-related toxicity was observed. CONCLUSIONS Epoetin-α was effective in maintaining the hemoglobin levels at 12–14 g/dL during RT. The application of epoetin-α significantly improved LC, and a trend was observed for OS. Cancer 2005. © 2005 American Cancer Society.

Background: The aim of this study was to assess the prognostc significance of nodal microinvolvement as well as the mode of spread in the early phase of lymphatic metastasis in patients with node-negative pancreatic ductal adenocarcinoma. Methods: Lymph nodes from 48 node-negative patients with R 0 resected pancreatic ductal adenocarcinoma were sampled from 3 different compartments: 1) distal hepatoduodenal ligament, 2) superior-anterior compartment, and 3) posterior-inferior. Tissue sections of 148 lymph nodes classified as tumor free by routine histopathology were examined, using a sensitive immunohistochemical assay with the antiepithelial monoclonal antibody Ber-EP4 for tumor cell detection. With regard to histopathologic tumor staging and grading, 26 (54.2%) of the patients were staged as pT 1 /pT 2 , 22 (45.8%) as pT3/pT4, while 31 (64.6%) as G 1 /G 2 and 17 (35.4%) patients as G 3 . Of the 148 tumor free lymph nodes, 56 contained Ber-EP4-positive tumor cells. These 56 lymph nodes were from 28 of the 4 8 patients. The multivariate Cox regression analysis revealed the independent prognostic impact of nodal microinvolvement on relapse-free and overall survival. Analysis by compartment, from which the lymph nodes were collected, revealed that overall survival time (P = 0.006) and time to local recurrence (P = 0.015) depend on the presence of nodal microinvolvement in the superior-anterior compartment. Conclusions: The influence of occult tumor cell dissemination n lymph nodes of patients with histologically proven pancreatic duct al adenocarcinoma supports the need for further tumor staging through immunohistochemistry. This could be a helpful tool in proper selection of patients for adjuvant chemotherapy.

In den westlichen Industrienationen sterben jahrlich ca.150.000 Patienten an einem Pankreaskarzinom, davon allein ca. 40.000 in Europa. Damit ist das Pankreaskarzinom die viert- bis funfthaufigste Todesursache bei Krebserkrankungen in der westlichen Welt. Mit einer insgesamt beschriebenen Funfjahresuberlebensrate von weniger als 1% stellt das Pankreaskarzinom somit eine der aggressivsten Tumorerkrankungen uberhaupt dar. Die Tumorresektion ist nach wie vor die einzige Moglichkeit, das Pankreaskarzinom zu heilen. Trotz groser klinischer Anstrengungen hat sich die Langzeitprognose von Pankreaskarzinompatienten nur unwesentlich verandert. Die Chirurgie des Pankreaskarzinoms hat in den vergangenen 10 Jahren allerdings wesentliche Fortschritte gemacht, und heute konnen mehr Patienten reseziert und die Operation sicher und mit geringer Morbiditat und Mortalitat ausgefuhrt werden. Ein groses Problem stellt die fruhzeitige Diagnose dar. Nur 10–15% aller Patienten mit der Diagnose eines Pankreaskarzinoms werden in einem resektablen Stadium diagnostiziert. Die dabei erzielten Funfjahresuberlebensraten konnten in der Vergangenheit auf ungefahr 25% gesteigert werden, sind aber weiterhin nicht befriedigend. Auf der anderen Seite tragen die niedrige Ansprechrate auf Chemotherapeutika, Radiotherapie, Immuntherapie und antihormonale Therapien zur schlechten Prognose von diesen Patienten bei.

Fur das souverane Agieren in der Thoraxchirurgie kann es von erheblicher Relevanz sein, grosere Eingriffe interdisziplinar zu planen und durchzufuhren. Eingriffe an Thoraxwand, Thoraxorganen und angrenzenden Korperregionen wie Hals, Axilla, Arm und Wirbelsaule konnen in Kombination erforderlich werden. Ausgedehnte onkologische Resektionen bei fortgeschrittenen Tumorleiden oder Folgezustande nach Bestrahlung oder Trauma erklaren die Vielfalt an moglichen chirurgischen Eingriffen. Die Notwendigkeit von Gefasersatz, Operation am Plexus brachialis, an der Halswirbelsaule, am Herzen sowie die plastische Defektdeckung und Thoraxwandstabilisierung bedingt hohe Anspruche an Infrastruktur und Operationstechnik, modernstes Equipment und die Anwendung des aktuellsten Know-hows. Wie haben exemplarisch einige Erkrankungen ausgewahlt, die unseres Erachtens Gegenstand interdisziplinarer Therapieplanung und -durchfuhrung sein konnen. Dabei sollten onkologische, funktionelle und nicht zuletzt rekonstruktive Aspekte beachtet werden.

A case of vascular malformations of the small intestine associated with malrotation Type I of the right colon is reported. Representing rare conditions, vascular malformations in the small bowel are not accessible endoscopically. Therefore, gastrointestinal haemorrhage originating from this "terra incognita" is difficult to diagnose. Our patient had a medical history of anaemia of 17 years before admitted to our hospital. After a preoperative blood pool scan had evidenced the bleeding source in the proximal jejunum, the patient underwent explorative laparotomy. The bleeding source was identified and resection of a jejunal segment was performed. Intraoperatively, malrotation type I was found. Histological examination revealed angiodysplasia extending full thickness of the intestinal wall with predominance in the submucosa and serosa. Secondary arterialisation was seen in the vessels of the serosa resembling varicosis-like lesions at gross inspection. The patient did not suffer from portal hypertension. Postoperative course was uneventful and no further bleeding occurred.

This study was devised to identify sepsis-relevant parameters that early and reliably predict a lethal outcome in intra-abdominal sepsis. In 18 Duroc pigs, peritonitis was induced through standardized gastrotomy. Twelve hours later the defect was oversewn and the abdominal cavity lavaged thoroughly. Sepsis relevant parameters were measured before initiating therapy, and 30 min later animals were extubated and observed for a period of 6 days under adequate analgesia with free access to water and food. All parameters were correlated with survival postoperatively. In the treatment group, 7 out of 18 pigs (39%) died within the observation period. Endotoxin level at 30 min after initiation of therapy [17.9 EU/mL ( &#45 12.1) vs. 110.9 EU/mL ( &#45 21); p < .001] and &#106 pHi [0.015 ( &#45 0.011) vs. &#109 0.039 ( &#45 0.013); p = .016] were identified as the two parameters with highest predictive power regarding mortality in a multivariate analysis. In conclusion measurement of endotoxin and gastric tonometry...

Impact of different modalities of continuous venovenous hemofiltration on sepsis-induced alterations in experimental pancreatitis. Background Continuous venovenous hemofiltration (CVVH) is assumed to attenuate systemic complications in septic diseases. The impact of different treatment intensities of CVVH on immunologic and systemic alterations in experimental pancreatitis was evaluated. Methods Eighty-four minipigs were allocated either to an untreated control group (group 1) or to one of six treatment groups (groups 2 to 7) that underwent CVVH in different modalities: ( 1 ): "late" CVVH, started after a decline of total peripheral resistance of 30% versus "prophylactic" CVVH started immediately after the induction of pancreatitis; ( 2 ) no change of hemofilters versus a periodic change of filters every 12 hours; ( 3 ) low-volume CVVH with a filtrate turnover of 20 mL/kg body weight (BW)/h versus high-volume CVVH (100 mL/kg/h). Pancreatitis was induced by intraductal injection of sodium-taurocholate (3%, 1 mL/kg BW) and enterokinase (2 U/kg BW). We focused on the occurrence of sepsis, serum cytokines, down-regulation of major histocompatibility complex II (MHC II) and the endotoxin receptor CD14 expression, bacterial translocation/endotoxemia, and pulmonary and renal histologic alterations. Results CVVH delayed or definitively prevented the occurrence of sepsis. Pancreatitis was associated with a tremendous initial tumor necrosis factor-α (TNF-α) response prior to a return to near baseline levels in the late course of sepsis. Endotoxin hyporesponsiveness, suggested by the dissociation of decreasing TNF-α levels and increasing endotoxemia in end-stage sepsis, was favorably influenced by CVVH. Down-regulation of MHC II and CD14 expression was prevented in non-septic animals. CVVH-related sepsis-protection led to a significant attenuation of histological injury in lungs and kidneys. "Prophylactic" CVVH prevented histological changes more effectively than "late" CVVH. Conclusions CVVH offers a therapeutic option for supportive treatment in severe pancreatitis. The efficiency of CVVH is associated with the duration of filter use and cumulative plasma turnover. Since CVVH may lead to sepsis-protection and long-term survival, further evaluation in controlled, clinical trials is warranted.

This article gives an overview about current thinking in pathogenesis and natural course /therapy in chronic pancreatitis. Alcohol consumption is still the most relevant factor in the development of chronic pancreatitis, a disease with enormous personal and social impact, shortening life expectancy up to 10-20 yrs. Pathogenesis of chronic pancreatitis has to be considered for different symptoms. Particularly pain, the most bothering symptom, is most likely due to a combination of hypertension in the organ and parenchymal alterations. Pathogenesis of pancreatic head enlargement remains largely elusive. In particular it is not known what triggers growth factors to step into action. Most other symptoms like common bile duct stenosis or portal hypertension are secondary to this enlargement of the head of the pancreas.

Background: Median OS after surgery in curative intent for non-metastasized pancreas cancer ranges under study conditions from 17.9 months to 23.6 months. Tumor recurrence occurs locally, at distant sites (liver, peritoneum, lungs), or both. Observational and autopsy series report local recurrence rates of up to 87% even after potentially “curative” R0 resection. To achieve better local control, neoadjuvant CRT has been suggested for preoperative tumour downsizing, to elevate the likelihood of curative, margin-negative R0 resection and to increase the OS rate. However, controlled, randomized trials addressing the impact of neoadjuvant CRT survival do not exist. Methods/Design: The underlying hypothesis of this randomized, two-armed, open-label, multicenter, phase III trial is that neoadjuvant CRT increases the three-year overall survival by 12% compared to patients undergoing upfront surgery for resectable pancreatic cancer. A rigorous, standardized technique of histopathologically handling Whipple specimens will be applied at all participating centers. Overall, 410 patients (n=205 in each study arm) will be enrolled in the trial, taking into regard an expected drop out rate of 7% and allocated either to receive neoadjuvant CRT prior to surgery or to undergo surgery alone. Circumferential resection margin status, i.e. R0 and R1 rates, respectively, surgical resectability rate, local and distant disease-free and global survival, and first site of tumor recurrence constitute further essential endpoints of the trial. Discussion: For the first time, the NEOPA study investigates the impact of neoadjuvant CRT on survival of resectable pancreas head cancer in a prospectively randomized manner. The results of the study have the potential to change substantially the treatment regimen of pancreas cancer. Trial registration: Clinical Trial gov: NCT01900327, DRKS00003893, ISRCTN82191749