Raloxifene inhibits pancreatic adenocarcinoma growth by interfering with ERß and IL-6/gp130/STAT3 signaling.

PURPOSE: Currently, the exact role of estrogen receptor (ER) signaling in pancreatic cancer is unknown. Recently, we showed that expression of phosphorylated ERß correlates with a poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here, we hypothesized that raloxifene, a FDA-approved selective ER modulator (SERM), may suppress PDAC tumor growth by interfering with ERß signaling. To test this hypothesis, we studied the impact of raloxifene on interleukin-6/glycoprotein-130/signal transducer and activator of transcription-3 (IL-6/gp130/STAT3) signaling. METHODS: Human PDAC cell lines were exposed to raloxifene after which growth inhibition was assessed using a BrdU assay. ER knockdown was performed using siRNAs specific for ERα and ERß. The effects of raloxifene on IL-6 expression and STAT3 phosphorylation in PDAC cells were assessed by ELISA and Western blotting, respectively. In addition, raloxifene was administered to an orthotopic PDAC tumor xenograft mouse model, after which tumor growth was monitored and immunohistochemistry was performed. RESULTS: Raloxifene inhibited the in vitro growth of PDAC cells, and this effect was reversed by siRNA-mediated knockdown of ERß, but not of ERα, indicating ER isotype-specific signaling. We also found that treatment with raloxifene inhibited the release of IL-6 and suppressed the phosphorylation of STAT3Y705 in PDAC cells. In vivo, we found that orthotopic PDAC tumor growth, lymph node and liver metastases as well as Ki-67 expression were reduced in mice treated with raloxifene. CONCLUSIONS: Inhibition of ERß and the IL-6/gp130/STAT3 signaling pathway by raloxifene leads to potent reduction of PDAC growth in vitro and in vivo. Our results suggest that ERß signaling and IL-6/gp130 interaction may serve as promising drug targets for pancreatic cancer and that raloxifene may serve as an attractive therapeutic option for PDAC patients expressing the ERß isotype.

Expression of estrogen receptor beta correlates with adverse prognosis in resected pancreatic adenocarcinoma.

BACKGROUND: The relevance of estrogen receptor (ER) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Clinical trials targeting ER with selective estrogen receptor modulators in pancreatic cancer did not show any benefit. Here, we analyze the impact of recently characterized ER isoform beta on survival in a cohort of patients with resected PDAC. METHODS: Eighty-four patients having undergone pancreatic resection for PDAC at a single institution were identified. Tissue microarrays were constructed of archival tumor specimens. The expression of ER beta was determined by immunohistochemistry and quantified by a system established for estrogen receptor expression in breast cancer. ER beta expression was then correlated with clinicopathological parameters, and univariate and multivariate survival analyses were performed. RESULTS: Nuclear expression of ER beta was found in 31% of tumors. No significant correlation was found between ER beta expression and TNM status, tumor grade, age or sex. Univariate analysis revealed nodal metastasis and the expression of ER beta as factors correlating with a shorter overall survival and disease free survival. When comparing ER beta expression in patients surviving more than 24 months with those who died from the tumor within 12 or 24 months, respectively, a significantly lower ER beta expression was found in the long term survivors. In multivariate analysis, ER beta expression was demonstrated to be an independent predictor of shorter overall survival. CONCLUSIONS: In resected PDAC, expression of ER beta seems to correlate with poor prognosis. These data may help to identify patients who may benefit from additional systemic therapy including selective estrogen receptor modulators.

Expression of phosphorylated estrogen receptor beta is an independent negative prognostic factor for pancreatic ductal adenocarcinoma.

PURPOSE: The role of estrogen receptor beta (ER-ß) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Ligand-independent phosphorylation and activation of ER-ß may play a relevant role in the IL-6/STAT3 signaling pathway and, as a result, in tumor progression. Here, we examined the effect of ER-ß, phosphorylated ER-ß (pER-ß), STAT3, phosphorylated STAT3 (pSTAT3) and IL-6 expression on the overall and recurrence-free survival in a cohort of patients with resected PDAC. METHODS: We identified 175 patients who underwent pancreatic resection for PDAC. Tissue microarrays were constructed from the archival tumor specimens. These were stained with specific antibodies for the above molecules. The expression of the markers was then correlated with clinicopathological parameters and survival analysis was performed. RESULTS: High nuclear expression of ER-ß was found in 61.7% and pER-ß in 80.6% of the tumors. STAT3 was expressed in 54.3% of the tumor samples, pSTAT3 in 68% and IL-6 in 76.6%. The median overall survival for patients with low pER-ß expression was 29 months, whereas for patients with high pER-ß expression was 15.1 months (p = 0.016). Multivariate analysis revealed that pER-ß expression was an independent factor correlating with shorter overall survival (hazard ratio 1.9; p = 0.013) and disease-free survival (hazard ratio 1.9; p = 0.029). CONCLUSIONS: Expression of pER-ß constitutes an independent prognostic marker for PDAC and is correlated with poor prognosis. These data may help in identifying novel drug targets in PDAC and patients who could benefit from additional therapeutic regimens, including selective estrogen receptor modulators.

Long-term quality of life after conservative treatment versus surgery for different stages of acute sigmoid diverticulitis.

PURPOSE: It is controversial whether patients fare better with conservative or surgical treatment in certain stages of acute diverticulitis (AD), in particular when phlegmonous inflammation or covered micro- or macro-perforation are present. The aim of this study was to determine long-term quality of life (QoL) for AD patients who received either surgery or conservative treatment in different stages. METHODS: We included patients treated for AD at the University Hospital Grosshadern, Munich, Germany, between January 1, 2000, and December 31, 2010. Patients were classified by the Hansen and Stock (HS) classification, the modified Hinchey classification, and the German classification of diverticular disease (CDD). Pre-therapeutic staging was based on multidetector computed tomography. Long-term QoL was assessed by the Cleveland Global Quality of Life (CGQL) questionnaire, the Short Form 36 (SF-36), and the Gastrointestinal Quality of Life Index (GIQLI). Data are mean ± SEM. RESULTS: Patients with phlegmonous AD (HS type 2a, Hinchey Ia and CDD 1b, respectively) had a better long-term QoL on the GIQLI when they were operated (78.5 ± 2.5 vs. 70.7 ± 2.1; p < 0.05). Patients with micro-abscess (CDD 2a) had a better long-term QoL on the GIQLI, CGQL, and the "Role Physical" scale of the SF-36 when they were not operated (GIQLI 86.9 ± 2.1 vs. 76.8 ± 1.0; p = 0.10; CGQL 82.8 ± 5.1 vs. 65.3 ± 11.0; p = 0.08; SF-36/Role Physical 100 ± 0.0 vs. 41.7 ± 13.9; p < 0.001). Patients with macro-abscess (CDD 2b) had a better long-term QoL when they were operated (GIQLI 89.3 ± 1.4 vs. 69.5 ± 4.5; p < 0.01; CGQL 80.3 ± 7.6 vs. 60.5 ± 5.8; p < 0.05; SF-36/Role Physical 95.8 ± 4.2 vs. 47.9 ± 13.6; p < 0.001). CONCLUSION: Considering long-term QoL, phlegmonous AD (HS type 2a, Hinchey Ia and CDD 1b, respectively) should be treated conservatively. In patients with covered perforation, abscess size should guide the decision on whether to perform surgery later on or not. In the light of long-term quality of life, patients fare better after elective sigmoid colectomy when abscess size exceeds 1 cm.

Infliximab does not affect postoperative complication rates in Crohn's patients undergoing abdominal surgery.

BACKGROUND: In patients with Crohn's disease (CD), the effect of anti-tumor necrosis factor alpha (TNF-α) antibody therapy on postoperative complications remains unclear. We aimed to determine the effects of infliximab on postoperative complication rates in patients undergoing abdominal surgery for CD. METHODS: Infliximab-treated CD patients undergoing abdominal surgery were identified in a prospective database. Gender- and age-matched CD patients without infliximab treatment served as controls. General and complication-related information was retrieved from patient records. RESULTS: Forty-eight patients underwent abdominal surgery within 3 months (median 60 days, range 1-90 days) after infliximab administration (56% female, median age 35 years, range 17-66 years). Forty-eight patients without infliximab served as controls (50% female, 39 [17-68] years). Patient characteristics and number of minor complications were comparable between groups: wound infection (infliximab: 19% vs. controls: 15%), prolonged postoperative ileus (15% vs. 4%), and urinary tract infection (2% vs. 0%; all P > 0.05). No differences were found in major complications: anastomotic leakage (infliximab: 4% vs. controls: 13%), abscess formation (6% vs. 10%), bowel perforation (2% vs. 4%), stoma complication (6% vs. 2%), postoperative hemorrhage (8% vs. 2%), and enterocutaneous fistula (4% vs. 0%; all P > 0.05). One malnourished infliximab-treated patient with a complicated course of disease died postoperatively after anastomotic leakage, sepsis, and cardiac arrhythmia. Eleven infliximab and 10 control patients required reoperation (P > 0.05). Hospital stay was comparable between groups (infliximab: 13 [5-41] vs. controls: 12 [5-54] days; P > 0.05). CONCLUSIONS: Infliximab does not affect postoperative complication rates, suggesting no need to alter surgical management in these patients.

Role of the vagus nerve on the development of postoperative ileus.

INTRODUCTION: Postoperative ileus involves reflex inhibition of intestinal motility within hours after surgery and a subsequent intestinal inflammatory response that is characterized by efferent vagal modulation via acetylcholine receptors on intestinal macrophages. We aimed to characterize the role of vagal modulation of intestinal motility during the early hours after surgery. METHODS: C57BL6 mice underwent laparotomy and standardized small bowel manipulation to induce postoperative ileus. Subgroups were vagotomized 3-4 days prior to experiments or received pharmacological inhibition of the acetylcholine alpha7 subunit with the inhibitor alpha-bungarotoxin, while control animals were sham operated and remained otherwise untreated. Three hours later, a 2-cm jejunal segment was harvested with the mesentery attached. Mesenteric afferent nerve recordings were established in an organ bath generating a multiunit signal with subsequent computerized analysis. Intraluminal pressure was continuously recorded to assess intestinal motility. Afferent nerve responses were quantified at baseline and to chemical stimulation with bradykinin (0.5 microM) or serotonin (5-HT; 500 microM) and following mechanical stimulation by continuous ramp distension to 60 mmHg. RESULTS: Peak amplitudes of intestinal motility and afferent nerve discharge at baseline were not different following chronic vagotomy, alpha-bungarotoxin or sham operation. Maximum afferent discharge to 5-HT following alpha-bungarotoxin was comparable to sham controls, while the response was reduced in chronically vagotomized animals (p < 0.05). Maximum afferent nerve discharge to bradykinin and peak firing during maximum distension at 60 mmHg was similar in the different subgroups. At luminal distension from 10 to 30 mmHg, afferent discharge was lower in vagotomized animals compared to sham controls (p < 0.05) but unchanged after alpha-bungarotoxin. CONCLUSIONS: Sensitivity to low-threshold distension and 5-HT is mediated via vagal afferents during postoperative ileus, while sensitivity to high-threshold distension and bradykinin is independent of vagal afferent innervation. Early inhibition of intestinal motility at 3 h after onset of postoperative ileus does not appear to depend on vagal innervation.

Stapled transanal rectal resection for symptomatic intussusception: morphological and functional outcome.

INTRODUCTION: Stapled transanal rectal resection (STARR) was developed to correct intussusception causing obstructed defecation. Some patients, however, do not profit from this operation as anticipated. We aimed to study the relationship between functional outcome and rectal morphology after STARR. METHODS: Fifteen consecutive female patients with median age of 64 years [interquartile range (IQR) 58-71 years] were studied before and after STARR. All patients had symptoms of obstructed defecation preoperatively. Pre- and postoperative workup consisted of standardized interview (including Wexner score) with physical examination including procto- and rectoscopy, anorectal manometry, and magnetic resonance (MR) defecography. Median follow up was 18 months (IQR 16-22 months). RESULTS: STARR was technically successful in all 15 patients without intra- or postoperative complications. Median (IQR) Wexner score of fecal incontinence was 0 (0-0) before and 3 (0-4.5) after surgery (p < 0.05). While all patients had repetitive incomplete defecation preoperatively, this symptom was present in seven patients postoperatively (p < 0.01). Third-degree intussusception was diagnosed during MR defecography in all patients preoperatively. After surgery, no patient had third-degree intussusception but one patient had first-degree and one patient had second-degree intussusception (p < 0.05). Size of rectocele was reduced from 2.9 cm (2.0-3.8 cm) to 0.8 cm (0.6-1.9 cm) (p < 0.05). Sphincter pressures were unchanged during anorectal manometry; however, first sensation during balloon distension in the rectum decreased from 50 ml (40-83 ml) before surgery to 30 ml (25-40 ml) after surgery (p < 0.05). CONCLUSION: Stapled transanal rectal resection (STARR) achieved a high rate of morphological correction of intussusception; however, symptoms of obstructed defecation were not improved to the same extent, which warrants exploration in future studies.

Determinants of morbidity and survival after elective non-curative resection of stage IV colon and rectal cancer.

PURPOSE: The benefit of elective primary tumor resection for non-curable stage IV colorectal cancer (CRC) remains largely undefined. We wanted to identify risk factors for postoperative complications and short survival. METHODS: Using a prospective database, we analyzed potential risk factors in 233 patients, who were electively operated for non-curable stage IV CRC between 1996 and 2002. Patients with recurrent tumors, resectable metastases, emergency operations, and non-resective surgery were excluded. Risk factors for increased postoperative morbidity and limited postoperative survival were identified by multivariate analyses. RESULTS: Patients with colon cancer (CC = 156) and rectal cancer (RC = 77) were comparable with regard to age, sex, comorbidity, American Society of Anesthesiologists score, carcinoembryonic antigen levels, hepatic spread, tumor grade, resection margins, 30-day mortality (CC 5.1%, RC 3.9%) and postoperative chemotherapy. pT4 tumors, carcinomatosis, and non-anatomical resections were more common in colon cancer patients, whereas enterostomies (CC 1.3%, RC 67.5%, p < 0.0001), anastomotic leaks (CC 7.7%, RC 24.2%, p = 0.002), and total surgical complications (CC 19.9%, RC 40.3%, p = 0.001) were more frequent after rectal surgery. Independent determinants of an increased postoperative morbidity were primary rectal cancer, hepatic tumor load >50%, and comorbidity >1 organ. Prognostic factors for limited postoperative survival were hepatic tumor load >50%, pT4 tumors, lymphatic spread, R1-2 resection, and lack of chemotherapy. CONCLUSIONS: Palliative resection is associated with a particularly unfavorable outcome in rectal cancer patients presenting with a locally advanced tumor (pT4, expected R2 resection) or an extensive comorbidity, and in all CRC patients who show a hepatic tumor load >50%. For such patients, surgery might be contraindicated unless the tumor is immediately life-threatening.

Independent determinants of early death in critically ill surgical patients.

Abnormalities in cardiocirculatory, respiratory, or coagulatory parameters are frequent after major surgery, but so far, no study has investigated their predictive value for early intensive care unit (ICU) mortality. We aimed to describe and quantify the relation between these parameters that are routinely determined on ICU admission and early death after complex surgery. Individual patient data were available from a local ICU database. We performed a retrospective observational cohort study using prospectively collected data from March 1, 1993, through February 28, 2005. A cohort of 4,214 cases who were admitted to the ICU immediately after operation was analyzed. We studied age, sex, number of red blood cell units transfused on admission day, and admission values for heart rate, systolic blood pressure, hemoglobin concentration, partial thromboplastin time, prothrombin time, respiratory function (Pao2/Fio2 ratio), and body temperature for their association with 4-day mortality. Effects were adjusted for the underlying disease and for disease severity during the first 24 h after admission. We used generalized additive models to fit continuous variables individually before combining them into the final generalized model. We found an independent linear association between the number of transfused red blood cell units, partial thromboplastin time, and body temperature with acute outcome. A smoothed model described the independent interaction between admission blood pressure and early death. Only values of less than 80 mmHg were associated with an increased risk of 4-day mortality. According to these results, bleeding complications after ICU admission should be treated aggressively to prevent early death of the patient. However, normotensive conditions do not seem to be required to prevent early mortality. Whether rapid rewarming may improve outcome needs further rigorous study.

Postoperative colonic motility in patients following laparoscopic-assisted and open sigmoid colectomy.

Clinical reports on laparoscopic-assisted sigmoid colectomy (LASC) suggest that the period of postoperative inhibition of gastrointestinal motility is shortened as compared to open sigmoid colectomy (OSC). We aimed to specifically investigate whether colonic motility increases more rapidly following LASC compared to OSC. LASC was performed in 11 patients and OSC in nine patients for recurrent diverticulitis or carcinoma. During surgery a manometry catheter was inserted into the colon via the anus, and the tip was placed in the splenic flexure. Continuous manometric recordings were performed from the day of surgery until postoperative day 3 with a four-channel microtransducer manometry system combined with a portable data logger. The postoperative colonic motility index was 101+/-18, 199+/-30, and 163+/-27 mm Hg/min on days 1, 2, and 3 after LASC, respectively, which was increased compared to indexes of 53+/-15, 71+/-18, and 76+/-23 following OSC (mean+/-standard error of the mean; P<0.05). The amplitude but not the frequency of contractions was higher following LASC compared to OSC. Following LASC, patients requested a similar amount of pain medication but resumed oral food more rapidly on postoperative days 2 and 3 (P<0.05), and they were discharged from the hospital earlier (P<0.05). Colonic motility in particular and the patient's condition in general seem to improve more rapidly following LASC compared to the open procedure.