[How does Diabetes Mellitus Influence Early Postoperative Results and Survival in Rectal Cancer?] / Wie beeinflusst der Diabetes mellitus das frühpostoperative und onkochirurgische Langzeit-"Outcome" beim Rektumkarzinom?

INTRODUCTION: Aim of this study was to investigate the influence of diabetes mellitus (DM) onto the early postoperative and long-term oncosurgical outcome after surgery for rectal cancer using data prospectively obtained in a representative number of patients. METHODS: Data (using a registration form of 68 items) from the ongoing multicenter observational study "rectal cancer (primary tumor) - elective surgery" on Quality Assurance was used including years 2008 to 2011. A voluntary and frequent follow-up was done to gain long-term data. Patients were grouped as non-diabetic and not-/insulin-dependent DM (NIDDM/IDDM). RESULTS: In total, 10 442 patients were enrolled; 11.0 % had NIDDM and 7.2 % IDDM. Average age of patients without DM was 67.3 [95 %-CI: 67,07; 67,55] years (yr) and was lower than in IDDM- (71.7 [95 %-CI: 71,01; 72,35] yr) and NIDDM-patients (70.9 [95 %-CI: 70.41; 71.45] yr) (p < 0.001). Tumor stages according to classification by UICC were comparable (p = 0.547). Patients with DM were more likely to be obese and to have cardiovascular and renal risk factors as well as a more critical ASA-classification (p < 0.001 each). Postoperative morbidity (in the group 65 - 74 yr; p = 0.006) and in-hospital mortality (< 65 yr; p = 0.011) was higher in patients with DM. The 5-year overall survival (OS) was 60.6 % in patients without DM. IDDM (46.4 %) and NIDDM (53.3 %) decreased the OS (p < 0.001 each). The 5-year disease-free survival (DFS) was also worsened by IDDM (p < 0.001) and NIDDM (p = 0.004). No difference was observed concerning 5-year local recurrence rate, neither for IDDM (p = 0.524) nor NIDDM (P = 0.058). DISCUSSION: The metabolic disorder DM has a significant impact onto the outcome after surgery for rectal cancer most likely due to its own risk potential and associated comorbidities. Postoperative morbidity and mortality were increased and the oncological survival was worsened.

Impact of Body Mass Index on Early Postoperative and Long-Term Outcome after Rectal Cancer Surgery.

BACKGROUND: The aim of this study was to investigate the impact of obesity and underweight onto early postoperative and long-term oncological outcome after surgery for rectal cancer. METHODS: Data from 2008 until 2011 was gathered by a German prospective multicenter observational study. 62 items were reported by the physicians in charge, and a consecutive follow-up was performed if the patient had signed a consent form. Patients were subclassified into: underweight, normal weight, overweight, and obese - using the definitions of the World Health Organization. RESULTS: In total, 9,920 patients were included, of whom 2.1% were underweight and 19.4% obese. The mean age was 68 years (range 21-99 years). Postoperative morbidity (mean 38.0%) was significantly increased in underweight and obese patients (p < 0.001). In-hospital mortality was 3.1% on average with no significant differences among patient groups (p = 0.176). The 5-year overall survival ranged between 36.9 and 61.3% and was worse in underweight and prolonged in overweight and obese patients compared to those with normal weight (p < 0.001 each). While the 5-year disease-free survival was increased in overweight and obese patients (p < 0.05 each), the 5-year local recurrence rate showed no correlation (p > 0.05 each). Multivariate analysis revealed that advanced age, higher ASA scoring, postoperative morbidity, and advanced tumor growth worsened the long-term survival independently. CONCLUSIONS: Underweight patients had a worse early and long-term outcome after rectal cancer surgery. Overweight and obesity were associated with a significantly better long-term survival.

Lost in translation? A systematic database of gene expression in breast cancer.

Ten years of translational research in breast cancer (BC) using high-throughput technologies such as cDNA arrays have produced an impressive amount of results. However, it is difficult for a single researcher to overview these results, since no critical synthesis is provided in the literature. This is a meta-analysis of gene expression in BC. Thirteen translational studies fulfilled the inclusion criteria, involving 553 BC patients and 79 controls. Large cohorts of patients and well-defined samples were rare. A total of 1,350 genes were reported at least once to be deregulated in BC. Out of these findings, 1,212 (90%) were not confirmed by other authors. A cohort of 138 genes of particular interest remained for further analysis. Of these, 79 were consistently reported to be overexpressed in BC, 41 to be underexpressed and in 18 cases results were contradictory. The most frequently reported deregulated genes in BC include: GATA binding protein 3, arylamine N-acetyltransferase, Myb-related protein B and zinc transporter SLC39A6 precursor (overexpressed); cadherin-3 precursor, keratin type I cytoskeletal 17 and type II cytoskeletal 5 (underexpressed). These genes obviously correlate with the presence and/or development of BC. More efforts should be devoted to the establishment of common standards in translational BC research.

Influence of subclinical tumor spreading on survival after curative surgery for colorectal cancer.

OBJECTIVE: To determine epithelial cell dissemination in patients with localized colorectal cancer. DESIGN: Prospective observational study. SETTING: Academic hospital. PARTICIPANTS: Two hundred twenty-two patients operated on for colorectal cancer. MAIN OUTCOME MEASURES: Epithelial cell dissemination was determined using immunohistochemistry or cytology in histologically negative lymph nodes, the peritoneal cavity, and bone marrow. Prognostic significance was determined in relation to 140 clinicopathological variables. Median follow-up was 61 months. RESULTS: Of 140 patients who underwent curative surgery; 25 (17.9%) died of cancer-related causes; 10 (7.1%), of other causes; and 11 (7.8%) developed local recurrence. Tumor cells were present in the peritoneal cavity of 22% of patients, but this finding had only borderline influence on disease-free survival (P = .07). Lymph node micrometastases correlated with T category but not with survival. The presence of epithelial cells in the bone marrow was detected in 64% of patients but was not associated with tumor stage or survival. Multivariate analysis failed to identify occult tumor cell dissemination into any body compartment as an independent prognostic factor of disease-free survival. CONCLUSIONS: Tumor cells disseminate into various body compartments in early stages of disease. In about two-thirds of patients, tumor cells are left in the body after so-called curative surgery. However, the presence of minimal residual disease has no independent prognostic significance in relation to established risk factors for tumor progression. Thus, other factors, such as the presence of a cellular metastatic phenotype and/or ineffective immunological response, must play an important role.

No prognostic impact of isolated lymphovascular invasion after radical resection of rectal cancer--results of a multicenter observational study.

BACKGROUND: The prognostic impact of isolated lymphovascular invasion (LVI) after radical resection of rectal cancer is controversially discussed. However, it could be relevant to decide for an adjuvant treatment. AIM: The aim of the analysis was, based on the data of an observational study, to determine the prognostic relevance of the isolated LVI. MATERIALS AND METHODS: Patients after radical resection of rectal cancer with no hemangioinvasion were subdivided in three groups: I-no LVI, no lymph node metastases (LNM); II-positive LVI, no LNM; III-positive LNM. Five-year local recurrence rate, distant metastases-free and disease-free survival were determined uni- and multivariate. RESULTS: Patients, n = 846, were studied (I, n = 471; II, n = 75; III, n = 300). The univariate comparison between the groups revealed the following 5-year results: local recurrence rate: 9.4 vs 10.0 vs 14.0%; distant metastases-free survival: 84.1 vs 82.5 vs 49.3%; disease-free survival: 83.2 vs 80.7 vs 45.5%. The differences between groups I and III were significant, but not between groups I and II. The determined higher disease-free survival rate in group II vs group III was significant (P = 0.041), but the differences in local recurrence rate and rate of distant metastases did not reach statistical significance. The multivariate analysis revealed no impact of the isolated LVI on the oncological outcome. CONCLUSION: The isolated LVI has no independent prognostic impact on the local recurrence rate and long-term survival after radical resection of rectal cancer. Based on this finding, no indication for an adjuvant treatment in these patients can be derived.

Incurable stenosing colorectal carcinoma: endoscopic stent implantation or palliative surgery?

BACKGROUND: Palliative surgery for the treatment of incurable obstructive colorectal carcinoma is associated with a considerable perioperative morbidity and mortality but no substantial improvement of the prognosis. The aim of the present study was to study the effectiveness of colorectal stenting compared with palliative surgery in incurable obstructive colorectal carcinoma. PATIENTS AND METHODS: From April 1999 to April 2005, data of consecutive patients with incurable stenosing colorectal carcinoma, either treated with stent implantation or palliative surgical intervention, were prospectively recorded with respect to age, sex, tumor location (including metastases), ASA-score, peri-interventional morbidity, mortality, rates of complications, and re-interventions as well as survival. RESULTS: Of 40 patients, 38 (95%) were successfully treated with a stent. Two patients (5%) underwent surgical intervention after stent dislocation. In contrast, 38 patients primarily underwent palliative surgical intervention. Stent patients were significantly older (P=0.020), had a higher ASA-score (P=0.012), and had more frequently distant metastases (P=0.011). After successful stent implantation, no early complications were observed, but late complications occurred in 11 subjects (29%). Following palliative surgical intervention, postoperative complications occurred in 12 individuals (32%) . Postoperative mortality was 5% in the surgery group, whereas no patient died following stent implantation. There was no significant differences in the survival of both groups (9.9 vs. 7.8 months, respectively; log rank: 0.506). CONCLUSIONS: Palliative treatment of incurable obstructive colorectal carcinoma using stents is an effective and suitable alternative to palliative surgery with no negative impact on the survival but less peri-interventional morbidity and mortality as well as comparable overall morbidity.

Laparoscopic cholecystectomy and gallbladder cancer.

Heightened awareness of the possible presence of gallbladder cancer (GBC) and the knowledge of appropriate management are important for surgeons practising laparoscopic cholecystectomy (LC). Long-term effects of initial LC versus open cholecystectomy (OC) on the prognosis of patients with GBC remain undefined. Patients who are suspected to have GBC should not undergo LC, since it is advantageous to perform the en-bloc radical surgery at the initial operation. Since preoperative diagnosis of early GBC is difficult, preventive measures, such as preventing bile spillage and bagging the gallbladder should be applied for every LC. Many port-site recurrences (PSR) have been reported after LC, but the incidence of wound recurrence is not higher than after OC. No radical procedure is required after postoperative diagnosis of incidental pT1a GBC. It is unclear if patients with pT1b GBC require extended cholecystectomy. In pT2 GBC, patients should have radical surgery (atypical or segmental liver resection and lymphadenectomy). In advanced GBC (pT3 and pT4), radical surgery can cure only a small subset of patients, if any. Additional port-site excision is recommended, but the effectiveness of such measure is debated.

Web-based data warehouse on gene expression in human colorectal cancer.

Based on biomedical literature databases, we tried a first step for constructing a gene expression "data warehouse" specific to human colorectal cancer (CRC). Results of genome-wide transcriptomic research were available from 12 studies, using various technologies, namely, SAGE, cDNA and oligonucleotide arrays, and adaptor-tagged amplification. Three studies analyzed CRC cell lines and nine studies of human samples. The total number of patients was 144. Out of 982 up- or down-regulated genes, 863 (88%) were found to be differentially expressed in a single study, 88 in two studies, 22 in three studies, 7 in four studies, and only 2 genes in six studies. Eight large-scale proteomics studies were published in CRC, using 2-D-, SDS- or free-flow electrophoresis, involving only 11 patients. Out of 408 differentially expressed proteins, 339 (83%) were found to be differentially expressed only in a single study, 16 in three studies, 10 in four studies, 3 in five, and 1 in eight studies. Confirmation at proteome level of results obtained with large-scale transcriptomics studies was possible in 25%. This proportion was higher (67%) for reproducing proteome results using transcriptomics technologies. Obviously, reproducibility and overlapping between published gene expression results at proteome and transcriptome level are low in human CRC. Thus, the development of standardized processes for collecting samples, storing, retrieving, and querying gene expression data obtained with different technologies is of central importance in translational research.

The impact of the risk factor "age" on the early postoperative results of surgery for colorectal carcinoma and its significance for perioperative management.

The risks and benefits of surgery for colorectal cancer in old patients have not been unequivocally defined. The present investigation was carried out in 309 hospitals as a prospective multicenter study. In the period between 1 January 2000 and 31 December 2001, a total of 19,080 patients were recruited for the study; 16,142 (84.6%) patients were younger than 80 years (<80) and 2932 (15.4%) were 80 years and older (> or =80). Significant differences between the age groups were observed for general postoperative complications (22.3% for <80 years; 33.9% for > or =80). Specific postoperative complications were identical in both groups. Overall, significantly elevated morbidity and mortality rates were found with increasing age (morbidity: 33.9% vs. 43.5%; mortality: 2.6% vs. 8.0%). The distribution of tumor stages revealed a significantly higher percentage of locally advanced tumors in the older age group (stage II: 28.0% vs. 34.4%). In contrast, no increase in metastasizing tumors was found in the older age group (stage IV: 17.4% vs. 14.1%). Logistic regression showed that, in concert with a number of other parameters, age is a significant influencing factor on postoperative morbidity and mortality. The increase in postoperative morbidity and mortality rates associated with aging is a result of the increase in general postoperative complications, in particular, pneumonia and cardiovascular complications. Age as such does not represent a contraindication for surgical treatment. The short-term outcome and quality of life are of overriding importance for the geriatric patient.

Expression and functional proteomics studies in colorectal cancer.

Cell dysfunction results from multiple rather than from single gene interactions in the majority of colorectal cancers (CRC). Proteins, not mRNA, are the functional molecules in the cell, and the relationship between gene expression measured at the mRNA level and the corresponding protein level is not linear. Current proteomics tools allow for the determination of post-translational modifications, and hence the presence of protein isoforms--some of them being disease-relevant. Thus, proteomics approaches are a welcome complement to traditional genetic approaches. In CRC, expression proteomics studies were carried out with colorectal cell lines, whole tissue biopsies, and purified epithelial cells. For CRC, two-dimensional electrophoresis reference maps, protein, and membrane protein databases are available on the internet. Functional proteomics studies have been performed to better understand signaling pathways, to characterize the molecular targets of novel drugs, and to identify tumor-associated antigens in CRC. The increasing use of proteomics technologies, when addressing clinical problems, will accelerate the evolution towards personalized medicine in CRC.

Using human samples in proteomics-based drug development: bioethical aspects.

Human samples and related medical data are expected to play an elevated role in application-based biomedical proteomics research. Against this framework, some facts should be kept in mind by academic and industrial researchers: international framework conditions on the use of human samples for research purposes are heterogeneous. For example, the value added by the use of human samples for product development is significant and the patient's personal and property rights may be affected. The body of national laws is growing and these laws are binding; guidelines published by international organizations should be respected. The most important aspect regards the informed consent of the patient, which is addressed in detail.

Ethical and regulatory issues arising from proteomic research and technology.

Over the last two decades, medical research has begun to make extensive use of products of human origin in therapeutics, oncology, and most recently, in genetic diseases. This has raised many ethical issues involving patient rights, including issues of consent. Besides informed consent, researchers should address several topics when designing studies using human tissues. Reward for the patient should be kept minimal. Sample transfer should be organized along non-profit lines, at least in Europe. Sampling procedures should be at no risk for human volunteers, and at minimal risk for patients. Biosafety aspects should be addressed, in particular when international collaborations are intended or when collaboration is existing between academia and industry. Regulations on importation and exportation of human tissues should be observed. Data acquisition and storage should be addressed in accordance with national data protection regulations, in particular when using computerized databases. If follow-up information is to be taken, the authorization for such information should be requested. The right for patient's information (or for no information) on the research results should also be addressed. The issues of validation and patenting should be also solved, usually by informing the patient that he/she will have no commercial rights on potential research results. The patient should be told if the samples are transferred to another research laboratory or private company. Samples and related data should be destroyed on request at any time point during the course of the study. If possible, traceability of the donor should be ensured.

Informed consent for molecular-based diagnostic and prognostic studies in the cancer patient.

The consent of the subject who is donating cells, tissues, organs or body fluid for research purposes is a precondition for biomedical research on human samples. Before such consent can be obtained, comprehensive information should be provided to the subject by the investigators. This information includes the scope of research, the intended use of subject's body parts and associated data, the risks and benefits associated with the research project, and the right to withdraw their consent at any time without prejudice. Consent is free and must not be obtained under any kind of pressure. The traditional practice of obtaining consent for unspecified future use of biological samples and data generated from clinical trials is no longer adequate for genetic research. However, the investigator has still interest to keep the definition of the field of research as broad as possible. Privacy is an issue of importance for the patient, who is the primary supplier of human samples, and for his relatives. Benefit sharing is another field of contradictory discussion. Normal volunteers are a special case among gene expression studies. An example of informed consent form is provided.

Tumor cell dissemination during laparoscopy: prevention and therapeutic opportunities.

Port-site recurrences (PSRs) are abdominal wall recurrences that occur in the subcutaneous tissue within a trocar site after cancer laparoscopy and are not associated with peritoneal carcinomatosis. In order to develop PSRs, viable tumor cells must be liberated from the primary tumor, be transported to a wound, and find there a favorable environment for growth. The short clinical delay in the occurrence of PSRs and their size suggest massive cell seeding into the abdominal wall. Traumatic handling of the tumor, slipping of trocars, liquid projection, as well as poor extraction techniques can all cause implantation of malignant cells into the subcutaneous tissue. Such contact can also occur postoperatively if the trocar channels remain open. Some histologies (e.g. gallbladder adenocarcinoma), the presence of ascites and advanced tumor stage are risk factors for PSRs. Further conditions--including the use of gas--might also play a limited role. The first preventive measure is the correct indication for a laparoscopic approach. Several techniques have been demonstrated to prevent PSRs in the animal model: (a) fixation of trocars to the abdominal wall; (b) prevention of leakage; (c) careful specimen handling; (d) reducing trauma to the abdominal wall; (e) specimen isolation before extraction from the abdominal cavity; (f) trocar-site irrigation with a cytotoxic solution, and (g) closure of peritoneum. Further innovative therapies are currently under investigation. In the clinical setting, correct indication, surgical expertise and application of prophylactic measures seem to be the best way to prevent the occurrence of PSRs.