Stapled hemorrhoidopexy versus Milligan-Morgan hemorrhoidectomy in circumferential third-degree hemorrhoids: long-term results of a randomized controlled trial.

BACKGROUND: The literature indicates higher recurrence rates for stapled hemorrhoidopexy than for conventional techniques. This could be due to inappropriate patient selection. OBJECTIVE: 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. DESIGN AND PATIENTS: 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. SETTINGS: The study was performed at the University Hospital Hamburg. MAIN OUTCOME MEASURES: Endpoints were pain, recurrence, bleeding, itching/burning, urinary retention, incontinence symptoms, and prolonged rate of wound healing. RESULTS: 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 < 0.001), and demonstrated less burning/itching sensation 4 weeks after surgery compared with the Milligan-Morgan group (4.9 vs. 19.7 %; p < 0.001). The postoperative bleeding rate was 4.9 % in both groups and the rate of urinary retention did not differ significantly (4.9 % vs. 1.6 %; p = 0.309). Postoperative incontinence symptoms (6.6 % versus 3.3 %; p = 0.40) resolved within the first 6 months. LIMITATIONS: Detailed measurement of incontinence was not possible because postoperative symptoms resolved between consultations, and pathological results were examined retrospectively. CONCLUSIONS: The results show a similar rate of recurrence in the long term and suggest increased patient comfort in the early postoperative course after stapled hemorrhoidopexy. In patients with circumferential third-degree hemorrhoids, stapled hemorrhoidopexy is as effective as the Milligan-Morgan procedure.

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.

Y-box-binding protein-1 is a potential novel tumour marker for neuroblastoma.

BACKGROUND: The Y-box-binding protein-1 (YB-1) is a member of a family of DNA-binding proteins and an oncogenic transcription factor that is highly expressed in cancers of the breast, lung and prostate. To date, no data are available on its role in neuroblastoma. The aim of the present study was to evaluate the YB-1 expression in neuroblastoma. MATERIALS AND METHODS: A tumour tissue microarray (TMA) was constructed from 36 neuroblastoma samples which were analysed by immunohistochemistry for YB-1 expression. RESULTS: Expression of YB-1 was detected in 35 of 37 (94.6%) neuroblastoma cases examined. Nevertheless, no correlation of YB-1 expression with survival, risk factors or stage of the disease was observed. CONCLUSION: As the majority of neuroblastomas express YB-1, this protein may play an important role in tumour pathogenesis. The results of this study suggest that YB-1 may serve as a novel immune marker for neuroblastoma and may be potentially useful as a therapeutic target.

Establishment and characterization of a new human pancreatic adenocarcinoma cell line with high metastatic potential to the lung.

BACKGROUND: Pancreatic cancer is still associated with devastating prognosis. Real progress in treatment options has still not been achieved. Therefore new models are urgently needed to investigate this deadly disease. As a part of this process we have established and characterized a new human pancreatic cancer cell line. METHODS: The newly established pancreatic cancer cell line PaCa 5061 was characterized for its morphology, growth rate, chromosomal analysis and mutational analysis of the K-ras, EGFR and p53 genes. Gene-amplification and RNA expression profiles were obtained using an Affymetrix microarray, and overexpression was validated by IHC analysis. Tumorigenicity and spontaneous metastasis formation of PaCa 5061 cells were analyzed in pfp-/-/rag2-/- mice. Sensitivity towards chemotherapy was analysed by MTT assay. RESULTS: PaCa 5061 cells grew as an adhering monolayer with a doubling time ranging from 30 to 48 hours. M-FISH analyses showed a hypertriploid complex karyotype with multiple numerical and unbalanced structural aberrations. Numerous genes were overexpressed, some of which have previously been implicated in pancreatic adenocarcinoma (GATA6, IGFBP3, IGFBP6), while others were detected for the first time (MEMO1, RIOK3). Specifically highly overexpressed genes (fold change > 10) were identified as EGFR, MUC4, CEACAM1, CEACAM5 and CEACAM6. Subcutaneous transplantation of PaCa 5061 into pfp-/-/rag2-/- mice resulted in formation of primary tumors and spontaneous lung metastasis. CONCLUSION: The established PaCa 5061 cell line and its injection into pfp-/-/rag2-/- mice can be used as a new model for studying various aspects of the biology of human pancreatic cancer and potential treatment approaches for the disease.

Insulin-like growth factor-1 receptor as a novel prognostic marker and its implication as a cotarget in the treatment of human adenocarcinoma of the esophagus.

Insulin-like growth factor-1 receptor (IGF-1R) and human epidermal growth factor receptor-2 (HER2) receptor expression has been found to be a key regulator of tumorigenesis. The purpose of our study was to establish the prognostic significance of IGF-1R in esophageal cancer and to determine the effect of IGF-1R and HER2 targeting with alpha-IR3 and Herceptin antibodies on the proliferation of esophageal cancer cells in vitro. IGF-1R expression and clinicopathological correlations were analyzed with a tissue microarray containing 234 esophageal cancer specimens (133 adenocarcinomas and 101 squamous cell carcinomas). Proliferation changes associated with Herceptin and alpha-IR3 blockage were evaluated with the unique human esophageal cancer cell lines Pt1590 and LN1590. IGF-1R and HER2 expression levels, activation and phosphorylation status of downstream signaling proteins involved in the activation pathways were analyzed by Western blotting. IGF-1R overexpression was detected in 121 (52%) of the 234 esophageal tumors examined. In the subgroup of 87 HER2-positive tumors, 93.1% showed concordant overexpression for IGF-1R. IGF-1R was identified as a variable associated with reduced overall survival for adenocarcinoma (p = 0.05), but not for squamous cell carcinoma. The combination of Herceptin and alpha-IR3 was more effective in inhibiting in vitro proliferation than treatment with either agent alone (p < 0.01). This was associated with a decrease in HER2 and IGF-1R protein levels and suppression of Akt- and MAP kinase phosphorylation. IGF-1R expression can be used as a novel prognostic marker for adenocarcinomas of the esophagus. Cotreatment with IGF-1R and HER2 antibodies might become a valuable and effective treatment option in esophageal adenocarcinoma.

Haeme oxygenase-1 promoter polymorphism is an independent prognostic marker of gastrointestinal stromal tumour.

AIMS: Gastrointestinal stromal tumours (GISTs) display genetic alterations on chromosome 22. GTn repeat (GTn) length polymorphism in the promoter of haeme oxygenase-1 gene (HMOX-1) is located on chromosome 22 and associated with malignant growth. The aim was to investigate the role of HMOX-1 promoter polymorphism in GIST patients. METHODS AND RESULTS: Tumour and corresponding healthy tissue DNA of 44 patients who underwent surgical resection of GIST were analysed by polymerase chain reaction, capillary electrophoresis and DNA sequencing. GTn polymorphism was classified into short (S) and long (L) allele. There was no difference detected in GTn genotype between tumour and healthy tissue DNA. Short GTn allele (SGTn) was significantly associated with metastatic disease, higher tumour recurrence rates and high risk GIST (consensus criteria 2001). Furthermore, SGTn allele carriers had significantly shorter disease-free and overall survival (log rank test, P < 0.0001). On multivariate Cox regression analysis, GTn polymorphism was identified as an independent prognostic factor for survival (P = 0.001). CONCLUSIONS: HMOX-1 promoter GTn polymorphism is a potential prognostic marker and may help to allocate patients to different risk groups, customized therapy and follow-up. Haeme oxygenase-1 could represent an important candidate gene in the pathogenesis and growth of GIST.

En bloc vascular resection for locally advanced pancreatic malignancies infiltrating major blood vessels: perioperative outcome and long-term survival in 136 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.

Y-box protein 1 mediates PDGF-B effects in mesangioproliferative glomerular disease.

The pivotal role of PDGF-B for mesangioproliferative glomerular disease is well established. Here, Y-box protein-1 (YB-1) was identified as a downstream signaling target of PDGF-B. In healthy kidney cells, YB-1 was located predominantly within the nuclear compartment. Subsequent to PDGF-B infusion and in the course of anti-Thy1.1-induced mesangioproliferative glomerulonephritis, relocalization of YB-1 into the cytoplasm was observed. In experimental models that lack profound mesangial cell proliferation (e.g., Puromycin-nephrosis, passive Heyman nephritis, spontaneous normotensive nephrosclerosis, hyperlipidemic diabetic nephropathy), YB-1 remained nuclear. This translocation coincided with upregulation of YB-1 protein levels within the mesangial compartment. Increased YB-1 expression and subcellular shuttling was dependent on PDGF-B signaling via the mitogen-activated protein kinase pathway because these alterations were prevented by specific PDGF aptamers and the mitogen-activated protein kinase pathway inhibitor U0126. Furthermore, PDGF-B strongly induced YB-1 expression in vitro. This induction was important because RNAi-dependent knockdown of YB-1 abolished the mitogenic PDGF-B effect. Taken together, YB-1 seems to represent a specific and necessary PDGF-B target in mesangioproliferative glomerular disease.