Could hyponatremia be a marker of anastomotic leakage after colorectal surgery? A single center analysis of 1,106 patients over 5 years.

PURPOSE: The aim of this study is to define the significance of hyponatremia as a marker of anastomotic leakage after colorectal surgery. METHODS: All anastomoses in colorectal surgery performed at a single institution between July 2007 and July 2012 (n = 1,106) were retrospectively identified. Serum sodium levels and leukocyte values measured when an anastomotic leak was diagnosed by CT scan and/or surgical reintervention (n = 81) were compared to the values preferably on postoperative day 5 in the absence of an anastomotic leak (n = 1,025). RESULTS: The leak rate in anastomoses of the rectum was 9.0 %, while the leak rate of the other anastomoses was 5.4 %. Mean serum sodium level was 138.8 mmol/l in the group with an anastomotic leak and 140.5 mmol/l in the group without. Hyponatremia (<136 mmol/l) was present in 23 % of patients in the group with an anastomotic leak and in 15 % in the group without (p < 0.001). In multivariate analysis, leukocytes and serum sodium level remained as significant markers of an anastomotic leak. As a marker of an anastomotic leak, hyponatremia had a specificity of 93 % and a sensitivity of 23 %, while the presence of either leukocytosis or hyponatremia had a sensitivity of 68 %, a specificity of 75 %, a positive predictive value of 18 %, and a negative predictive value of 97 %. CONCLUSIONS: Hyponatremia could be a specific and relevant marker of anastomotic leakage after colorectal surgery. If hyponatremia and leukocytosis are present after colorectal surgery, anastomotic leakage should be suspected and a CT scan with rectal contrast dye is recommended.

Molecular staging of lymph node-negative colon carcinomas by one-step nucleic acid amplification (OSNA) results in upstaging of a quarter of patients in a prospective, European, multicentre study.

BACKGROUND: Current histopathological staging procedures in colon carcinomas depend on midline division of the lymph nodes with one section of haematoxylin & eosin (H&E) staining only. By this method, tumour deposits outside this transection line may be missed and could lead to understaging of a high-risk group of stage UICC II cases, which recurs in ∼20% of cases. A new diagnostic semiautomated system, one-step nucleic acid amplification (OSNA), detects cytokeratin (CK) 19 mRNA in lymph node metastases and enables the investigation of the whole lymph node. The objective of this study was to assess whether histopathological pN0 patients can be upstaged to stage UICC III by OSNA. METHODS: Lymph nodes from patients who were classified as lymph node negative after standard histopathology (single (H&E) slice) were subjected to OSNA. A result revealing a CK19 mRNA copy number >250, which makes sure to detect mainly macrometastases and not isolated tumour cells (ITC) or micrometastases only, was regarded as positive for lymph node metastases based on previous threshold investigations. RESULTS: In total, 1594 pN0 lymph nodes from 103 colon carcinomas (median number of lymph nodes per patient: 14, range: 1-46) were analysed with OSNA. Out of 103 pN0 patients, 26 had OSNA-positive lymph nodes, resulting in an upstaging rate of 25.2%. Among these were 6/37 (16.2%) stage UICC I and 20/66 (30.3%) stage UICC II patients. Overall, 38 lymph nodes were OSNA positive: 19 patients had one, 3 had two, 3 had three, and 1 patient had four OSNA-positive lymph nodes. CONCLUSIONS: OSNA resulted in an upstaging of over 25% of initially histopathologically lymph node-negative patients. OSNA is a standardised, observer-independent technique, allowing the analysis of the whole lymph node. Therefore, sampling bias due to missing investigation of certain lymph node tissue can be avoided, which may lead to a more accurate staging.

Activation of the PI3K/AKT pathway correlates with prognosis in stage II colon cancer.

BACKGROUND: Patients with UICC/AJCC stage II colon cancer have a high 5-year overall survival rate after surgery. Nevertheless, a significant subgroup of patients develops tumour recurrence. Currently, there are no clinically established biomarkers available to identify this patient group. We applied reverse-phase protein arrays (RPPA) for phosphatidylinositide-3-kinase pathway activation mapping to stratify patients according to their risk of tumour recurrence after surgery. METHODS: Full-length proteins were extracted from formalin-fixed, paraffin-embedded tissue samples of 118 patients who underwent curative resection. RPPA technology was used to analyse expression and/or phosphorylation levels of six major factors of the phosphatidylinositide-3-kinase pathway. Oncogenic mutations of KRAS and BRAF, and DNA microsatellite status, currently discussed as prognostic markers, were analysed in parallel. RESULTS: Expression of phospho-AKT (HR=3.52; P=0.032), S6RP (HR=6.3; P=0.044), and phospho-4E-BP1 (HR=4.12; P=0.011) were prognostic factors for disease-free survival. None of the molecular genetic alterations were significantly associated with prognosis. CONCLUSIONS: Our data indicate that activation of the PI3K/AKT pathway evidenced on the protein level might be a valuable prognostic marker to stratify patients for their risk of tumour recurrence. Beside adjuvant chemotherapy targeting of upregulated PI3K/AKT signalling may be an attractive strategy for treatment of high-risk patients.

[Open surgical versus laparoscopic treatment of iatrogenic colon perforation - results of a 13-year experience]. / Offen chirurgische versus laparoskopische Versorgung der iatrogenen Kolonperforation - Ergebnisse nach 13 Jahren Erfahrungen.

BACKGROUND: Iatrogenic colon perforation is a rare but life-threatening complication of colonscopy. As in other diseases, laparoscopic treatment has increasingly been propagated for the treatment of colonic disorders in the last years. The aim of this comparative study was to answer the question of whether laparoscopic surgical treatment may serve as a suitable treatment for the acute colon perforation comparable to open surgery. PATIENTS AND METHODS: The data of all patients who underwent surgery for iatrogenic colon perforation within a 13-year time period (1997-2009) were recorded prospectively and analysed retrospectively with regard to different perioperative parameters. In the following analysis the laparoscopically and open surgically treated patients were compared. RESULTS: In the observation period 24 patients with iatrogenic colon perforation were treated laparoscopically and 12 patients with open surgery. There were no significant differences concerning age in both groups. In both groups resection of the affected region was preferred [open surgically: 58 % (n = 7), laparoscopically: 80 % (n = 19)]. The median operation time was 105 min (range: 35 - 180) for the open surgically treated patients and 165 min (90 - 420) for laparoscopic procedures (p = 0.006). In 4 cases of the laparoscopic group a conversion via laparotomy was -necessary. There was no significant difference concerning the hospital stay between both groups with 14.5 days (7-40) for the open surgical and 11 days (7-25) for the laparoscopic group. Concerning the postoperative morbidity a significantly higher incidence could be seen in the open surgical group (p < 0.0001). CONCLUSION: An iatrogenic colon perforation mostly leeds to the immediate indication for a surgical treatment. The morbidity and mortality is -primarily determined through the appearance of postoperative complications due to delays in diagnostics and treatment. In this study the feasibility of a laparoscopic treatment could be shown. The laparoscopy with its minimal access trauma offers an enlargement of the diagnostics as well as a safe treatment of the perforation in most patients. However, the laparoscopic treatment especially in emergancy situations requires -advanced experience of the surgeon and always needs a critical benefit-risk consideration in the individual situation.

Laparoscopic extraperitoneal rectal cancer surgery: the clinical practice guidelines of the European Association for Endoscopic Surgery (EAES).

BACKGROUND: The laparoscopic approach is increasingly applied in colorectal surgery. Although laparoscopic surgery in colon cancer has been proved to be safe and feasible with equivalent long-term oncological outcome compared to open surgery, safety and long-term oncological outcome of laparoscopic surgery for rectal cancer remain controversial. Laparoscopic rectal cancer surgery might be efficacious, but indications and limitations are not clearly defined. Therefore, the European Association for Endoscopic Surgery (EAES) has developed this clinical practice guideline. METHODS: An international expert panel was invited to appraise the current literature and to develop evidence-based recommendations. The expert panel constituted for a consensus development conference in May 2010. Thereafter, the recommendations were presented at the annual congress of the EAES in Geneva in June 2010 in a plenary session. A second consensus process (Delphi process) of the recommendations with the explanatory text was necessary due to the changes after the consensus conference. RESULTS: Laparoscopic surgery for extraperitoneal (mid- and low-) rectal cancer is feasible and widely accepted. The laparoscopic approach must offer the same quality of surgical specimen as in open surgery. Short-term outcomes such as bowel function, surgical-site infections, pain and hospital stay are slightly improved with the laparoscopic approach. Laparoscopic resection of rectal cancer is not inferior to the open in terms of disease-free survival, overall survival or local recurrence. Laparoscopic pelvic dissection may impair genitourinary and sexual function after rectal resection, like in open surgery. CONCLUSIONS: Laparoscopic surgery for mid- and low-rectal cancer can be recommended under optimal conditions. Still, most level 1 evidence is for colon cancer surgery rather than rectal cancer. Upcoming results from large randomised trials are awaited to strengthen the evidence for improved short-term results and equal long-term results in comparison with the open approach.

Different surgical strategies for chronic pancreatitis significantly improve long-term outcome: a comparative single center study.

OBJECTIVE: In general, chronic pancreatitis (CP) primarily requires conservative treatment. The chronic pain syndrome and complications make patients seek surgical advice, frequently after years of progression. In the past, surgical procedures involving drainage as well as resection have been employed successfully. The present study compared the different surgical strategies. - PATIENTS AND METHODS: From March 2000 until April 2005, a total of 51 patients underwent surgical treatment for CP at the Department of surgery, University of Schleswig-Holstein, Campus Lübeck. Out of those 51 patients, 39 (76.5%) were operated according to the Frey procedure, and in 12 cases (23.5%) the Whipple procedure was performed. Patient data were documented prospectively throughout the duration of the hospital stay. The evaluation of the postoperative pain score was carried out retrospectively with a validated questionnaire. RESULTS: Average operating time was 240 minutes for the Frey group and 411 minutes for the Whipple group. The medium number of blood transfusions was 1 in the Frey group and 4.5 in the Whipple group. Overall morbidity was 21% in the Frey group and 42% in the Whipple group. 30-day mortality was zero for all patients. During the median follow-up period of 50 months, an improvement in pain score was observed in 93% of the patients of the Frey group and 67% of the patients treated according to the Whipple procedure. CONCLUSION: The results show that both the Frey procedure as well as partial pancreaticoduodenectomy are capable of improving chronic pain symptoms in CP. As far as later endocrine and exocrine pancreatic insufficiency is concerned, however, the extended drainage operation according to Frey proves to be advantageous compared to the traditional resection procedure by Whipple. Accordingly, the Frey procedure provides us with an organ-preserving surgical procedure which treats the complications of CP sufficiently, thus being an alternative to partial pancreaticoduodenectomy if there is no suspicion of malignancy.

Intensified surveillance after surgery for colorectal cancer significantly improves survival.

BACKGROUND: Postoperative surveillance after curative resection for colorectal cancer has been demonstrated to improve survival. It remains unknown however, whether intensified surveillance provides a significant benefit regarding outcome and survival. This study was aimed at comparing different surveillance strategies regarding their effect on long-term outcome. METHODS: Between 1990 and 2006, all curative resections for colorectal cancer were selected from our prospective colorectal cancer database. All patients were offered to follow our institution's surveillance program according to the ASCO guidelines. We defined surveillance as "intensive" in cases where >70% appointments were attended and the program was completed. As "minimal" we defined surveillance with <70% of the appointments attended and an incomplete program. As "none" we defined the group which did not take part in any surveillance. RESULTS: Out of 1469 patients 858 patients underwent "intensive", 297 "minimal" and 314 "none" surveillance. The three groups were well balanced regarding biographical data and tumor characteristics. The 5-year survival rates were 79% (intensive), 76% (minimal) and 54% (none) (OR 1.480, (95% CI 1.135-1.929); p <0.0001), respectively. The 10-year survival rates were 65% (intensive), 50% (minimal) and 31% (none) (p <0.0001), respectively. With a median follow-up of 70 months the median time of survival was 191 months (intensive), 116 months (minimal) and 66 months (none) (p <0.0001). After recurrence, the 5-year survival rates were 32% (intensive, p = 0.034), 13% (minimal, p = 0.001) and 19% (none, p = 0.614). The median time of survival after recurrence was 31 months (intensive, p <0.0001), 21 months (minimal, p <0.0001) and 16 month (none, p <0.0001) respectively. CONCLUSION: Intensive surveillance after curative resection of colorectal cancer improves survival. In cases of recurrent disease, intensive surveillance has a positive impact on patients' prognosis. Large randomized, multicenter trials are needed to substantiate these results.

Diffuse postoperative peritonitis -- value of diagnostic parameters and impact of early indication for relaparotomy.

OBJECTIVE: Current criteria for performing relaparotomy for suspected peritonitis are non explicit and based on non-quantitative, subjective arguments or hospital practice. The aim of this study was to determine the value of routinely used clinical and diagnostic parameters in early detection of postoperative, diffuse peritonitis (PP). Furthermore, the prognosis and outcome after early indication for relaparotomy in patients with PP compared to community-aquired peritonitis (CAP) was evaluated. METHODS: Between 1999 and 2008, a total of 251 patients with diffuse secondary peritonitis either postoperative (PP) or community acquired (CAP) were analyzed retrospectively. PP (n = 114) and CAP (n = 137) were compared regarding physical examination, MPI-Score, APACHE II-Score, evidence of organ failure, laboratory parameters, diagnostic instruments and clinical course. The treatment regimen comprised surgical source control (with/without programmed lavage), abdominal closure and relaparotomy on demand, broad spectrum antibiotic therapy and intensive care support. RESULTS: The APACHE II-Score (20 CAP vs. 22 PP, p = 0.012), MPI-Score (27 CAP vs. 30 PP, p = 0.001) and the number of lavages differed significantly. Positive phyiscal testing and signs of sepsis (abdominal pain (81.6% PP vs. CAP 97.1%, p = 0.03), rebound tenderness (21.9% vs. 35.8%, p = 0.02), fever (35.1% vs. 51.8%, p = 0.03)) occurred significantly less often in the PP patients than in the CAP group. Conventional radiography (66.2%) and ultrasonography (44.3%) had a lower diagnostic sensitivity than did abdominal CT-scan (97.2%). Mortality was higher in the PP group but did not differ significantly between the two groups (47.4% PP vs. 35.8% CAP, p = 0.06). CONCLUSION: The value of physical tests and laboratory parameters in diagnosing abdominal sepsis is limited. CT-scanning revealed the highest diagnostic accuracy. A treatment regimen of early relaprotomy appears to be the most reasonable strategy for as early discovery of postoperative peritonitis as possible.

[Does the third staple line of a new endostapler offer an advantage?]. / Bringt die dritte Klammernahtreihe eines neuen Endostaplers einen medizinischen Vorteil?

BACKGROUND: In laparoscopic colon surgery, endostaplers generate 2 parallel rows of staples. The aim of this paper is to analyse whether the introduction of a new endostapler generating a third row of staples influences the rate of anastomotic leakage and bleedings. METHOD: 362 patients of the Department of Surgery, University Clinic of Schleswig-Holstein, Campus Lübeck, were included in this study. All patients underwent colon resection with performance of double-stapling anastomosis. In Group I (n = 148; 7 / 2004 to 12 / 2005), the Endopath TSB 45 endostapler (2 rows of staples) was used, whereas in Group II (n = 214; 7 / 2006 to 12 / 2007), the Echelon60 EC60 stapler (3 rows of staples) was used. All further operational steps were identical for both groups. Target parameters were the postoperative anastomotic leakage and anastomotic bleeding rates. RESULTS: Between July 2004 and December 2005, the number of anastomotic leaks (Stapler Endopath, TSB 45) was n = 4 (2.7 %), for the second period (Stapler Echelon60 EC60), it was n = 9 (3.7 %) (not significant). Using the Endopath TSB 45 stapler, the number of anastomotic bleedings was n = 12 (8.1 %), and for the Echelon60 EC60 stapler, it was n = 8 (3.7 %) (p = 0.074; not significant). Within the 18-month period between July 2006 and December 2007, the number of endoscopic colon operations (n = 214) rose by 44.6 % compared to the 18-month period between July 2004 and December 2005 (n = 148). CONCLUSION: The application of the advanced Echelon endostapler has no impact on the number of anastomotic leaks, and reduces the number of anastomotic bleedings slightly but not significantly. The increased number of endoscopic procedures in the second period results both from the growing number of indications for the application of endoscopic techniques and the positive findings of recent studies carried out by our own and other working groups.

Proteomic identification of p53-dependent protein phosphorylation.

The p53 tumor suppressor regulates transcription of target genes. We have previously analysed the p53-dependent proteome and identified novel protein targets. Here we have examined p53-dependent phosphorylation using two-dimensional gel electrophoresis and staining with the fluorescent phosphoprotein dye Pro-Q Diamond. We report that p53 induces phosphorylation of a subset of proteins including Nm23, DJ-1, ANXA1 and PrxII. Our identification of p53-dependent phosphorylation of specific target proteins reveals new aspects of the p53-dependent cellular response and suggests that such posttranslational modifications may contribute to p53-mediated tumor suppression.

[Progress in diagnostics of anorectal disorders. Part II: radiology]. / Fortschritte in der Diagnostik anorektaler Erkrankungen. Teil II: Radiologische Verfahren.

Diagnostics and therapy of anorectal disorders remain a surgical question. In close cooperation between different departments (radiology and gastroenterology, urology and gynecology, dermatology and psychology), the role of radiologic imaging is of growing importance. Exact knowledge of functional anatomy and precise clinical examination constitute the basis of the according therapeutic strategies. In this context radiology has contributed decisively. Developments in imaging techniques, e.g. dynamic MRI, highly contributed to better understanding of complex functional pelvic floor disorders. The combination of nanotechnology and high-resolution imaging allows precise staging, especially in rectal cancer. Furthermore, advances in virtual colonoscopy could lead to widely acceptable and patient-friendly screening for colorectal malignancies.

[Progress in diagnostics of anorectal disorders. Part I: anatomic background and clinical and neurologic procedures]. / Fortschritte in der Diagnostik anorektaler Erkrankungen. Teil I: Anatomische Grundlagen sowie klinische und neurologische Verfahren.

Diagnostics and therapy of anorectal disorders are still questions of surgery. Exact knowledge of functional anatomy and precise clinical examination constitute the basis for the resulting therapeutic strategies. Three-dimensional endosonography and technical advances in flexible endoscopy using high-resolution chromoendoscopy and narrow-band imaging enable exact staging and diagnosis, even of malignancies in earliest stages. Furthermore new in-vivo staining methods combined with high-resolution imaging facilitate the discrimination of inflammatory and neoplastic lesions, which often lead to diagnostic difficulties in chronic inflammatory bowel disease. Developments in neurologic testing, including surface electromyography and sacral nerve stimulation, complement the diagnostic armamentarium.

Undifferentiated pelvic adenocarcinomas: diagnostic potential of protein profiling and multivariate analysis.

BACKGROUND AND AIMS: Despite improved techniques, the determination of tumor origin in poorly differentiated adenocarcinomas still remains a challenge for the pathologist. Here we report the use of protein profiling combined with principal component analysis to improve diagnostic decision-making in tumor samples, in which standard pathologic investigations cannot present reliable results. MATERIALS AND METHODS: A poorly differentiated adenocarcinoma of unknown origin located in the pelvis, infiltrating the sigmoid colon as well as the ovary, served as a model to evaluate our proteomic approach. Firstly, we characterized the protein expression profiles from eight advanced colon and seven ovarian adenocarcinomas using two-dimensional gel electrophoresis (2-DE). Qualitative and quantitative patterns were recorded and compared to the tumor of unknown origin. Based on these protein profiles, match sets from the different tumors were created. Finally, a multivariate principal component analysis was applied to the entire 2-DE data to disclose differences in protein patterns between the different tumors. RESULTS: Over 89% of the unknown tumor sample spots could be matched with the colon standard gel, whereas only 63% of the spots could be matched with the ovarian standard. In addition, principal component analysis impressively displayed the clustering of the unknown case within the colon cancer samples, whereas this case did not cluster at all within the group of ovarian adenocarcinomas. CONCLUSION: These results show that 2-DE protein expression profiling combined with principal component analysis is a sensitive method for diagnosing undifferentiated adenocarcinomas of unknown origin. The described approach can contribute greatly to diagnostic decision-making and, with further technical improvements and a higher throughput, become a powerful tool in the armentarium of the pathologist.

Modelling mass transfer and agitator performance in multiturbine fermentors.

A methodology for mathematically analyzing agitator performance and mass transfer in large multiturbine production fermentors is presented. The application of this approach provides a method for determining axial dissolved oxygen profiles under conditions of known mass transfer rates as a function of agitation-aeration characteristics. A stagewise approach is used which divides the fermentor into a series of mixing cells. This allows for each turbine and mixing cell to be individually optimized. The model also permits the determination of the mass transfer coefficient for each turbine based upon limited dissolved oxygen data. The primary limitation of this approach rests in the limited data and correlations available for multiturbine systems. The structure of the modelling approach can serve as a basis for testing single turbine correlations and adapting them to multiturbine systems. The step-by-step details of the mathematical analysis are presented and interpreted. A series of computer simulations demonstrate the effect of typical fermentor operating variables on the axial dissolved oxygen profile. Further simulations demonstrate the effect of modifying agitator blade numbers on the dissolved oxygen profile and agitator power requirement.

Effects of phosphate, glucose, and ammonium on cell growth and lincomycin production by Streptomyces lincolnensis in chemically defined media.

Cell growth and lincomycin production were measured in batch cultures of Streptomyces lincolnensis in chemically defined media. In these fermentations the specific rate of antibiotic production was maximal during growth and always declined at the end of the growth phase. It was found that both phosphate and ammonium salts, while required for cell growth, had negative effects on antibiotic production. By increasing the concentration of magnesium sulfate, it was possible to increase both the production rates and final titers of lincomycin. The mechanism for this effect was found to be the reduction of soluble phosphate in the medium through the precipitation of ammonium magnesium phosphate. Lincomycin production rates were not inhibited by glucose at concentrations of up to 30 g/L.

Sterilization of oils: Data to support the use of a continuous point-of-use sterilizer.

The continuous slow feed of animal and vegetable oils is frequently found to be an economically attractive method for maintaining antibiotic fermentations at a highly productive rate. The sterilization of oil feeds can present a major problem in the production plant. In this article, we present data and methodology on the kinetics of the thermal sterilization of No. 2 lard oil and soybean oil. It was also determined that dry heat sterilization condition could occur if dry spores were added to dry oil. This condition could only be partially alleviated by the addition of water to the oil. The theory and design of a small tubular coil continuous sterilizer for sterilizing oils at the point of use is also presented. This type of sterilizer is economical and versatile and simplifies control and instrument requirements. It provides a realistic alternative to the use of sterile feed tanks and sterile headers.

Analysis of double-substrate limited growth.

Mathematical models which relate the growth rate of a microorganism to a single limiting substrate concentration have long been established. In recent years, it has become apparent that, under certain conditions, the growth rate of an organism may be simultaneously limited by two or more substrates. Mathematical models of double-substrate limitation fall into two categories: interactive and noninteractive models. A discussion of both types of models is presented in both conceptual and mathematical terms. An analogous case of an enzyme which requires two different substrates to produce a single product is presented. This enzyme analog indicates that both types of double-substrate limitation models appear to be feasible under certain conditions. Based upon stoichiometry and specific growth rate-substrate concentration contour plots, a method for determining the operational conditions which will lead to double-substrate limitation is presented.