Martin K. Schilling

Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors.

Molecular alterations play a key role in the pathogenesis of gastrointestinal cancers. In the present paper we describe relevant molecular alterations in human pancreatic adenocarcinomas. Overexpression of growth factor receptors (EGF receptor, c-erbB2, c-erbB3, TGFβ receptor I–III), growth factors (EGF, TGFα, TGFβ-1-3, aFGF, bFGF), adhesion molecules (ICAM-1, ELAM-1) and gene mutations (p53, K-ras, DCC, APC) are present in a significant number of these tumors. These changes stimulate tumor growth and enhance the metastatic behavior of pancreatic cancer cells and thereby may contribute to shorter postoperative survival following tumor resection.

Antibiotic coating of abdominal closure sutures and wound infection

BACKGROUND Poor wound healing and the development of infection in incisional wounds continue to be among the most common complications of open abdominal surgery. Various bacteria may contaminate not only the tissue in the operative wound, but also the actual suture material. To prevent the contamination of suture material in surgical wounds, triclosan-coated polyglactin 910 suture materials with antibacterial activity (Vicryl plus) was developed. The aim of this study was to ascertain if the use of Vicryl plus reduced the number of wound infections after midline laparotomy comparing to polydioxanon suture (PDS II). METHODS We performed 2,088 operations in our department between October 2004 and September 2006 via midline incision. In the first time period (TP1), a PDS II loop suture was used. In the second time period (TP2), we used Vicryl plus. All variables were recorded prospectively in a database. The primary outcome was the number of wound infections. Risk factors for poor wound healing were collected prospectively to compare the 2 groups. RESULTS Using a PDS loop suture for abdominal wall closure in TP1, 10.8% of patients with wound infections were detected. The number of patients with wound infections decreased in TP2 using Vicryl plus for abdominal wall closure to 4.9% (P < .001) despite no other changes in protocols of patient care. Other risk factors for the development of site infections were comparable in the 2 groups. CONCLUSION The use of antibiotic-coated loop suture for abdominal wall closure can decrease the number wound infections after abdominal surgery.

High coincidence of Mirizzi syndrome and gallbladder carcinoma

BACKGROUND Mirizzi syndrome is a rare complication of long-standing cholelithiasis. It is defined as obstructive jaundice caused by external compression of the common hepatic duct by an impacted stone in the gallbladder neck. Gallstone disease and cholelithiasis-associated chronic biliary inflammation may play a causative role in the pathogenesis of gallbladder carcinoma. The purpose of this study was to investigate the coincidence of gallbladder carcinoma associated with Mirizzi syndrome. Furthermore, the diagnostic value of elevated CA 19-9 levels as indicator for a coincidental gallbladder carcinoma in this syndrome was studied. METHODS Patient demographics, clinical findings, laboratory data, results of diagnostic studies, pathologic reports, and intraoperative findings of 1579 patients undergoing cholecystectomy were obtained from patient records and were retrospectively studied. Only patients with proven Mirizzi syndrome (i.e., extrinsic mechanical compression of the common hepatic duct by impacted gallstones, associated chronic cholecystitis, and a history of jaundice) were included in this study. RESULTS Eighteen cases of Mirizzi syndrome (1.0%) out of 1759 cholecystectomies performed between January 1986 and March 1995 were identified. The seven male patients and 11 female patients had an average age of 74.8 years (range, 32 to 87 years). In five of these patients (27.8%) coincidental cases of gallbladder carcinoma were detected. The incidence of unsuspected malignancies in long-standing gallstone disease was 36 (2%) of 1759 and was statistically significantly different (p < 0.001) from the incidence in patients with Mirizzi syndrome (27.8%, 5 of 18). No significant difference was noted in age, gender, duration of jaundice, and type of lesions between these two groups. Tumor-associated antigen CA 19-9 level was elevated in 12 patients with Mirizzi syndrome, but it was significantly higher (p < 0.0001) in all five patients with coincidental gallbladder neoplasm and peaked at 1000 units/ml. All patients diagnosed with gallbladder carcinoma died within 18 months after operation. CONCLUSIONS There is high association of gallbladder cancer in Mirizzi syndrome. Elevated CA 19-9 levels in this syndrome are indicative of a coincidental gallbladder malignancy. Because of this high coincidence of Mirizzi syndrome and gallbladder cancer we recommend an intraoperative frozen section of the gallbladder in all patients presenting with Mirizzi syndrome.

Preoperative Galactose Elimination Capacity Predicts Complications and Survival After Hepatic Resection

ObjectiveTo analyze a single center’s 6-year experience with 258 consecutive patients undergoing major hepatic resection for primary or secondary malignancy of the liver, and to examine the predictive value of preoperative liver function assessment. Summary Background DataDespite the substantial improvements in diagnostic and surgical techniques that have made liver surgery a safer procedure, careful patient selection remains mandatory to achieve good results in patients with hepatic tumors. MethodsIn this prospective study, 258 patients undergoing hepatic resection were enrolled: 111 for metastases, 78 for hepatocellular carcinoma (HCC), 21 for cholangiocellular carcinoma, and 48 for other primary hepatic tumors. One hundred fifty-eight patients underwent segment-oriented liver resection, including hemihepatectomies, and 100 had subsegmental resections. Thirty-two clinical and biochemical parameters were analyzed, including liver function assessment by the galactose elimination capacity (GEC) test, a measure of hepatic functional reserve, to predict postoperative (60-day) rates of death and complications and long-term survival. All variables were determined within 5 days before surgery. Data were subjected to univariate and multivariate analysis for two patient subgroups (HCC and non-HCC). The cutoffs for GEC in both groups were predefined. Long-term survival (>60 days) was subjected to Kaplan-Meier analysis and the Cox proportional hazard model. ResultsIn the entire group of 258 patients, a GEC less than 6 mg/min/kg was the only preoperative biochemical parameter that predicted postoperative complications and death by univariate and stepwise regression analysis. A GEC of more than 6 mg/min/kg was also significantly associated with longer survival. This predictive value could also be shown in the subgroup of 180 patients with tumors other than HCC. In the subgroup of 78 patients with HCC, a GEC less than 4 mg/min/kg predicted postoperative complications and death by univariate and stepwise regression analysis. Further, a GEC of more than 4 mg/min/kg was also associated with longer survival. ConclusionsThis prospective study establishes the preoperative determination of the hepatic reserve by GEC as a strong independent and valuable predictor for short- and long-term outcome in patients with primary and secondary hepatic tumors undergoing resection.

Involvement of chemokine receptor CCR6 in colorectal cancer metastasis.

Various chemokine receptors, namely CXCR4, CCR6 and CCR7, have recently been shown to be involved in the regulation of metastasis in malignant tumors. However, little is known about the role of these receptors in promoting tumor metastasis of colorectal cancer (CRC) to the primary site of CRC metastasis in the liver. To investigate this issue, we analyzed the expression of the chemokine receptors CXCR4, CCR6 and CCR7 in colorectal tumors and colorectal liver metastases. In the present study, 30 human cancer samples from colorectal tissue, 30 human samples from colorectal liver metastases and the adjacent nontumorous liver tissues were screened using quantitative real-time PCR, Western blot analysis, histochemistry, microdissection and the enzyme-linked immunosorbent assay (ELISA). While an overexpression of all the chemokine receptors was found in CRC, in colorectal liver metastases only the chemokine receptors CXCR4 and CCR6 were significantly upregulated. Consequently, we investigated the expression of the corresponding ligands CXCL12/SDF1α, CCL20/MIP3α, CCL19/MIP3β and CCL21/6Ckine in various organs, such as the stomach, esophagus, pancreas, colon and rectum, in comparison with their expression in the liver as the primary site of metastatic spread in CRC. We found that only CCL20 exhibits peak levels of expression in the liver, thus indicating that an increased production of CCL20 may contribute to the selective recruitment of CCR6-expressing cancer cells in CRC. Furthermore, we could demonstrate that CRC patients who developed liver metastases express significantly more CCL20 and CCL21 in the liver in comparison with an unaffected control group. Therefore, our findings strongly suggest an association between CCL20/CCR6 expression in human CRC and the promotion of colorectal liver metastasis.

Over-expression of ICAM-1, VCAM-1 and ELAM-1 might influence tumor progression in colorectal cancer

Adhesion molecules might play a role in tumor progression. We investigated expression of the adhesion molecules ICAM‐1, VCAM‐1 and ELAM‐1 in 24 primary colorectal carcinomas using immuno‐histochemistry and Northern blot analysis. Normal colonic tissue from the same patients served as controls. ICAM‐1 immunostaining was restricted to the intercellular matrix and vascular endothelial cells. The vast majority of normal tissue samples revealed only faint ICAM‐1 immunoreactivity. However, moderate to strong immunostaining was found in 86% of cancerous sections. The ICAM‐1 immunoreaction was more intense in well‐differentiated carcinomas as well as in the adenomatous parts and transition zones of cancers. Similarly, the cancers exhibited markedly enhanced VCAM‐1 and ELAM‐1 immunostaining in the endothelial cells of small blood vessels. The intense vascular immunostaining by ICAM‐1 and VCAM‐1 was associated with a strong presence of CD3‐positive T lymphocytes, whereas ELAM‐1 immunoreactivity did not correlate with round cell infiltration. On Northern blot analysis, ICAM‐1, VCAM‐1 and ELAM‐1 mRNA levels were increased in 67%, 57% and 63% of carcinomas, respectively, in comparison with normal tissue samples. Densitometric analysis of Northern blots revealed an increase in ICAM‐1 by 2.1‐fold, an increase in VCAM‐1 by 3.4‐fold and an increase in ELAM‐1 by 2.2‐fold in cancerous tissues compared to normal controls. Over‐expression of ICAM‐1 might prevent cell–cell disruption and, hence, tumor dissemination. Furthermore, over‐expression of ICAM‐1 and VCAM‐1, but not ELAM‐1, might favor host anti‐tumor defense by trafficking of lymphocytes. Int. J. Cancer (Pred. Oncol.) 79:76–81, 1998.

Netrin-1 Mediates Early Events in Pancreatic Adenocarcinoma Progression, Acting on Tumor and Endothelial Cells

BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. It is characterized by substantial tumor cell invasion and early-stage metastasis. We developed an in vivo model to analyze interactions between cancer and stromal cells during early stages of PDAC. METHODS Human pancreatic adenocarcinoma cells were grafted onto the chick chorioallantoic membrane (CAM). Human and chicken GeneChips were used simultaneously to study gene regulation during PDAC cell invasion. Bioinformatic analysis was used to identify human orthologs and cell specificity of gene expression. The effects of netrin-1 encoded by NTN1 were investigated in adhesion, invasion, and apoptosis assays. The effects of NTN1 silencing with small interfering RNAs were investigated in PDAC cells in vivo. NTN1 expression was measured in human PDAC samples. RESULTS PDAC cells rapidly invade the CAM stroma and remodel the CAM vasculature. Around 800 stromal genes were up-regulated by >2-fold; the angiogenesis regulators vascular endothelial growth factor D, thrombospondin 1, and CD151 were among the most highly regulated genes. Silencing of tumor cell NTN1, which is up-regulated 4-fold in the PDAC model, inhibited tumor cell invasion in vivo. Netrin-1 conferred apoptosis resistance to tumor and endothelial cells in vitro, induced their invasion, and provided an adhesive substrate for tumor cells. NTN1 and its gene product are strongly overexpressed in human PDAC samples. CONCLUSIONS We developed a useful tool to study the invasive mechanisms of early-stage PDAC. Netrin-1 might be an important regulator of pancreatic tumor growth that functions in tumor and endothelial cells.

Presence of two signaling TGF-β receptors in human pancreatic cancer correlates with advanced tumor stage

Transforming growth factor-β (TGF-β)signal transduction is mediated via specific cellsurface signaling TGF-β receptors, most notably thetype I ALK5 (TβR-IALK5)and the type II(TβR-II). We evaluated TβR-IALK5 andTβR-II expression in 41 human pancreatic cancertissue samples and correlated these findings withclinical data of the patients. Northern blot analysisindicated that, in comparison with the normal pancreas,pancreatic adenocarcinomas exhibited 8.0-fold and4.5-fold increases (P < 0.01), respectively, in mRNAlevels encoding TβR-IALK5 andTβR-II. In situ hybridization showed that both TβR-IALK5 mRNAwere highly expressed in the majority of pancreaticcancer cells. Immunohistochemical analysis ofTβR-IALK5 and TβR-II revealedpositive immunostaining in 73% and 56% of the tumors, respectively. Both receptorswere concomitantly present in 54% of the pancreaticcancer samples. The presence ofTβR-IALK5 or TβR-II and theconcomitant presence of TβR-IALK5 and TβR-II in the cancer cells was associatedwith advanced tumor stage (P < 0.01). These findingsshow that in many human pancreatic cancers, increasedlevels of the two signaling TβRs are present. The presence of the signaling TβRs inadvanced tumor stages indicates a role in diseaseprogression.

One-stage sigmoid colon resection for perforated sigmoid diverticulitis (Hinchey stages III and IV).

IntroductionGuidelines for the treatment of complicated sigmoid diverticulitis recommend Hartmann’s procedure or anastomosis with protective colostomy for Hinchey stage III diverticulitis and Hartmann’s procedure only for Hinchey stage IV diverticulitis. We evaluated the outcome of patients with perforated sigmoid diverticulitis Hinchey III/IV undergoing one-stage colon resection and primary anastomosis without protective colostomy.MethodsAfter implementation of a protocol to treat Hinchey III/IV diverticulitis with primary anastomosis without protective ileocolostomy, the patients’ data were recorded prospectively between August 2001 and August 2003 and analyzed retrospectively from a computer-related database.ResultsOf 41 patients, 34 (81%%) underwent one-stage sigmoid resection and primary anastomosis, 3 of 41 patients (7%%) underwent primary anatomosis with protective ileostomy, and 5 of 41 patients (12%%) had a Hartmann’s procedure. The mortality was 11%% in patients undergoing primary anastomosis and 60%% in patients with Hartmann’s procedure. The relative risk of co-morbidity factors for lethal outcome after sigmoid resection was 6.94 for preceding operations, 3.75 for renal failure or renal transplantation, and 3.25 for immunosuppression.ConclusionsOne-stage sigmoid resection and primary anastomosis can be performed safely in nearly 90%% of all patients with perforated sigmoid diverticulitis (Hinchey III/IV) by surgeons of different training levels. Patients with immunosuppression, chronic renal failure, liver cirrhosis, or previous organ transplantation or complex cardiovascular reconstructive procedures have a significantly increased risk of dying after sigmoid resection for perforated diverticulitis.

Laryngeal Complications After Thyroidectomy: Is It Always the Surgeon?

HYPOTHESIS Laryngeal dysfunction after thyroidectomy is a common complication. However, few data are available to differentiate whether these complications result from injury to the recurrent nerve or to the vocal folds from intubation. SETTING University medical center. PATIENTS Seven hundred sixty-one patients who underwent surgery to the thyroid gland from 1990 to 2002. Of these patients, 8.4% underwent a revision thyroidectomy. INTERVENTION Preoperative and postoperative laryngostroboscopic examination. MAIN OUTCOME MEASURE Laryngostroboscopic evaluation of laryngeal complications. RESULTS The overall rate of laryngeal complications was 42.0% (320 patients). Complications from an injury to the vocal folds occurred in 31.3% of patients. Weakness or paresis of the recurrent nerve was initially present in 6.6% and was related to the nerves at risk. This rate was higher in revision thyroidectomies than in primary surgical interventions (6.2% vs 11.6%; P = .04). The rate of laryngeal injuries was higher in patients older than 65 years (39.8% vs 30.8%; P = .03). CONCLUSIONS These data suggest that laryngeal complications after thyroidectomies are primarily caused by injury to the vocal folds from intubation and to a lesser extent by injury to the laryngeal nerve. We recommend documentation of informed consent, especially for patients who use their voice professionally, such as singers, actors, or teachers.