Gene Expression of Col11A1 Is a Marker Not only for Pancreas Carcinoma But also for Adenocarcinoma of the Papilla of Vater, Discriminating Between Carcinoma and Chronic Pancreatitis.

AIM: For tumors of the periampullary region clinical differentiation between primary and tumor-associated pancreatitis might be difficult. Early diagnosis of these malignancies is essential, as they present with early invasion of surrounding tissue thus limiting therapeutic options. Using molecular markers, the preoperative diagnosis (EUS-guided needle biopsy, brush biopsy pancreatic duct) could be optimized and surgical therapy potentially adapted. Alpha1 (XI) collagen Col11A1 is essential for the extracellular matrix and normal skeletal development and has been associated with carcinogenesis. MATERIALS AND METHODS: Forty-three patients with adenocarcinoma of the pancreas, 11 with adenocarcinoma of the papilla of Vater and 23 patients with chronic pancreatitis were included in the study. For all patients mRNA expression of Col11A1 was quantified by TaqMan RT-PCR in tumor or pancreatitis specimen, as well as in the corresponding normal uninvolved tissue and correlated with diagnosis of cancer and chronic pancreatitis. RESULTS: Col11A1 mRNA expression was 5.25-fold higher in adenocarcinoma of the pancreas (p=0.006) and 8.25-fold in the papilla of Vater (p=0.002) compared to that of chronic pancreatitis specimen. CONCLUSION: Differential mRNA expression of Col11A1 may be applied to preoperatively differentiate between tumors of the periampullary region and chronic pancreatitis and this may potentially have a positive effect on patient survival.

Molecular markers predicting lymph node metastasis in early esophageal cancer.

AIMS: The aim of this study was to identify molecular markers predicting depth of tumor infiltration and presence of lymph node metastasis in early esophageal cancer. METHODS: Between 1996 and 2004, 67 patients with pT1 esophagus cancer underwent esophagectomy. Resected tumors and lymph nodes were analyzed by immunohistochemistry for tissue infiltration, lymph node metastasis (LNM), micrometastasis and extracapsular lymph node infiltration (ELNI). We focused on MMP-2 (matrix-metalloproteinase-2), TIMP-2 (tissue inhibitor of metalloproteinase-2), PIM-1 and survivin as the most promising marker candidates. The data was correlated with the patients' long term follow-up (median follow-up time 11.4 years). RESULTS: We found 22 pT1a and 45 pT1b carcinomas. None of the mucosal carcinomas, but 58% (26 patients) of the submucosal carcinomas showed lymph node metastasis or micrometastasis. The rate of LNM positively correlated with the depth of tumor infiltration (23% LNM in sm1 tumors and 82% LNM in sm3 tumors). Low grade PIM-1 expression (<30%) was significantly associated with occurrence of LNM (p=0.034) while high expression TIMP-2 (>70%) were detected in submucosal tumors. Logistic regression analysis revealed PIM-1 and Grading G3 as independent risk factors for LNM (p<0.001). Survival of patients with micrometastasis was comparable to those with LNM (median survival: 5.05 years versus 5.52 years). Patients with ELNI had the worst prognosis (median survival: 1.7 years). CONCLUSIONS: PIM-1 is a promising marker for prediction of lymph node metastasis in early esophagus cancer. Extracapsular lymph node infiltration has an independent worse prognostic impact.

Extracapsular lymph node spread as a negative prognostic factor of adenocarcinoma of the pancreas and cancer of the papilla of vater.

OBJECTIVE: The aim of this study was to analyze the incidence and impact of extracapsular lymph node spread (ELNS) in pancreatic cancer (PC) and cancer of the papilla of Vater (CPV). METHODS: Between 2004 and 2009, 148 patients underwent surgical therapy for PC (n = 112) and CPV (n = 36). The resected lymph nodes (LNs) were further analyzed for ELNS. RESULTS: In 95 (64.2%) patients, LN metastasis was present. In 45 (47.3%) of these patients, an ELNS was present on histopathology. The patients' survival was negatively affected by ELNS. For PC, the 5-year survival rate was 37% for patients with no LN metastasis compared with 4% and 0% for patients with LN metastasis (pN1) but without extracapsular LN involvement and patients with pN1 disease with extracapsular LN involvement of at least 1 LN, respectively (P < 0.001). In patients with CPV, the 5-year survival rate was 56% for patients with no LN metastasis and 44% and 0% for patients with pN1 disease but without extracapsular LN involvement and patients with pN1 disease with extracapsular LN involvement of at least 1 LN, respectively (P = 0.006). Multivariate analysis revealed ELNS as an independent prognostic factor of survival for both tumor types. CONCLUSIONS: Extracapsular LN spread is an independent negative prognostic factor in PC and CPV. In future staging systems, ELNS should be included.

Health-related quality of life after Ivor Lewis esophagectomy.

PURPOSE: Transthoracic Ivor Lewis esophagectomy is a surgical standard therapy for esophageal carcinoma. The aim of this study was to assess health-related quality of life (HRQL) in mid- and long-term survivors. METHODS: Patients with cancer-free survival of at least 12 months after esophageal resection for cancer were identified from a prospectively maintained database. EORTC questionnaires were sent out to assess health-related general (QLQ-C30) and esophageal cancer-specific (QLQ-OES18) quality of life (QOL). A numeric score was calculated in each conceptual area and compared with reference data. RESULTS: One hundred forty-seven patients completed the self-rated questionnaires. They were 121 men and 26 women with a mean age of 63.4 (21-83) years; median FU was 39 (12-139) months. Global health status, functional scales, and symptom scores were significantly reduced compared with healthy reference populations. Also, there was no significant impact of tumor histology, neoadjuvant treatment, minimally invasive approach, or duration of follow-up on HRQL. However, more than half of the patients reported a HRQL similar to that of the healthy reference population. CONCLUSIONS: Despite the major psychosocial and physiological impacts of the disease, more than 50 % of mid- and long-term survivors of the Ivor Lewis procedure for esophageal cancer have a HRQL similar to that of the healthy reference population.

Effect of aging on esophageal motility in patients with and without GERD.

BACKGROUND/AIMS: The impact of aging on esophageal motility is not completely understood. This study aims at assessing 1) whether degeneration of esophageal body motility occurs with age and 2) whether this development is influenced by gastroesophageal reflux disease (GERD). METHODS: 326 consecutive patients with symptoms of GERD underwent a diagnostic work-up including a water-perfused esophageal manometry. Patients were divided by age: 17-39 years (group 1, n=75), 40-49 years (group 2, n=79), 50-59 years (group 3, n=64), 60-69 years (group 4, n=74), and >70 years (group 5, n=34). GERD was diagnosed if patients had erosive esophagitis at endoscopy, a positive pH-metry, or both. The amplitude of esophageal contraction waves 3 cm and 8 cm above the lower esophageal sphincter and the percentage of peristaltic contraction waves of the tubular esophagus were analyzed and correlated to GERD. RESULTS: A normal esophageal manometry was found in 86.7%, 73.4%, 67.2%, 58.1%, and 55.9% (p<0.01) in groups 1-5, respectively. Esophageal contraction wave amplitudes were affected by age in patients positive for GERD only (p<0.01). Esophageal body peristalsis was affected by age (p<0.01) independent of the diagnosis of GERD. CONCLUSION: Aging is correlated to esophageal motor abnormalities. GERD has a significant impact on esophageal contraction wave amplitude, but not on peristalsis.

Inhibition of oesophageal squamous cell carcinoma progression by in vivo targeting of hyaluronan synthesis.

BACKGROUND: Oesophageal cancer is a highly aggressive tumour entity with at present poor prognosis. Therefore, novel treatment options are urgently needed. Hyaluronan (HA) is a polysaccharide present in the matrix of human oesophageal squamous cell carcinoma (ESCC). Importantly, in vitro ESCC cells critically depend on HA synthesis to maintain the proliferative phenotype. The aim of the present study is (1) to study HA-synthase (HAS) expression and regulation in human ESCC, and (2) to translate the in vitro results into a mouse xenograft model of human ESCC to study the effects of systemic versus tumour targeted HAS inhibition on proliferation and distribution of tumour-bound and stromal hyaluronan. METHODS: mRNA expression was investigated in human ESCC biopsies by semiquantitative real-time RT PCR. Furthermore, human ESCC were xenografted into NMRI nu/nu mice. The effects on tumour progression and morphology of 4-methylumbelliferone (4-MU), an inhibitor of HA-synthesis, and of lentiviral knock down of HA-synthase 3 (HAS3), the main HAS isoform in the human ESCC tissues and the human ESCC cell line used in this study, were determined. Tumour progression was monitored by calliper measurements and by flat-panel detector volume computed tomography (fpVCT). HA content, cellular composition and proliferation (Ki67) were determined histologically. RESULTS: mRNA of HAS isoform 3 (HAS3) was upregulated in human ESCC biopsies and HAS3 mRNA was positively correlated to expression of the epidermal growth factor (EGF) receptor. EGF was also proven to be a strong inductor of HAS3 mRNA expression in vitro. During the course of seven weeks, 4-MU inhibited progression of xenograft tumours. Interestingly, remodelling of the tumour into a more differentiated phenotype and inhibition of cell proliferation were observed. Lentiviral knockdown of HAS3 in human ESCC cells prior to xenografting mimicked all effects of 4-MU treatment suggesting that hyaluronan produced by ESCC is accountable for major changes in tumour environment in vivo. CONCLUSIONS: Systemic inhibition of HA-synthesis and knockdown of tumour cell HAS3 cause decreased ESCC progression accompanied by tumour stroma remodelling and may therefore be used in novel approaches to ESCC therapy.

Laparoscopic deroofing of nonparasitic liver cysts with or without greater omentum flap.

BACKGROUND: Laparoscopic deroofing is the standard therapy for simple nonparasitic liver cysts. The operation is performed with or without a greater omentum flap sutured into the former cyst cavity. The aim of this study was to determine whether a greater omentum flap has influence on the recurrence rate of nonparasitic liver cysts during the long-term follow-up. METHODS: From September 1999 to November 2009, 23 patients underwent laparoscopic deroofing for single or multiple nonparasitic symptomatic liver cysts. A greater omentum flap to fill the former cyst cavity was used in 8 patients, whereas in 15 patients operation was carried out without such an omentum flap. The patients were identified retrospectively and subject to a follow-up examination. The 2 groups of patients were compared according to the recurrence of the liver cysts. RESULTS: The median follow-up time was 59±40 months. There was an overall recurrence rate of 4.3% (1 of 23), with 1 cyst recurrence in the greater omentum flap group (1 of 8). The Fisher exact test showed no difference in the recurrence rate between the 2 groups (P=0.35). CONCLUSION: The overall recurrence rate is low. A greater omentum flap to prevent a local cyst recurrence after laparoscopic deroofing is dispensable and is a potential source of additional complications.

Impact of duct-to-mucosa pancreaticojejunostomy with external drainage of the pancreatic duct after pancreaticoduodenectomy.

BACKGROUND: A variety of different techniques are established for the management of the pancreatic remnant after partial pancreaticoduodenectomy. Although pancreaticojejunostomy is one of the most favored methods, technical details are still under discussion. We report about a series of duct-to-mucosa pancreaticojejunostomies with total external drainage of the pancreatic duct. PATIENTS AND METHODS: Between 1998 and 2007 257 patients underwent surgical therapy for malignant disease of the pancreas and the periampullary region and for chronic pancreatitis. Of these, 153 partial pancreaticoduodenectomies (85 pylorus preserving resections and 68 Whipple's procedures) were performed. In all of these cases, the pancreatic remnant was drained by a duct-to-mucosa pancreaticojejunostomy with external drainage of the pancreatic duct. Presence of postoperative pancreatic fistula (PPF) was defined according to the International Study Group on Pancreatic Fistula (ISGPF). RESULTS: Postoperative mortality was 1.9%. The incidence of postoperative pancreatic fistula (PPF) was 19.6% according to the ISGPF criteria. Only one patient required re-laparotomy for complications caused by PPF. Patients with PPF had a significantly longer operation time (7.3 h versus 6.6 h; P=0.041). Incidence of PPF was not influenced by histology. In all cases the fistulas resolved under conservative treatment. CONCLUSION: Duct-to-mucosa PJ with external drainage is a safe procedure to enteralize the pancreatic stump after partial pancreaticoduodenectomy.

Prognostic relevance of skip metastases in esophageal cancer.

BACKGROUND: Presence of nodal skip metastasis is an established prognostic factor for patients with non-small cell lung cancer. Little is known about this form of lymphatic spread in esophageal cancer. The aim of this study was to assess nodal skip metastasis and its clinical importance for patients with cancer of the esophagus. METHODS: Resected lymph nodes of 128 patients with esophageal cancer and pN1 status (adenocarcinoma, n = 67; squamous cell cancer, n = 61) were mapped according to the Japanese lymph-node classification for esophageal cancer. Skip metastases were defined as tumor-free N1 lymph nodes, whereas N2 through N4 lymph nodes harbor metastases. RESULTS: Skip metastases were present in 26 of 128 (20%) patients. There was a higher rate of skip metastasis in early tumors (39% versus 23% versus 14% for T1, T2, and T3 tumors; p = 0.032) and tumors in the middle and upper third of the esophagus (37% versus 15% for upper- and middle-third and lower-third tumors; p = 0.022). Patients with skip metastasis had a significantly better 5-year survival rate than patients with continuous metastasis (53% versus 15%; p < 0.0001). Multivariate analysis revealed skip metastasis as an independent prognostic factor. CONCLUSIONS: Skip metastasis is a common form of lymphatic spread in esophageal cancer, which is associated with a favorable prognosis.

Botox, dilation, or myotomy? Clinical outcome of interventional and surgical therapies for achalasia.

PURPOSE: Achalasia is a rare, but well-defined primary esophageal motor disorder. Classic therapeutic approaches include botulinum toxin injection, balloon dilation, and surgical myotomy of the lower esophageal sphincter. This report summarizes our experience with different treatment modalities for achalasia. METHODS: Forty-three patients with achalasia treated in our hospital were subdivided according to therapeutic strategy: endoscopic botulinum toxin injection into the lower esophageal sphincter (EBTI; n = 7), endoscopic esophageal balloon dilation (EBD; n = 16), surgical myotomy after failed esophageal balloon dilation (EBD-HM; n = 14), and first-line surgical myotomy (HM; n = 6). Therapeutic efficiency was evaluated comparing standardized symptom scores preoperatively and at follow-up. RESULTS: There was no mortality and no significant difference between the groups for age, sex, or morbidity. The mean follow-up was at 9, 35, 38, and 17 months. At follow-up, recurrent or persistent symptoms were found in 71.4%, 6.3%, 35.7%, and 16.7% in EBTI, EBD, EBD-HM, and HM, respectively. Considering EBD-HM patients as failures of esophageal dilation, the total rate of recurrent or persistent symptoms after EBD was 50%. Poor symptomatic outcome was correlated to a low esophageal sphincter pressure during pretherapeutic manometry (p = 0.03) and to sigmoid-shaped esophageal dilatation (p = 0.06). CONCLUSION: Surgical myotomy is the most reliable first-line therapy for achalasia, particularly in patients with a high sphincter pressure and moderate esophageal dilatation. Botox injection has a high failure rate and should be reserved for exceptional cases. Endoscopic dilation provides about 50% of patients with long-term symptomatic relief; in most cases, failure can be successfully treated surgically.

Radiomorphology of the Habib sealer-induced resection plane during long-time followup: a longitudinal single center experience after 64 radiofrequency-assisted liver resections.

BACKGROUND: Radiofrequency (RF-) assisted liver resection devices like the Habib sealer induce a necrotic resection plane from which a small margin of necrotic liver tissue remains in situ. The aim of the present paper was to report our long-time experience with the new resection method and the morphological characteristics of the remaining necrotic resection plane. METHODS: 64 RF-assisted liver resections were performed using the Habib sealer. Followup was assessed at defined time points. RESULTS: The postoperative mortality was 3,6% and morbidity was 18%. The followup revealed that the necrotic zone was detectable in all analyzed CT and MRI images as a hypodense structure without any contrast enhancement at all time points, irrespectively of the time interval between resection and examination. CONCLUSION: Liver resection utilizing radiofrequency-induced resection plane coagulation is a safe alternative to the established resection techniques. The residual zone of coagulation necrosis remains basically unchanged during a followup of three years. This has to be kept in mind when evaluating the follow up imaging of these patients.

Preoperative survivin mRNA detection in peripheral blood is an independent predictor of outcome in esophageal carcinoma.

AIMS: Survivin (SVV) mRNA expression levels in peripheral blood of patients with gastrointestinal malignancies change significantly during the course of treatment. We wanted to scrutinize these findings in patients with esophageal carcinoma and furthermore evaluate whether the detection of mRNA and the change in detecting ability have an association with overall survival. MATERIALS & METHODS: Whole blood was drawn 1 day pre- and 10 days post-operatively from 62 patients with esophageal carcinoma. Tumor cells were enriched from whole blood by density-gradient centrifugation prior to extraction of total cellular RNA and subsequent direct quantitative reverse transcriptase-PCR assays. RESULTS: SVV was detectable in 48 out of 62 patients (77%). Stepwise multivariate Cox linear regression models demonstrated a significant and independent association of measured SVV with overall survival (6.6 exp[b]; 95% CI: 1.97-22.12; p = 0.002). Increased SVV levels after the operation were linked to shorter overall survival (p = 0.04). CONCLUSION: Preoperative SVV expression levels appear to be associated with overall survival in patients with esophageal cancers. Increasing levels could potentially indicate a higher risk for shorter overall survival and therefore demand adapted treatment modalities.

Variable 18F-fluorodeoxyglucose uptake in gastric cancer is associated with different levels of GLUT-1 expression.

OBJECTIVES: Detection rates of gastric cancer in F-fluorodeoxyglucose (FDG)-PET depend on the histopathological characteristics of the primary tumor. To clarify this observation, FDG uptake in gastric carcinoma was analyzed by focusing on histopathology and on the expression of the glucose transporter (GLUT-1) in the primary tumor. METHODS: Thirty-five patients with the diagnosis of gastric cancer underwent FDG-PET with visual image analysis and measurement of maximum standardized uptake value (SUV(max)) before surgical treatment. Resected tumor samples were categorized according to Union internationale contre le cancer, WHO, and Laurén classification and tumor differentiation. GLUT-1 expression was graded semiquantitatively by immunohistochemistry. Statistical analysis was done for the correlation of histology, different classifications, and tumor grading with SUV(max) and GLUT-1 expression. RESULTS: SUV(max) significantly correlated with histopathological classifications according to the WHO (P=0.009) and Laurén classification (P=0.034). Signet-ring cell carcinoma had a median SUV(max) of only 3.0 (range, 1.0-11.5). Median SUV(max) for papillary and tubular carcinoma was 7.8 (range, 1.8-14.4). In 21 (60%) cases, GLUT-1 expression in the primary tumor was positive. GLUT-1 expression correlated significantly with tumor differentiation (P=0.018) and the classification according to Laurén (P=0.023) and WHO (P<0.001). Thirteen (76%) of 17 signet-ring cell carcinoma cases did not show any GLUT-1 expression. SUV(max) in relation to GLUT-1 expression showed a significant correlation (P=0.002). For cases with detectable GLUT-1 expression the median SUV(max) was 6.9 (range, 2.3-14.1) versus a median of 3.1 (range, 1-8.8) for cases without GLUT-1 expression. CONCLUSION: FDG uptake in gastric cancer depends on GLUT-1 expression. One major reason for low FDG uptake in signet-ring cell carcinoma is the low GLUT-1 expression in this histological subtype of gastric cancer.

Methylated DAPK and APC promoter DNA detection in peripheral blood is significantly associated with apparent residual tumor and outcome.

BACKGROUND: Death-associated protein kinase (DAPK) and adenomatous polyposis coli gene (APC) have been recently shown to be associated with outcome in patients with esophageal carcinoma, especially adenocarcinoma. We wanted to validate the correlation of these two markers with outcome by detecting methylated DNA sequences in peripheral blood. METHODS: Circulating cell-free DNA extracted from blood plasma of 59 patients with esophageal cancer was analyzed before and after surgical resection by quantitative real-time methylation-specific RT-PCR (TaqMan) assays. RESULTS: Thirty-six of 59 patients (61.0%) with esophageal cancer had detectable levels of methylated DAPK or APC promoter DNA and preoperative detection was significantly associated with an unfavorable prognosis as revealed by multivariate Cox proportional hazards regression analysis [Exp(b) = 4.578; P = 0.01]. The combination of both markers significantly increased sensitivity and specificity for discriminating between short (<2.5 years) and long survivors (P = 0.04, ROC curve analysis). Postoperative APC detection was significantly different if residual tumor was apparent (P = 0.03). CONCLUSIONS: Preoperative measurement of methylated DAPK and APC promoter DNA in peripheral blood may contribute to better estimate postoperative survival chances of patients with esophageal carcinoma, especially adenocarcinoma. The postoperative detection of methylated APC in peripheral blood might provide crucial information on apparent residual tumor and might be used as a "molecular" R0-Marker in addition to the pathologic examination.

Strong impact of micrometastatic tumor cell load in patients with esophageal carcinoma.

BACKGROUND: To assess the role of immunohistochemically detectable nodal microinvolvement of patients with "curatively" resected esophageal carcinoma. METHODS: 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%, and > or =11%). RESULTS: 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). CONCLUSION: 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.

Which parameters are needed for targeting a multitined radiofrequency device--an approach to a simple algorithm.

BACKGROUND: The use of radiofrequency ablation (RFA) for treatment of liver malignancies is limited by the high rate of local recurrences. The aim of this experimental study was to evaluate parameters describing the reproducible target volume of a RFA procedure in order to facilitate better applicator placement. MATERIALS AND METHODS: RFA was performed in perfused and nonperfused pig livers. The following parameters were measured: axial and transverse diameter, front margin, coagulation center, diameter of sphere ablated (D(S)), distance to center (DC), and volume. Graphic overlays were utilized to visualize variability. Parameters were evaluated for Rita XL (2 algorithms), LeVeen, and Rita Xli applicators. RESULTS: The best prediction of a reproducibly ablated target volume can be made by the diameter of the sphere ablated and the distance of the applicator tip to center of the sphere (DC). The spheres were significantly different in diameter (D(S)) depending on the applicator Rita XL 29 +/- 6 mm, Rita XL(wet) 35 +/- 5 mm, LeVeen 35 +/- 8 mm, Rita Xli 44 +/- 5 mm (perfused livers, p < 0.001). Graphic overlay demonstrated differences in variability that can influence the reliability of the system. CONCLUSIONS: D(S) and DC as specific values for each applicator and algorithm facilitate a placement of the applicator relative to the target volume that maximizes the chance of complete ablation.

High expression of heparanase is significantly associated with dedifferentiation and lymph node metastasis in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA and via HIF1a to HB-EGF and bFGF.

BACKGROUND: Pancreatic cancer still has one of the worst prognoses of all cancers with a 5-year survival rate of 5%, making it necessary to find markers or gene sets that would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens. Especially heparanase (HPSE) has recently been discussed as a key factor in pancreatic cancer. MATERIALS AND METHODS: Paraffin-embedded tissue samples were obtained from 41 patients with pancreatic adenocarcinoma who were scheduled for primary surgical resection. Direct quantitative real-time reverse transcriptase polymerase chain reaction (TaqMan) assays were performed in triplicates to determine HPSE, hypoxia inducible factor-1 alpha (HIF1a), platelet-derived growth factor alpha (PDGFA), heparin-binding EGF-like growth factor (HB-EGF), and basic fibroblast growth factor (bFGF) gene expression levels. RESULTS: HPSE was significantly correlated to PDGFA (p = 0.04) and HIF1a (p = 0.04). The correlation of HIF1a to bFGF and HB-EGF was significant (p = 0.04, p = 0.02). Stepwise multiple linear regression models showed a significant independent association of HPSE with lymph node metastasis (p = 0.025) and with dedifferentiation (p = 0.042). CONCLUSIONS: Heparanase seems to be significantly associated with lymph node metastasis (p = 0.025) as well as dedifferentiation (p = 0.042). We assume that HPSE plays a crucial role for the aggressiveness of pancreatic cancer. Larger studies including more patients seem to be warranted.

Portal vein arterialization increases hepatocellular apoptosis and inhibits liver regeneration.

BACKGROUND: Portal vein arterialization is performed in particular situations to guarantee sufficient blood flow in the portal vein. In addition, some authors have postulated a proliferation-promoting influence of portal vein arterialization on the liver tissue. However, portal vein arterialization is an unphysiological procedure: It increases portal blood flow and blood pressure as well as oxygenation of the liver tissue. On the other hand, it reduces the influx of hepatotrophic factors from the portal venous blood. The aim of these experiments was to investigate apoptosis and proliferation of hepatocytes during various conditions of the portal perfusion. MATERIALS AND METHODS: After 70% liver resection in Lewis rats, the following four experimental groups were formed differing in portal perfusion: (I) hyperperfused, nonarterialized; (II) flow-regulated, nonarterialized; (III) hyperperfused, arterialized; (IV) flow-regulated, arterialized. A warm ischemia of 30 min was kept in all groups. RESULTS: Portal vein arterialization of 70% reduced rat livers significantly reduced liver regeneration as shown by a significant reduction in liver weight, body weight, and liver function after 6 wk, in contrast to the group with 70% liver mass reduction and portal venous inflow of the portal vein. Furthermore, we found a significantly elevated number of apoptotic hepatocytes after portal vein arterialization. These results were independent from blood flow regulation of the arterialized portal vein, which caused no improvement of the results. CONCLUSIONS: Portal vein arterialization should be performed only temporarily and is clinically not recommended as a permanent option, because of the increased hepatocellular apoptosis and the very distinctive, negative long-term effects on liver weight.

High expression of HIF1a is a predictor of clinical outcome in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA, VEGF, and bFGF.

PURPOSE: Pancreatic cancer still has one of the worst prognoses in gastrointestinal cancers with a 5-year survival rate of 5%, making it necessary to find markers or gene sets that would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens. In this study, we investigated the prognostic values of HIF1a, bFGF, VEGF, and PDGFA gene expressions as well as their interrelationships. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded tissue samples were obtained from 41 patients with pancreatic adenocarcinoma (age, 65; range, 34-85 years). After laser capture microdissection, direct quantitative real-time reverse transcription-polymerase chain reaction assays were performed in triplicates to determine HIF1a, PDGFA, VEGF, and bFGF gene expression levels. Multivariate Cox proportional hazards regression analysis was used to assess the impact of HIF1a gene expression on prognosis. RESULTS: HIF1a was significantly correlated to every gene we tested: bFGF (P = .04), VEGF (P = .02), and PDGFA (P = .03). Tumor size, P = .04, and high HIF1a mRNA expression (cutoff, 75th percentile) had a significant impact on survival, P = .009 (overall model fit, P = .02). High HIF1a expression had a sensitivity of 87.1% and a specificity of 55.6% for the diagnosis short (<6 months) versus long (6-60 months) survival. CONCLUSIONS: Measuring PDGFA, bFGF, and HIF1a expression may contribute to a better understanding of the prognosis of patients with pancreatic cancer and may even play a crucial role for the distribution of patients to multimodal therapeutic regimens. Larger studies including patients treated with actual chemotherapeutics seem to be warranted.