Frank Benedix

Comparison of 17,641 Patients With Right- and Left-Sided Colon Cancer: Differences in Epidemiology, Perioperative Course, Histology, and Survival

PURPOSE: There is a growing amount of data suggesting that carcinomas of the right and left colon should be considered as different tumor entities. Using the data and analysis compiled in the German multicentered study “Colon/Rectum Cancer,” we aimed to clarify whether the existing differences influence clinical and histological parameters, the perioperative course, and the survival of patients with right- vs left-sided colon cancer. METHODS: During a 3-year period data on all patients with colon cancer were evaluated. Right- and left-sided cancers were compared regarding the following parameters: demographic factors, comorbidities, and histology. For patients who underwent elective surgery with curative intent, the perioperative course and survival were also analyzed. RESULTS: A total of 17,641 patients with colon carcinomas were included; 12,719 underwent curative surgery. Patients with right-sided colon cancer were significantly older, and predominantly women with a higher rate of comorbidities. Mortality was significantly higher for this group. Final pathology revealed a higher percentage of poorly differentiated and locally advanced tumors. Rate of synchronous distant metastases was comparable. However, hepatic and pulmonary metastases were more frequently found in left-sided, peritoneal carcinomatosis in right-sided carcinomas. Survival was significantly worse in patients with right-sided carcinomas on an adjusted multivariate model (odds ratio, 1.12). CONCLUSIONS: We found that right- and left-sided colon cancers are significantly different regarding epidemiological, clinical, and histological parameters. Patients with right-sided colon cancers have a worse prognosis. These discrepancies may be caused by genetic differences that account for distinct carcinogenesis and biological behavior. The impact of these findings on screening and therapy remains to be defined.

Primary appendiceal carcinoma – Epidemiology, surgery and survival: Results of a German multi-center study

BACKGROUND While carcinoma of the colon is a common malignancy, primary carcinoma of the appendix is rare. Many retrospective reviews outlined experience from different centers on appendiceal neoplasms. However, the study population is often small because it is so rare. The aim of this study was to analyze the type of surgery and survival of patients with appendiceal malignancies using data from a German multi-center observational study (31 341 patients). METHODS During a five-year period, 196 consecutive patients with malignant appendiceal tumors were distributed into four groups: appendiceal carcinoids, adenocarcinoma, mucinous adenocarcinoma and adenosquamous carcinoma. The following parameters were analyzed: demographics, clinical presentation, comorbidities, type and appropriateness of surgery, final pathology and survival. RESULTS Adenocarcinoma had the highest incidence (50.5%). The most common presentation was that of acute appendicitis. Mean age at presentation was youngest for carcinoid tumors. Carcinoid tumors had lowest tumor size and localized disease was present in 72.9%. Metastatic spread at presentation was highest for adenosquamous and mucinous adenocarcinoma and each had a distinct pattern. Right hemicolectomy was performed in 71.4%, limited resection in 11.7%. Overall 5-year survival was 83.1% for carcinoid vs. 49.2% for non-carcinoid tumors. Histological subtype and tumor stage significantly affected survival. CONCLUSIONS Long-term outcome of carcinoid tumors is superior to non-carcinoid neoplasms. Among all appendiceal neoplasms, adenosquamous carcinoma is the rarest histological subtype which is most commonly associated with advanced tumor stage and worst prognosis. Appropriate oncologic resection is being performed in a significant percentage of cases in Germany. However, the high rate of right hemicolectomy in patients with small carcinoid tumors needs to be critically discussed.

Influence of anatomical subsite on the incidence of microsatellite instability, and KRAS and BRAF mutation rates in patients with colon carcinoma

There is a growing amount of data supporting the concept that cancers originating from the proximal and distal colon are distinct clinicopathological entities. The incidence of MSI and BRAF mutation is strongly associated with right sided tumor location, whereas there are conflicting results for KRAS mutation rates. However, to date, no data exist whether and to what extent defined colonic subsites influence MSI status, KRAS and BRAF mutation rates. We selected primary colon cancer from 171 patients operated on at our institution between 2007 and 2010. BRAF, KRAS mutation rates and microsatellite instability were determined and correlated with clinicopathological features and tumor location. MSI-h cancers were significantly associated with poor histological grade but a lower rate of distant metastases. KRAS-mutated tumors were linked to lower T-stage and better differentiation. Colon carcinomas with BRAF mutation were significantly associated with distant metastatic spread and poor histological grade. Furthermore, we found that MSI-h status, KRAS and BRAF mutation rates varied remarkably among the colonic subsites irrespective of right- and left-sided origin, respectively. The results of the current study provide further evidence that a simple classification into right- and left-sided colon carcinoma does not represent the complexity of this tumor entity.

miR-221 Mediates Chemoresistance of Esophageal Adenocarcinoma by Direct Targeting of DKK2 Expression.

Background: Chemoresistance is a main obstacle to effective esophageal cancer (EC) therapy. We hypothesize that altered expression of microRNAs (miRNAs) play a role in EC cancer progression and resistance to 5-fluorouracil (5-FU) based chemotherapeutic strategies. Methods: Four pairs of esophageal adenocarcinoma (EAC) cell lines and corresponding 5-FU resistant variants were established. The expression levels of miRNAs previously shown to be involved in the general regulation of stem cell pathways were analyzed by qRT-PCR. The effects of selected miRNAs on proliferation, apoptosis, and chemosensitivity were evaluated both in vitro and in vivo. We identified a particular miRNA and analyzed its putative target genes in 14 pairs of human EC tumor specimens with surrounding normal tissue by qRT-PCR as well as Wnt pathway associated genes by immunohistochemistry in another 45 EAC tumor samples. Results: MiR-221 was overexpressed in 5-FU resistant EC cell lines as well as in human EAC tissue. DKK2 was identified as a target gene for miR-221. Knockdown of miR-221 in 5-FU resistant cells resulted in reduced cell proliferation, increased apoptosis, restored chemosensitivity, and led to inactivation of the Wnt/&bgr;-catenin pathway mediated by alteration in DKK2 expression. Moreover, miR-221 reduction resulted in alteration of EMT-associated genes such as E-cadherin and vimentin as well as significantly slower xenograft tumor growth in nude mice. RT2 profiler analysis identified a substantial dysregulation of 4 Wnt/&bgr;-catenin signaling and chemoresistance target genes as a result of miR-221 modulation: CDH1, CD44, MYC, and ABCG2. Conclusion: MiR-221 controls 5-FU resistance of EC partly via modulation of Wnt/&bgr;-catenin-EMT pathways by direct targeting of DKK2 expression. MiR-221 may serve as a prognostic marker and therapeutic target for patients with 5-FU resistant EAC.

Karzinome des rechten und linken Kolons – verschiedene Tumorentitäten?

PURPOSE Colorectal cancer is one of the most common malignancies in the Western world. In the past two decades, a growing amount of data has been reported suggesting that carcinomas of the right and left colon should be considered as different tumour entities. The aim of this review is to present a detailed analysis of the current knowledge regarding differences between right- and left-sided colon cancer and potential consequences for daily practice. METHODS For this report all articles with relevant information on differences between right- and left-sided colon carcinoma found via Pubmed searches were analysed. Furthermore, findings of a previous study performed by our group were included. RESULTS Patients with right-sided colon cancer are significantly older, predominantly women, with a higher rate of comorbidities. Most of the large epidemiological studies reported a continued rightward shift of colorectal cancer. Histopathologically, carcinoma of the right colon show a higher percentage of poorly differentiated, locally advanced tumours with a higher rate of mucinous carcinoma and different pattern of metastatic spread. Survival is significantly worse in patients with right-sided carcinomas. There are numerous genetic differences which account for the distinct carcinogenesis and biological behaviour. CONCLUSIONS The numerous findings regarding differences between right- and left-sided colon cancers should have an impact on colon cancer screening and therapy. Firstly, there are defined risk groups which should receive complete colonoscopy, particularly if they present with symptoms suspicious for colon carcinoma. Furthermore, location of the colon cancer should be considered before group stratification into genetic, clinical and especially chemotherapy trials. A more tailored approach to colon cancer treatment would be highly desirable if future trials further support the hypothesis of two distinct tumour entities.

Nutritive Defizite nach bariatrischer Chirurgie – systematische Literaturanalyse und Empfehlungen für Diagnostik und Substitution

The increasing prevalence of morbid obesity in Germany is associated with an increasing number of metabolic surgical interventions. Short-term surgical and long-term metabolic complications such as nutrient deficiencies can be considered the main risks of metabolic surgery and its restrictive and malabsorbant surgical procedures. The aim of this compact short overview based on a selective literature search and our own clinical experience is to characterise the long-term metabolic complications, which are specific for the various bariatric procedures, and to refine the published guidelines for supplementation. Restrictive bariatric procedures can be associated with well-known surgical problems such as pouch dilatation or band migration, e.g., after gastric banding. After sleeve gastrectomy, emerging reflux disease can become a substantial problem. The most frequent deficiencies after restrictive procedures are related to B-vitamins whereas iron, folate, vitamin B1 and B12 and vitamin D deficiencies are associated with the malabsorptive procedure such as biliopancreatic diversion, duodenal switch and Roux-en-Y gastric bypass. Due to possible metabolic and surgical complications after bariatric surgery, patients need to undergo life-long medical follow-up investigations. The currently available guidelines of German Society of Treatment of Obesity (CAADIP) of DGAV for supplementation should be known and followed, in particular, by the physicians who i) are exceptionally involved in medical care of obese people and ii) do it in full awareness of the obligatory postoperative clinical observation.

Actual Situation of Thromboembolic Prophylaxis in Obesity Surgery: Data of Quality Assurance in Bariatric Surgery in Germany

Background. Evidence-based data on optimal approach for prophylaxis of deep venous thrombosis (VTE) and pulmonary embolism (PE) in bariatric operations is discussed. Using antithrombotic prophylaxis weight adjusted the risk of VTE and its complications have to be balanced with the increased bleeding risk. Methods. Since 2005 the current situation for bariatric surgery has been examined by quality assurance study in Germany. As a prospective multicenter observational study, data on the type, regimen, and time course of VTE prophylaxis were documented. The incidences of clinically diagnosed VTE or PE were derived during the in-hospital course and follow up. Results. Overall, 11,835 bariatric procedures were performed between January 2005 and December 2010. Most performed procedures were 2730 gastric banding (GB); 4901 Roux-en-Y-gastric bypass (RYGBP) procedures, and 3026 sleeve gastrectomies (SG). Study collective includes 72.5% (mean BMI 48.1 kg/m2) female and 27.5% (mean BMI 50.5 kg/m2) male patients. Incidence of VTE was 0.06% and of PE 0.08%. Conclusion. VTE prophylaxis regimen depends on BMI and the type of procedure. Despite the low incidence of VTE and PE there is a lack of evidence. Therefore, prospective randomized studies are necessary to determine the optimal VTE prophylaxis for bariatric surgical patients.

[Revision after failed bariatric surgery--review of complications and current therapeutic options].

BACKGROUND Obesity is increasing worldwide at an alarming rate. Particularly in Western countries, obesity and related problems have become a serious medical problem and an enormous socio-economic burden. DISCUSSION Currently, surgery is the only avail-able treatment for patients with severe obesity which leads to sustained weight loss and cure of co-morbidities in the majority of the patients. The increase in the number of bariatric operations and the occasional failure and complications of these surgical procedures have resulted in an increased need for revision surgery. Overall, 10-25 % of patients are expected to need a revision for failure of the primary bariatric procedure. The main indications for revision procedures are inadequate weight loss, surgery-related complications as well as surgical emergencies and long-term complications caused by malnutrition or -vitamin deficiencies. Unfortunately, there are currently no randomised trials to answer the question as to which operation should be performed in which patient and after which procedure. Decisions are often influenced by the expertise and preference of the operating surgeon as well as by patients preference. Thus, a systematic review of published data to this complex issue appears to be helpful and important for daily surgical practise. CONCLUSIONS Revision bariatric procedures are technically more complex and associated with increased postoperative complications. These operations should basically be performed in centres with profound expertise in this field of surgery, and - whenever possible - laparoscopically. However, every abdominal surgeon should be able to diagnose and treat some acute complications. After failed restrictive procedures, revision is recommended only in cases of complications but with adequate weight loss at the time of failure. Otherwise, conversion to combined procedures should be considered. After the failure of combined procedures, further weight loss or successful treatment of complications can be achieved by adding more restriction and/or malabsorption components. The latter is associated with an increased risk of nutritional sequelae.

Einfluss des muzinösen und siegelringzelligen Subtyps auf epidemiologische, histologische und molekularbiologische Eigenschaften sowie auf die Prognose des kolorektalen Karzinoms

BACKGROUND Colorectal cancer (CRC) is one of the most common malignancies in the Western world. Histopathologically, adenocarcinomas are mostly diagnosed. Mucinous and signet-ring cell subtypes occur with a very low incidence. However, these subtypes differ remarkably in terms of clinical, histological and molecular biological characteristics. The aim of this review is to present a detailed analysis of current knowledge regarding differences between classical adenocarcinoma and mucinous, and signet-ring cell CRC along with potential consequences for daily practice. METHODS For this report all articles with relevant information on differences between classical adenocarcinoma and mucinous, and signet-ring cell CRC found via Pubmed searches were analysed. Furthermore, findings of our previous study were included. RESULTS Mucinous CRC occur with a reported incidence of 10 - 20 % in Western countries and are predominantly found in younger patients and females. They are more often diagnosed in the proximal colon and present with a higher stage at diagnosis. Furthermore, there is a higher rate of lymph node-positive tumours and peritoneal carcinomatosis. Results of molecular biological studies confirm that they may represent a different tumour entity. The response to well established chemotherapy regimens is poorer which may be attributed to the higher rate of microsatellite-instable tumours and an increased mucin secretion. The poorer outcome is likely related to the higher stage at the time of diagnosis. Signet-ring cell type CRC are rare with an incidence ranging between 0,9 % to 4 %. They are also more common in the right colon and are associated with a poorer outcome compared to adenocarcinoma and mucinous CRC. CONCLUSIONS However, it should be noted that most of the results come from studies with a very low number of patients which can be attributed to the low incidence of mucinous and signet-ring cell CRC. Based on the findings of the present analysis, a more radical surgical approach should be considered providing that the exact preoperative histology is available. Furthermore, the histological subtype should be taken into account in future chemotherapy trials to avoid unnecessary therapy. A closer follow-up, especially for patients with signet-ring cell CRC should be discussed. In the near future, a more tailored therapy in patients with colorectal cancer would be highly desirable.

Continuous intra-arterial chemotherapy with 5-fluorouracil and cisplatin for locally advanced anaplastic carcinoma of the pancreas

Dear Editor, The majority of malignant tumors of the pancreas are of epithelial derivation. Undifferentiated malignancies are generally accepted to represent probable carcinomas, making up a small percentage of all pancreatic tumors (2– 7%). Anaplastic carcinomas of the pancreas (ACPs) are rare and frequently display a variety of growth pattern. ACPs generally occur with greater frequency in the head of the pancreas, usually in older men. They tend to have an aggressive nature with rapid local and distant spread. Weight loss, fatigue, loss of appetite, abdominal pain, nausea, vomiting, and diarrhea are the usual clinical presenting symptoms. Radiological findings of APCs are nonspecific. Currently, there are no established treatment options that can generally be recommended. Intra-arterial (i.a.) chemotherapy is a procedure used to apply higher concentrations of anticancer drugs directly into the artery supplying the vascular bed of a tumor. Hence, local concentration at the target site is significantly increased as compared to intravenous infusion with reduction of systemic effects. The feasibility and efficacy of i.a. chemotherapy in locally advanced or metastatic adenocarcinoma of the pancreas has been already investigated by different authors in the first-line and second-line setting, respectively, with response rates of up to 21.9%. Pain reduction and weight gain were also observed. We hereby report our experience with i.a. chemotherapy in a patient with locally advanced APC. This is, to our knowledge, the first report about locoregional chemotherapy for irresectable anaplastic carcinoma of the pancreas. A 53-year-old female patient presented in November 2006 to a nearby hospital for routine follow-up after breastpreserving therapy of a breast cancer (T1 N0 M0) which she had 7 years ago. On physical examination, she was found to have a suspect right cervical lymph node, which subsequently was completely removed. Histological examination revealed a metastasis of an anaplastic carcinoma. Computed tomography (CT) scan of both chest and abdomen was performed and showed a tumor of the cauda pancreatis, 7.5 cm in diameter with central necrosis and infiltration of surrounding tissue, splenic artery, and vein. There was no evidence of either hepatic or pulmonary metastases but enlarged retroperitoneal lymph nodes were found. Diagnosis of an anaplastic carcinoma of the tail of the pancreas was established histologically following a percutaneous CT-guided needle aspiration biopsy. Patient was referred to our hospital to discuss therapeutic options. Due to locally advanced tumor growth with irresectability, decision for primary i.a. chemotherapy followed by optional surgical intervention in case of adequate tumor response was made. The patient was given detailed information about the procedure and written informed consent was obtained. To assess the hemodynamic status around the pancreas and to establish whether there are congenital abnormalities with a potential risk of misperfusion, a preliminary selective angiography was conducted. It revealed normal vascular anatomy with vascular infiltration of the tumor Int J Colorectal Dis (2008) 23:729–731 DOI 10.1007/s00384-008-0441-0