Does neoadjuvant treatment before oncologic esophagectomy affect the postoperative quality of life? A prospective, longitudinal outcome study.

To evaluate the cancer patients' quality of life (QoL) following esophagectomy the focus was placed on the impact of neoadjuvant treatment before surgery. For patients undergoing oncologic surgery, the QoL is generally accepted as an important outcome parameter in addition to clinical parameters. This prospective nonrandomized study evaluated QoL in patients treated by preoperative chemo(radio)therapy followed by either surgery or surgery alone with special focus on the postoperative course. QoL was assessed in 131 consecutive patients who underwent surgery for esophageal cancer. The EORTC-QLQ-C30 and a tumor-specific module were administered before surgery, at discharge, 3, 6, 12, and 24 months after surgery. Clinical data were collected prospectively and a follow up was performed every 6 months. The histological type of cancer was squamous cell carcinoma in 49.6% and adenocarcinoma in 50.4%. There was no significant difference between patients that were treated neoadjuvantly and those that were first operated on with regard to morbidity, mortality, and survival rates (5-year survival rate of 34%). Most QoL scores dropped significantly below the baseline in the early postoperative period and recovered slowly during the follow-up period to almost preoperative levels in many scores. There was no statistically significant difference in any of the QoL scales between neoadjuvantly treated or primary operated patients. Esophageal resections are associated with significant deterioration of QoL, which slowly recovers during the follow-up period to an almost preoperative level. Neoadjuvant treatment seems to not further negatively affect the QoL deterioration.

Use of a NOTES closure device for full-thickness suturing of a postoperative anastomotic esophageal leakage.

Leakages at surgical anastomoses in the gastrointestinal tract represent a challenging clinical problem. Standard therapy entails conservative or surgical revision of the anastomotic area with high morbidity and mortality up to 30 %. None of the previous endoscopic approaches, which include stenting, endoscopic clip closure, and fibrin glue injection, are sufficiently established for routine clinical use. We report a case of a 68-year-old woman with a postoperative leakage and abscess at the esophagojejunostomy. The defect was closed with two anchor-lock sutures. The patient was able to resume oral food intake 5 days later and made a full recovery with endoscopically documented mucosal healing at the site of the anastomosis. In summary, endoscopic suturing may be a promising approach for the treatment of postoperative leaks that warrants further, controlled investigation.

Drainage of esophageal leakage using endoscopic vacuum therapy: a prospective pilot study.

BACKGROUND AND STUDY AIMS: Major leakage from an esophageal anastomosis is a life-threatening surgical complication. Endoscopically guided endoluminal vacuum therapy using polyurethane sponges is a new method for treating such leakage. PATIENTS AND METHODS: Between June 2007 and June 2009, five patients (mean age 68 years) who developed anastomotic leakage after esophageal surgery were prospectively evaluated. After endoscopic diagnosis of a major leakage, polyurethane sponges were endoscopically positioned in the wound cavity of the anastomosis. Continuous suction was applied via drainage tubes fixed to the sponges. Initially sponges were endoscopically changed three times per week. RESULTS: In all five patients treatment was successful. Median time to reduce levels of inflammation markers by 50 % was 10 days for white blood cell (WBC) count and 7 days for C-reactive protein (CRP). The smallest initial wound cavity size was 42 cm (3) and the largest was 157 cm (3). The median duration of drainage was 28 days, with a median of 9 sponge changes and a median time to total cavity closure of 42 days. Two patients needed anastomotic dilation by Savary-Miller bougienage due to stenosis found on further follow-up. One of these patients died of acute severe hemorrhage from an aortoanastomotic fistula after the dilation procedure. CONCLUSIONS: Endoscopically assisted vacuum therapy is a well-tolerated and effective therapeutic option for treatment of major esophageal leaks after surgery. Additional surgery was avoided in all cases. However, the occurrence of a delayed aortoesophageal fistula calls for careful further investigation of this new technique.

Dissecting the role of TGF-beta type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation is crucial for both the tumor suppressive and prometastatic function.

In the present study, we have analysed the effects of transforming growth factor-beta (TGF-beta) signaling on the growth behavior of pancreatic carcinoma cells in vitro and on their tumorigenicity in vivo. Ectopic expression of dominant-negative mutants of the TGF-beta type II receptor or type I receptor/activin receptor-like kinase 5 (ALK5) in TGF-beta-sensitive pancreatic ductal adenocarcinoma PANC-1 cells prevented the TGF-beta-induced activation of transfected Smad-responsive reporter genes and growth arrest. The growth-inhibitory effect was mimicked by stable expression of kinase-active ALK5 (ALK5-T204D), and was dependent on ALK5's ability to activate Smad signaling, as a ALK5-derived mutant with an intact kinase domain but deficient in its ability to activate Smads (RImL45) failed to suppress proliferation in the absence of added TGF-beta. Moreover, this mutant often displayed opposite effects to those of ALK5-TD and blocked various ligand-induced responses in vitro, indicating that it acts in a dominant-negative fashion to inhibit endogenous wild-type receptors. ALK5-TD-, but not RImL45-TD-transduced cells underwent epithelial-to-mesenchymal transition, exhibited a higher ratio of thrombospondin-1 to vascular endothelial growth factor-A expression and upregulated various metastasis-associated genes. Upon orthotopic transplantation of PANC-1 clones into immunodeficient mice, ALK5-TD, but not RImL45-TD, greatly reduced tumor size and induced the formation of liver metastases in otherwise non-metastatic PANC-1 cells. These results suggest a causal, dominant role for the endogenous Smad2/3 signaling pathway in the tumor suppressor and prometastatic activities of TGF-beta in pancreatic tumor cells.

TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has attracted considerable attention for its potential use in tumor therapy, as some recombinant variants of this ligand induce apoptosis in tumor cells without harming most normal cells. Here, we show that TRAIL strongly induces the expression of the proinflammatory cytokines interleukin-8 and monocyte chemoattractant protein 1 and enhances the invasion of apoptosis-resistant pancreatic ductal adenocarcinoma cells in vitro by upregulation of the urokinase-type plasminogen activator expression. Most importantly, we also demonstrate for the first time that TRAIL treatment results in strongly increased distant metastasis of pancreatic tumors in vivo. We orthotopically transplanted human pancreatic ductal adenocarcinoma cells to the pancreata of severe combined immunodeficiency mice and observed a dramatic increase in metastatic spread including a sixfold increase in the volume and fourfold increase in the number of liver metastases upon TRAIL treatment. Our results point to the necessity to carefully evaluate in vivo side effects of TRAIL and to select therapy conditions that not only enhance apoptosis induction but in addition prevent proinvasive and proinflammatory non-apoptotic TRAIL signaling.

Multimodal therapy of anal cancer added by new endosonographic-guided brachytherapy.

BACKGROUND: The most appropriate therapy for anal cancer is external beam radiotherapy (EBRT) combined with chemotherapy (CTX). The significance of additional brachytherapy is still under evaluation. We report on our experience of combined modality therapy of anal cancer and transrectal ultrasound (TRUS)-guided high-dose rate (HDR) afterloading therapy, referring to results of a study published in 1998 by the coauthors. METHODS: From 1993 to 2001, 50 patients with anal cancer were treated. After combined RCTX, HDR 2 x 4 Gy brachytherapy was administered based on TRUS imaging as a target. RESULTS: In five patients (10%), tumor recurrence occurred or the tumor did not respond to therapy, and four (8%) developed distant lymph nodes or organ metastases. Five patients (10%) had to undergo salvage abdominoperineal resection because of suspected recurrence. Specific disease-related 5-year survival was 82%. Therapy-associated complications in terms of sphincter necrosis and incontinence were observed in three patients (6%). CONCLUSIONS: TRUS-guided brachytherapy permits excellent local tumor control and results in minimal treatment-related morbidity. Consequently, TRUS-guided brachytherapy may be a useful addition to current combined modality treatment regimens for anal cancer.

Transduction of human pancreatic tumor cells with vesicular stomatitis virus G-pseudotyped retroviral vectors containing a herpes simplex virus thymidine kinase mutant gene enhances bystander effects and sensitivity to ganciclovir.

We examined the suitability of Moloney murine leukemia virus (MLV) 4070A-, cat endogenous virus (CEV) RD114-, or vesicular stomatitis virus G (VSV-G)-pseudotyped retroviruses containing the humanized enhanced green fluorescent protein (hEGFP) or one of two herpes simplex virus thymidine kinase (HSV-TK) genes to transduce and provide gene expression in human pancreatic tumor cells. Fluorescence-activated cell sorter analysis demonstrated that VSV-G-pseudotyped hEGFP vector infected a greater percentage of cells and generated more robust gene expression than MLV 4070A- or CEV RD114-pseudotyped vectors. Dot blot and Southern blot analysis of genomic DNA revealed up to 10-fold more gene copies in G418-selected VSV-G hEGFP vector-transduced cells compared with genomic DNA from cells transduced with MLV 4070A or CEV RD114 pseudotypes. Cells transduced with VSV-G pseudotypes of HSV-TK(WT) or the HSV-TK30 vectors were 5- to 10-fold more sensitive to ganciclovir (GCV) than other pseudotype-transduced cells. A 40- to 61-fold difference in sensitivity to GCV was observed between cells transduced with VSV-G HSV-TK30 vector and cells transduced with MLV 4070A HSV-TK(WT) vector in vitro. A 13-fold reduction in tumor volume was observed in severe combined immunodeficient mice inoculated with PancTuITK30 cells compared with mice inoculated with PancTuITK(WT) cells during GCV treatment. We conclude that the choice of glycoprotein envelope and the potency of a particular suicide gene were therapeutically additive and increased the number of HSV-TK-positive cells and sensitivity toward GCV in human pancreatic tumors cells for prodrug gene therapy.

[The role of magnetic resonance imaging in the preoperative evaluation of the peripancreatic vasculature in pancreas carcinoma]. / Wertigkeit der Magnetresonanzangiographie zur präoperativen Beurteilung des peripankreatischen Gefässstatus bei Pankreaskarzinomen.

PURPOSE: To evaluate the accuracy of magnetic resonance angiography (MRA) to predict vascular involvement in pancreas carcinoma. MATERIALS AND METHODS: This prospective trial included 42 patients with suspected pancreas carcinoma. All patients underwent MRA, different tomographic sequences (MRI) and surgery. Peripancreatic vessels were analyzed for vascular involvement, with the tumor infiltration graded on a scale of 0 to 4 (grade 0 - 4). The imaging findings were correlated with surgery and histopathology. RESULTS: The sensitivity of MRA to predict vascular involvement was 61 % (19 of 31 evaluated vessels) and the specificity 97 % (148 of 153). Sensitivity and specificity for axial MRI were both 94 % (29 of 31 and 144 of 153 evaluated vessels). The difference in the sensitivities of MRA and MRI was statistically significant (p < 0.01). Vascular involvement was correctly graded in 58 % (18 of 31) by MRA and in 74 % (23 of 31) by MRI. CONCLUSION: MRA alone is not sufficient to diagnose vascular involvement in pancreas carcinoma, but provides an adequate overview of the vascular anatomy. A combined protocol of MRA and MRI is needed for an acceptable evaluation of the peripancreatic vessels.

Palliative partial pancreaticoduodenectomy impairs quality of life compared to bypass surgery in patients with advanced adenocarcinoma of the pancreatic head.

BACKGROUND: Some surgical centres consider palliative resection (PR) to be superior to double loop bypass (DLB) as treatment for advanced carcinoma of the pancreatic head. We performed a retrospective study with prospectively collected data at a single centre to compare PR and DLB in regard to quality of life (QoL). METHODS: From January 1996 to September 2008, 196 patients were given palliative surgery for advanced pancreatic cancer at the University Hospital of Kiel. Forty-two patients underwent PR and 154 underwent DLB. These groups were compared with regard to survival, post-operative morbidity, and QoL. The EORTC QLQ-C30 was used to assess QoL before surgery, at discharge, three months after surgery, and six months after surgery. RESULTS: The median survival time after PR was 7.5 months (95% CI: 4.95-10.05) and after DLB was 6 months (95% CI: 4.98-7.02; log rank test: p = 0.066). There were no significant differences in mortality and morbidity rates (7.1% and 45.2% for PR; 3.9% and 38.3% for DLB, respectively). Assessment of QoL indicated that patients who underwent PR had more impairment of some functional metrics and increased symptoms compared to those who underwent DLB. CONCLUSION: There was no significant difference in survival or morbidity after PR and DLB, but patients who underwent DLB had better QoL than patients who underwent PR. Therefore, clinicians may want to reconsider the use of PR for patients with advanced pancreatic cancer.

TLR-3 polymorphism is an independent prognostic marker for stage II colorectal cancer.

BACKGROUND: Clinicopathologic stage is still the main parameter to evaluate the prognosis of newly diagnosed colorectal cancer (CRC) patients. Although molecular markers have been suggested for follow up of treated CRC patients, their complete clinical application is still under evaluation. MATERIALS AND METHODS: To evaluate the association of immune-related genes with CRC prognosis and survival, a total of 19 single nucleotide polymorphisms (SNPs) were genotyped in 614 German patients within the Kiel cohort (POPGEN). RESULTS: A promoter variant (rs1800872) in the Interleukin-10 (IL-10) gene was associated with an increased lymph node metastasis involvement [odds ratio (OR) = 2.1, 95% confidence interval (CI) = 1.03-4.2, for carriers of the TT genotype]. More importantly, among 582 followed up patients the SNP rs3775291 in the toll-like receptor 3 (TLR-3) gene was associated with CRC specific survival (150 events). Patients carrying the TT genotype had a 93% increased risk of death compared with the CC carriers [hazard ratio (HR) = 1.93, 95% CI 1.14-3.28]. The observed effect of the TLR-3 variant was restricted to stage II patients (HR = 4.14, 95% CI 1.24-13.84) and to patients who did not receive adjuvant therapy (HR = 3.2, 95% CI 1.4-7.7). CONCLUSIONS: Our results may provide additional candidates for risk assessment in stage II CRC patients for treatment decision. Further validation of the presented findings is warranted.

Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease and one of the cancer entities with the lowest life expectancy. Beside surgical therapy, no effective therapeutic options are available yet. Here, we show that 4-phenylbutyrate (4-PB), a known and well-tolerable inhibitor of histone deacetylases (HDAC), induces up to 70% apoptosis in all cell lines tested (Panc 1, T4M-4, COLO 357, BxPc3). In contrast, it leads to cell cycle arrest in only half of the cell lines tested. This drug increases gap junction communication between adjacent T3M-4 cells in a concentration-dependent manner and efficiently inhibits cellular export mechanisms in Panc 1, T4M-4, COLO 357 and BxPc3 cells. Consequently, in combination with gemcitabine 4-PB shows an overadditive effect on induction of apoptosis in BxPc3 and T3M-4 cells (up to 4.5-fold compared to single drug treatment) with accompanied activation of Caspase 8, BH3 interacting domain death agonist (Bid) and poly (ADP-ribose) polymerase family, member 1 (PARP) cleavage. Although the inhibition of the mitogen-activated protein kinase-pathway has no influence on fulminant induction of apoptosis, the inhibition of the JNK-pathway by SP600125 completely abolishes the overadditive effect induced by the combined application of both drugs, firstly reported by this study.

Quality of life after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head.

BACKGROUND: This study examined quality of life (QoL) after classical partial pancreaticoduodenectomy (PPD) and pylorus-preserving pancreaticoduodenectomy (PPPD) in patients with adenocarcinoma of the pancreatic head, and also evaluated the influence of extended lymphadenectomy (ELA). METHODS: Between January 1993 and March 2004, QoL was analysed in a prospective single-centre study that included 91 patients. Thirty-four patients underwent PPD and 57 had a PPPD. Seventy patients had an ELA and 21 underwent regional lymphadenectomy (RLA). QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire and a pancreatic cancer-specific module. Data were collected before operation and for 24 months after surgery. RESULTS: The overall 5-year survival rate was 18 percent for all patients and 21 percent in those who had an R0 resection. QoL was impaired for 3-6 months after surgery and then recovered to preoperative levels. There was no significant difference in long-term survival after PPD versus PPPD and ELA versus RLA. Patients who had ELA reported clinically significant higher levels of diarrhoea and pain. PPPD showed a disadvantage in terms of pain. CONCLUSION: The surgical techniques of resection and reconstruction did not affect QoL, but extended lymphadenectomy was associated with an impairment in QoL.

Bypass surgery versus palliative pancreaticoduodenectomy in patients with advanced ductal adenocarcinoma of the pancreatic head, with an emphasis on quality of life analyses.

BACKGROUND: In some centers, palliative resection (PR; partial pancreaticoduodenectomy) is, in selected cases, promoted in preference to double loop bypass (DLB) surgery for advanced pancreatic cancer. This prospective study compares PR with DLB, placing particular focus on patients' quality of life (QoL). METHODS: From 01/1993 to 09/2004, 167 patients were analyzed in a prospective single center study of palliative surgical treatment of advanced ductal adenocarcinoma of the pancreatic head. Thirty-eight underwent PR and 129 underwent palliative DLB. Patients undergoing DLB were divided into: (1) locally advanced disease (LAD-subgroup; n = 61; 47%) and (2) metastasized disease (MD-subgroup; n = 68; 53%). QoL was assessed using the EORTC QLQ-C30 questionnaire supplemented by a pancreatic cancer specific module. QoL data were collected pre-operatively and for up to 12 months after surgery. RESULTS: Median survival was 7.0 months (95% CI 4.09; 9.91) in PR patients and 6.0 months (95% CI 5.39; 6.61) in patients who received DLB. Mortality and morbidity were, respectively, 7.8 and 58% for PR, and 2.6 and 42% for DLB. QoL decreased more after PR than after DLB. The DLB-group recovered quicker, reaching pre-operative QoL levels after 3 months, and were less impaired when discharged. The LAD-subgroup and the MD-subgroup presented with equal levels of QoL. CONCLUSIONS: QoL analysis revealed favorable QoL data after DLB. Additionally, the survival rates of the two groups did not differ significantly, but morbidity and mortality rates in the PR group were elevated. Therefore, the use of PR for advanced pancreatic cancer needs to be carefully evaluated.

Apoptosis by gemcitabine in non-small cell lung cancer cell line KNS62 is induced downstream of caspase 8 and is profoundly blocked by Bcl-xL over-expression.

BACKGROUND: This study assesses the chemotherapeutic drug gemcitabine in the human non-small cell lung cancer (NSCLC) cell line KNS62 in relation to the CD95-induced apoptotic pathway, and the role of the anti-apoptotic protein Bcl-xL in vitro and in vivo. MATERIALS AND METHODS: Apoptosis was determined by JAM assay and DAPI staining analysis. Activation of key apoptotic proteins, including caspases 3, 8 and 9 and BID, as well as cytochrome c release and mitochondrial transmembrane potential (MTP), were measured. The impact of the caspase inhibitor zVAD on gemcitabine-induced apoptosis was quantified. The in vitro results were verified in vivo in an orthotopic murine xenotransplantation model. RESULTS: Gemcitabine treatment, as well as stimulation of CD95, resulted in cleavage of effector caspase 3 as well as its substrate PARP and caspase 9, followed by DNA fragmentation. Cleavage of caspase 8 was demonstrated after CD95 activation but not after the application of gemcitabine. In KNS62-Bcl-xL clones, release of cytochrome c and loss of mitochondrial transmembrane potential were suppressed. Consequently, apoptosis after gemcitabine therapy, as well as CD95-induced apoptosis, were significantly inhibited. Caspase inhibitor zVAD only partly reversed gemcitabine-induced DNA fragmentation. In vivo, there was a significant reduction in tumour volume under gemcitabine therapy. Bcl-xL over-expressing tumours were completely resistant to gemcitabine therapy. CONCLUSIONS: In NSCLC cell line KNS62 gemcitabine activated the mitochondrial apoptotic pathway downstream of mitochondria without activation of initiator caspases. Bcl-xL over-expression induced significant resistance to gemcitabine. In vivo, the anti-apoptotic effect of Bcl-xL was more pronounced than in vitro. Gemcitabine also induced caspase-independent DNA fragmentation in KNS62 cells.

Therapy of anastomotic leaks by means of covered self-expanding metallic stents after esophagogastrectomy.

BACKGROUND AND STUDY AIMS: The mortality rate for surgical revision of gastroesophageal anastomotic leakage after resection for cancer approximates 60 %. The efficacy of endoscopically placed covered metallic stents for treatment of gastroesophageal leakage was evaluated. PATIENTS AND METHODS: Between June 1996 and June 2002 we treated 21 patients with proven gastroesophageal leakage; 18 had anastomotic leakage and three patients had perforation for different reasons. The extent of the leaks ranged from one-quarter of the intestinal circumference to its complete dehiscence. The average time from surgery to detection of leakage was 6.1 days (range 3 - 15 days). Mortality, healing rate, length of hospital stay, and complications were assessed. RESULTS: The insertion of stents was performed endoscopically under radiological guidance without any complication in all patients. In 9.5 % (2/21) of patients complete sealing of the leak was not achieved. The mortality associated with anastomotic leakage was 23.8 % (5/21). In 80.1 % (17/21) patients complete healing of the leakage was achieved. The average hospital stay was 67 days (range 14 - 158 days). Of 23 stents, 13 (56.5 %) were removed, and three patients developed stenosis after removal. CONCLUSION: The treatment of gastroesophageal leakage with covered stents appears to reduce mortality and the complication rate associated with major leakage. Therefore this technique seems to be a reasonable alternative in the treatment of clinically relevant anastomotic leakage.