Different types of K-Ras mutations are conversely associated with overall survival in patients with colorectal cancer.

A glycine to valine substitution at codon 12 (G12V) in Kirsten-Ras (K-Ras) gene has been associated with reduced overall survival in colorectal cancer patients; however, the effect of other K-Ras mutations than G12V still remains unclear. Therefore, we investigated the role of different K-Ras mutations on overall survival in a homogeneous, large patient cohort with standardized therapy and uniform analysis of K-Ras mutation status. The study included 342 patients with histopathologically proven colorectal cancer. Survival data were provided by the federal agency for statistics in Austria. Occurrence of K-Ras mutations at codons 12, 13 and 61 were determined by capillary sequencing. The overall K-Ras mutation frequency in carcinoma tissue was 28%. Carriers of the G12V mutation at the K-Ras gene showed a significantly decreased overall survival compared to carriers of the wild-type [HR=2.56 (1.15-5.69)]. Other mutations than G12V were associated with better overall survival compared to wild-type [HR=0.44 (0.2-0.99)]. In conclusion, for the first time, our study showed clearly that different types of K-Ras mutations are conversely associated with overall survival in patients with colorectal cancer.

Clostridium perfringens liver abscess after pancreatic resection.

BACKGROUND: Liver abscess is a rare complication after pancreatectomy. Clostridium perfingens is a rare cause of intrahepatic infections. CASE REPORT: A 65-year-old woman with pancreatic cancer underwent explorative laparotomy, during which encasement of the hepatic artery by the tumor was found. Neoadjuvant radiochemotherapy with capecitabine was started, which caused tumor regression, and duodenopancreatectomy was performed. The portal vein was occluded and infiltrated by cancer and therefore was resected and not reconstructed. After a slow recovery, the patient developed hemorrhage at the gastrojejunal anastomosis, which was controlled by fibrin injection. Within a few days, she presented with signs of sepsis, and blood cultures yielded Clostridium perfringens, Streptococcus oralis, Staphylococcus aureus, and Candida albicans. The source of the sepsis proved to be a 9-cm liver abscess, which was drained; cultures grew C. perfringens, Hafnia alvei, and Enterobacter cloacae. Despite antibiotic treatment, the patient died from sepsis and multiorgan failure 27 days after pancreatic surgery. CONCLUSION: Such rare infections can follow pancreatic resection with neoadjuvant radiochemotherapy. Clostridium perfringens-associated liver abscess maintains a high mortality rate.

• Pancho trial (p53-adapted neoadjuvant chemotherapy for resectable esophageal cancer) completed-mutation rate of the marker higher than expected.

BACKGROUND: In operable esophageal cancer patients, neoadjuvant therapy benefits only those who respond to the treatment. The • Pancho trial represents the first prospective randomized trial evaluating the relevance of the mark53 status for predicting the effect of two different neoadjuvant chemotherapies. METHOD: Biomarker analysis was conducted using the mark53 analysis. Calculation of patient number needed was based on a 60% rate of marker positivity, deduced from the results of a phase II pilot study. RESULTS: From 2007-2012, the • Pancho trial recruited 235 patients with operable esophageal cancer in Austria. A total of 181 patients were eligible and could be subjected to mark53 analysis and randomization. After randomizing 74 patients, the overall TP53 mutation rate was 79%. However, due to the high prevalence of marker positivity, the number of projected patients was increased to 181 patients in order to ensure a sufficient number of marker-negative patients. After completion of the trial, the overall TP53 mutation rate was 77.9%. CONCLUSION: Due to high medical need, the recruitment for the academic trial was excellent. Mark53 analysis clearly detected more mutations in the TP53 gene as compared to the cancer-specific p53 literature. Final analysis examining the interaction between the mark53 status and the effect of chemotherapies applied in the • Pancho trial is now awaited.

Intra-operative sonography: a valuable aid during breast-conserving surgery for occult breast cancer.

BACKGROUND: Breast cancer is increasingly detected during an early non-palpable stage. Together with pre-operative marking of the mass, intra-operative imaging provides invaluable clues. This study was designed to evaluate the usefulness of intra-operative sonography in the hands of the surgeon. METHODS: Between July 2001 and October 2006, 567 patients underwent treatment for operable breast cancer at the landeskrankenhaus (LHK) Feldkirch. Three hundred and sixty lesions were not palpable. Two hundred and ninety-nine patients with poorly definable or non-definable lesions well seen by ultrasound imaging underwent intra-operative sonography (group 1), while 61 patients with non-palpable lesions only seen on mammography (group 2) were subjected to pre-operative needle localization. The study was non-randomized with prospective data acquisition RESULTS: All lesions were identified by both sonography and pre-operative needle localization. In the ultrasound group (group 1) 81% of the lesions were successfully removed by primary intention without metachronous secondary surgery versus 62% in group 2 (p < 0.00228). Eighty-eight percent of the lesions in group 1 were eligible for breast-conserving surgery versus 75% in group 2. The mean clear margin in group 1 was substantially smaller (4.8 mm) than in group 2 (7.2 mm) (p < 0.0001). CONCLUSION: Intra-operative sonography proved to be a reliable and helpful tool in the hands of the surgeon, not only for tumor localization, but also for orientation during tumor excision. It simplifies organizational work and spares the patient the discomfort of pre-operative needle localization.

Complications after oesophagectomy with possible contribution of neoadjuvant therapy including an EGFR-antibody to a fatal outcome.

BACKGROUND: Different molecular therapies like the EGFR-inhibiting antibody cetuximab have come into clinical practice. Cetuximab is EMEA-approved for metastatic colorectal cancer and advanced squamous-cell head and neck cancer. Administration is said to be safe and well tolerated with common, usually mild dermatologic side effects. CASE PRESENTATION: We present the case of a patient with fatal complications after oesophagectomy and neoadjuvant chemotherapy including cetuximab for squamous-cell esophageal cancer. A transthoracic en-bloc oesophagectomy was performed. Few days later the patient died due to gas exchange dysfunction and circulation instability after a previously unseen combination of drain-erosion of the stomach with subsequent pleurisy and air leak of the left main bronchus. CONCLUSION: So far we have never observed this fatal combination of drain erosion of the stomach with fibrinous pleurisy and unmanageable progressive tracheal defect before. The role of cetuximab in the multifactorial aetiology of damages of stomach and trachea after oesophagectomy remains unclear since we are not able to link the complication directly to cetuximab or definitely exclude it as a sole surgical complication. Clinicians should be aware of the possibility of fatal side effects and careful recording of all complications is necessary in ongoing and planned studies to obtain more evidence about safety and tolerance of targeted therapies.

[Sentinel node biopsy in breast cancer: techniques and indications]. / Sentinel Node Biopsie beim Mammakarzinom: Technik und Indikation.

Sentinel node biopsy (SNB) has proved to be a useful and accurate procedure for lymph node staging in breast cancer and melanoma and should be standard of care in the treatment of these tumors. In other malignancies (colon, rectum, stomach, esophagus, head and neck and thyroid, cervix uteri) it is still under investigation. SNB in breast cancer was accepted as a sole and reliable diagnostic method in breast cancer from the panel of distinguished experts at the 8th international conference of primary therapy of early breast cancer 2003 in St. Gallen. Combination of the current techniques with radiocolloids and blue dye, applicated superficially (intradermal, subdermal, peri- and subareolar) and deeply (peritumoral, intratumoral, subtumoral) enables high identification rates and negative predictive values. It should be performed by teams consisting of surgeons, pathologists and nuclear medicine specialists with appropriate training and experience. Accepted indications are uni- and multifocal tumors smaller than 3 cm without suspicious findings in the axilla, furthermore SNB is indicated in patients with large ductal carcinoma in situ (>2cm) and/or with assumed microinvasion. Albeit SNB could be shown to be safe after preoperative chemotherapy and in multicentric breast cancer, due to lack of sufficient data it is still under discussion in these cases. Expedience of this procedure in other lymph node basins, along the mammaria interna vessels or in the infra- and supraclavicular region is considered to be at an investigative stage as well. SNB allows the pathologist to focus on a small number of nodes most likely to contain metastases. Application of serial sectioning and immunhistochemistry results in a more accurate staging than routine examination. Detection of additional micrometastases that are found in 10-15% leads to an upgrading from N0 to N1. Broad application and refurbishment led to scientific discussion of prognostic importance of micrometastases and its relevance according axillary dissection and adjuvant systemic treatment. Although many unicentric and multicentric observational studies validated by complete axillary dissection could demonstrate that SNB is accurate and suitable for all operable clinically node-negative breast cancers, longterm results and especially the incidence of axillary recurrence and its sequelae are outstanding. Findings of ongoing large prospective randomized trials like NSABP 32, Z0010 and Z0011 of the American College of Surgeons (ACOSOG), the AMAROS-Trial of the European Organisation of Research and Treatment of Cancer (EORTC) and the ALMANAC-Trial of the British Association of Surgical Oncology (BASO) will give a conclusive answer. Significant improvement in morbidity and quality of life measurements could be revealed several times in unicentric and even in muticentric studies like ALMANAC. Sentinel node biopsy is a team approach, requirements are good cooperation and well-defined stuctures of quality indicators and documentation. Participation in national clinical studies is recommended.

[Mesenteric inflammatory veno-occlusive disease (MIVOD)--a rare cause of intestinal ischemia]. / Mesenteric inflammatory veno-occlusive disease (MIVOD)--seltene Ursache für intestinale Ischämie.

Mesenteric inflammatory veno-occlusive disease (MIVOD) is a relatively recently known and not very often diagnosed form of ischemic bowel disease of low incidence und unknown etiology. We present the case of a patient who after presentation of inconclusive signs of epigastric pain and rectal bleeding suddenly developed right abdominal pain with local peritonism. Suspecting intestinal ischemia or perforated appendicitis we first performed laparoscopy, which showed an inflammable tumor of cecum, ascending colon and appendix with massive adhesions to the abdominal wall. We performed an open right hemicolectomy with primary anastomosis. The patient developed a deep vein thrombosis of the vena tibialis post. and vena saphena parva. After 12 months our patient is free of complaints and recurrence. Investigations carried out showed no evidence of hypercoagulopathy. The presentation of MIVOD can range from chronic inflammatory bowel disease with recurrent abdominal pain in combination with nausea, emesis and bloody diarrhea to acute abdomen. Therefore diagnostic misinterpretation and mistherapy as well as underdiagnosis is common. Histologic investigation shows a variable inflammatory infiltration of multiple veins of the intestinal wall and the mesentery as well as thrombotic vessel occlusion in different stages without involvement of the arteries. All forms of hypercoagulopathy, parasitic disease, sepsis and malignancy have to be excluded. Therapeutic success can only be achieved with surgical resection of the affected bowel, whereon in general no recurrence will occur.

25-hydroxyvitamin D3-1alpha-hydroxylase expression in normal and malignant human colon.

1,25-dihydroxyvitamin D(3) has anti-mitotic, pro-differentiating, and pro-apoptotic activity in tumor cells. We demonstrated that the secosteroid can be synthesized and degraded not only in the kidney but also extrarenally in intestinal cells. Evaluation of 1,25-dihydroxyvitamin D(3)-synthesizing CYP27B1 hydroxylase mRNA (real-time PCR) and protein (immunoblotting, immunofluorescence) showed enhanced expression in high- to medium-differentiated human colon tumors compared with tumor-adjacent normal mucosa or with colon mucosa from non-cancer patients. In high-grade undifferentiated tumor areas expression was lost. Many cells co-expressed CYP27B1 and the vitamin D receptor. We suggest that autocrine/paracrine antimitotic activity of 1,25-dihydroxyvitamin D(3) could prevent intestinal tumor formation and progression.

Analysis of hepatic resection of metastasis originating from gastric adenocarcinoma.

Few patients with metastatic gastric cancer have disease that is amenable to curative surgery. Thus far, little is known about liver surgery for metastases arising from gastric adenocarcinoma and prognostic factors. Of 73 patients operated on between 1980 and 1999 for noncolorectal, non-neuroendocrine hepatic metastases, 15 underwent liver resection for gastric adenocarcinoma metastasis. Ten patients underwent synchronous hepatic resection and five underwent metachronous hepatic surgery after a median disease-free interval of 10 months (range 6.1 to 47.3 months). None of the patients died within the first 30 days after surgery, and the in-hospital mortality rate was 6.7%. Among patients in the synchronous group, 26.7% experienced major complications mainly associated with gastric surgery. Overall median survival was 8.8 months (range 4 to 51 months); two patients survived more than 3 years. Univariate analysis revealed that the appearance of liver metastasis (synchronous vs. metachronous), the distribution of liver metastases (unilobar vs. bilobar), and the primary tumor site (proximal vs. distal) were marginally significant predictive factors regarding overall survival. Because of its high morbidity, synchronous liver resection for metastases originating from gastric adenocarcinoma is rarely followed by survival longer than 2 years. Primary tumor localization within the proximal third of the stomach and bilobar liver involvement appear to be predictive of poor outcome. On the other hand, curative resection of metachronous liver metastases may allow long-term survival in selected patients.

Gastrointestinal autonomic nerve tumors: a surgical point of view.

AIM: Gastrointestinal autonomic nerve tumors are uncommon stromal tumors of the intestinal tract. Their histological appearance is similar to that of other gastrointestinal stromal tumors. We report two cases and performed an analysis of the literature by comparing our findings with the available case reports in the medical literature. METHODS: Two patients were admitted with abdominal tumor masses. One occurred in the stomach with large multiple liver metastases and the second originated in Meckel's diverticulum. The latter site has never been reported previously. Both patients underwent surgery. In one patient gastrectomy, right liver resection and colon transversum resection were performed to achieve aggressive tumor debulking. In the other patient the tumor bearing diverticulum was removed. RESULTS: Postoperative recovery of both patients was uneventful. Histological examination, immunohistochemical analysis and electron microscopy revealed the diagnosis of a gastrointestinal autonomic nerve tumor. The patient with the tumor in Meckel's diverticulum died 6 mo after surgery because of pneumonia. The patient with liver metastases have been alive 13 years after initial tumor diagnosis and 7 years after surgery with no evidence of tumor progression. In light of our results, we performed a thorough comparison with available literature reports. CONCLUSION: Radical surgical resection of gastrointestinal autonomic nerve tumors seems to be the only available curative approach to date, and long term survival is possible even in large metastasized tumors.

[Treatment of achalasia]. / Behandlung der Achalasie.

Achalasia is a condition of unknown etiology. It represents a motor disorder of the esophagus characterized by absent or incomplete relaxation of the lower esophageal sphincter upon swallowing and by non-propulsive swallow-induced contraction waves or amotility of the esophageal body. Dysphagia and regurgitation of ingesta are the most frequent symptoms. Medical treatment, i.e. by calcium-channel blockers and nitric oxide donors, may be tried in patients with mild dysphagia or in elderly patients but rarely yields adequate symptom relief. Mechanical dilatation of the achalasic sphincter may be performed as an initial treatment option. Intrasphincteric injections of botulinum toxin seemed to be a promising alternative, but it has become obvious that, in most cases, repeated applications of the toxin are required to maintain patients symptom-free. Myotomy of the achalasic sphincter with or without fundoplication to prevent gastroesophageal reflux, is employed mainly in patients in whom dilatations have failed, but since the introduction of minimally invasive surgery, myotomy has become the primary treatment at many centers. This article aims to provide an overview of the development of the conservative and surgical treatment of achalasia.

[Pregnancy and labor after adjustable gastric banding for therapy of morbid obesity]. / Schwangerschaft und Geburt nach adjustierbarer Magenbandoperation zur Therapie der morbiden Adipositas.

Surgical placement of an adjustable gastric band has become a widely used method for treatment of morbid obesity. As a consequence, a higher number of pregnancies after weight loss is observed. Information is limited on pregnancy outcome after gastric banding, whereas metabolic and nutritional complications are reported after gastric bypass procedures. We report on two cases of pregnancy after laparoscopic gastric banding. Both patients had uncomplicated full-term pregnancies. In both cases, neither during nor after the pregnancy fluid removal from the gastric band was necessary. There seems to be a low probability for gestational and metabolic complications in pregnancy due to gastric banding. However, more specific information about pregnancies and fetal outcomes after gastric banding in a larger patient population would be desirable.

Surgery for gastrointestinal stromal tumors of the stomach.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the main mesenchymal neoplasms in the gastrointestinal tract. Tumor size, mitotic rate, and location correlate with potential malignancy and recurrence rate. Results of surgical treatment of gastric GIST are analyzed with emphasis on recurrence of disease after intermediate follow-up. METHODS: From 1998 to 2006, a total of 63 patients (median age 62.1 +/- 14.1) underwent gastric resection for GIST. Fifty-five patients (93.6%) returned for follow-up investigations, which included computed tomography in 45, gastroscopy in 32, and endosonography in 29. Positron emission tomography was done in five patients. RESULTS: Mean tumor size was 5.3 +/- 3.8 cm. Open atypical gastric resection was done in 32, distal gastric resection in five, and remnant gastrectomy in four patients. Laparoscopic gastric resection was initiated in 22 patients; the conversion rate was four of 22 (18.2%). Overall, R0 resection was reached in 61/63 patients (96.8%). According to the Fletcher criteria, 33 tumors (52.4%) were classified as intermediate or high risk GIST. Six patients (9.5%) died of unrelated causes before follow-up. After a median follow-up of 2.5 years, overall recurrence rate was 7.0% after R0 resection. CONCLUSION: Histologically proven complete resection is an effective treatment for gastric GIST. Laparoscopic procedures were carried out successfully in selected patients.

Multicentric breast cancer: a new indication for sentinel node biopsy--a multi-institutional validation study.

PURPOSE: Multicentric breast cancer has been considered to be a contraindication for sentinel node (SN) biopsy (SNB). In this prospective multi-institutional trial, SNB-feasibility and accuracy was evaluated in 142 patients with multicentric cancer from the Austrian Sentinel Node Study Group (ASNSG) and compared with data from 3,216 patients with unicentric cancer. PATIENTS AND METHODS: Between 1996 and 2004, 3,730 patients underwent SNB at 15 ASNSG-affiliated hospitals. Patient data were entered in a multicenter database. One hundred forty-two patients presented with multicentric invasive breast cancer and underwent SNB. RESULTS: Intraoperatively, a mean number of 1.67 SNs were excised (identification-rate, 91.5%). The incidence of SN metastases was 60.8% (79 of 130). This was confirmed by axillary lymph node dissection (ALND) in 125 patients. Of patients with positive SNs, 60.8% (48 of 79) showed involvement of nonsentinel nodes (NSNs), as did three patients with negative SNs (false-negative rate, 4.0). Sensitivity, negative predictive value, and overall accuracy were 96.0%, 93.3%, and 97.3%, respectively. Ninety-one percent of the patients underwent mastectomy, and 9% were treated with breast conserving surgery. None of the patients have shown axillary recurrence so far (mean follow-up, 28.8 months). Compared with 3,216 patients with unicentric cancer, there was a significantly higher rate of SN metastases as well as in NSNs, whereas there was no difference in detection and false-negative rates. CONCLUSION: Multicentric breast cancer is a new indication for SNB without routine ALND in controlled trials. Given adequate quality control and an interdisciplinary teamwork of surgical, nuclear medicine, and pathology units, SNB is both feasible and accurate in this disease entity.

Management of postoperative esophageal leaks with the Polyflex self-expanding covered plastic stent.

BACKGROUND: Esophageal anastomotic leaks can lead to prolonged hospitalization. In this article we present our experience with the placement of the Polyflex self-expanding plastic stent (Willy Ruesch GMBH, Kernen, Germany) for leak occlusion. METHODS: Between April 2000 and November 2003, 24 patients were included into this prospective study and underwent Polyflex stent placement for postoperative esophageal anastomotic leaks. The primary operation was esophagectomy in 13 patients, gastrectomy in 7, cardia resection in 2, and other procedures in 2 patients. The median interval between operation and stent placement was 19 days (range, 4 to 65). The effectiveness of leak occlusion was evaluated by water-soluble contrast swallow and the clinical course. RESULTS: In 2 patients stent misplacement produced an enlarged anastomotic dehiscence that necessitated reoperation. Radiologic evaluation was impossible in 4 patients because of their generally restricted condition. Among 18 evaluable patients, leak occlusion was successful with a single stent in 16 patients (89%) based on radiologic evaluation. Immediate oral feeding was well tolerated by these patients. After a median follow-up of 220 days (range, 7 to 1221), 9 cases of late stent dislocation were observed. Stent removal in patients after esophagectomy with gastric pull-up led to dysphagia from anastomotic strictures in 2 patients. Symptomatic strictures did not develop in the 5 evaluable postgastrectomy patients after stent removal. CONCLUSIONS: The placement of self-expanding plastic stents is a highly effective treatment for esophageal anastomotic leaks. Because clinically-relevant anastomotic strictures can be expected, we do not recommend stent removal after esophagectomy with gastric pull-up reconstruction.

Current value of intraoperative sonography during surgery for hepatic neoplasms.

Noninvasive liver imaging has developed rapidly resulting in increased accuracy for detecting primary and secondary hepatic tumors. Intraoperative ultrasonography (IOUS) was commonly considered to be the gold standard for liver staging, but the current value of IOUS is unknown in view of more sophisticated radiologic tools. The purpose of this prospective study was to evaluate the impact of IOUS on the treatment of 149 patients undergoing liver surgery for malignant disease (colorectal metastasis, 61 patients; hepatoma, 52 patients; other hepatic malignant tumors, 36 patients). The sensitivities of computed tomography (CT), helical CT, magnetic resonance imaging, and IOUS in patients with colorectal metastases were 69.2%, 82.5%, 84.9%, and 95.2% in a segment-by-segment analysis; in patients with hepatoma their sensitivities were 76.9%, 90.9%, 93.0%, and 99.3%; and in patients with other hepatic malignancies they were 66.7%, 89.6%, 93.3%, and 98.9%, respectively. Additional malignant lesions (AMLs) were first detected by inspection and palpation in 20 patients (13.4%). In another 18 patients (12.1%) IOUS revealed at least one AML. Overall, the findings obtained only by IOUS changed the surgical strategy in 34 cases (22.8%). It was concluded that IOUS, having undergone some refinement as well, still has immense diagnostic value in hepatectomy candidates. Frequently avoiding palliative liver resection and occasionally disproving unresectability as assessed by preoperative imaging, IOUS still has a significant impact on surgical decision making and should still be considered the gold standard.