[Perioperative fluid management]. / Perioperatives Volumenmanagement.

An appropriate perioperative infusion management is pivotal for the perioperative outcome of the patient. Optimization of the perioperative fluid treatment often results in enhanced postoperative outcome, reduced perioperative complications and shortened hospitalization. Hypovolemia as well as hypervolemia can lead to an increased rate of perioperative complications. The main goal is to maintain perioperative euvolemia by goal-directed therapy (GDT), a combination of fluid management and inotropic medication, to optimize perfusion conditions in the perioperative period; however, perioperative fluid management should also include the preoperative and postoperative periods. This encompasses the preoperative administration of carbohydrate-rich drinks up to 2 h before surgery. In the postoperative period, patients should be encouraged to start per os hydration early and excessive i.v. fluid administration should be avoided. Implementation of a comprehensive multimodal, goal-directed fluid management within an enhanced recovery after surgery (ERAS) protocol is efficient but the exact status of indovodual items remains unclear at present.

Evaluation of the MDACC clinical classification system for pancreatic cancer patients in an European multicenter cohort.

BACKGROUND: The MDACC group recommends to extend the current borderline classification for pancreatic cancer into three groups: type A patients with resectable/borderline tumor anatomy, type B with resectable/borderline resectable tumor anatomy and clinical findings suspicious for extrapancreatic disease and type C with borderline resectable and marginal performance status/severe pre-existing comorbidity profile or age>80. This study intents to evaluate the proposed borderline classification system in a multicenter patient cohort without neoadjuvant treatment. METHODS: Evaluation was based on a multicenter database of pancreatic cancer patients undergoing surgery from 2005 to 2016 (n = 1020). Complications were classified based on the Clavien-Dindo classification. χ2-test, Kaplan-Meier estimator and Cox regression hazard model were used for statistical analysis. RESULTS: Most patients (55.1%) were assigned as type A patients, followed by type C (35.8%) and type B patients (9.1%). Neither the complication rate, nor the mortality rate revealed a correlation to any subgroup. Type B patients had a significant worse progression free (p < 0.001) and overall survival (p = 0.005). Type B classification was identified as an independent prognostic marker for progression free survival (p = 0.005, HR 1.47). CONCLUSION: The evaluation of the proposed classification in a cohort without neoadjuvant treatment did not justify an additional medical borderline subgroup. A new subgroup based on prognostic borderline patients might be the main target group for neoadjuvant protocols in future.

Blood fibrinogen levels discriminate low- and high-risk intraductal papillary mucinous neoplasms (IPMNs).

BACKROUND: The risk assessment of intraductal papillary mucinous neoplasms (IPMN) to either guide patients to surgical resection or watchful waiting is still under debate. Additional markers to better separate low and high-risk lesions would improve patient selection. METHODS: Patients who underwent pancreatic resections for IPMNs between January 2008 and December 2012 with available blood samples were selected and retrospectively assessed. Data on cyst characteristics such as cyst size, duct relation and main-duct dilatation were collected and plasma fibrinogen levels were measured. RESULTS: A total of 73 patients fulfilled the inclusion criteria by pancreatic resection for pathologically confirmed IPMN and available blood sample. Histologically, IPMNs were classified as low-grade and borderline in 52 (71.2%, group 1) and as high-grade and invasive in 21 (28.8%, group 2) of all cases. Fibrinogen levels showed significant differences between the two groups (group 1: mean 3.62 g/L (SD ± 1.14); group 2: mean 4.49 g/L (SD ± 1.57); p = 0.027). A ROC-curve analysis calculated cut-off value of 4.71 g/L separated groups 1 and 2 (p = 0.008). Fibrinogen levels remained as the only significant factor in multivariable analysis, cyst size and duct relation were not significant. CONCLUSION: Blood fibrinogen differed between low and high risk IPMNs and therefore, the use of fibrinogen as an additional discriminator in the pre-operative risk assessment of IPMNs should be further evaluated.

HRG/HER2/HER3 signaling promotes AhR-mediated Memo-1 expression and migration in colorectal cancer.

Colorectal cancer (CRC) is a complex disease with still unsatisfactory prognosis even in western societies, although substantial progress has been made in pre-screening programs, surgical techniques and targeted therapy options. Mediator of motility-1 (Memo-1) was previously recognized as an important effector of cell migration downstream of receptor tyrosine kinase signaling in breast cancer. This study identified Memo-1 as frequently overexpressed in CRC and established a close link between extracellular HER2 activation, AhR/ARNT transcriptional activity and Memo-1 expression. Dissection of the hMemo-1 gene promoter using reporter assays and chromatin IP techniques revealed recruitment of Aryl hydrocarbon receptor (AhR)/Aryl hydrocarbon receptor nuclear-translocator (ARNT) complex, which positively influenced Memo-1 expression in cancer cells. We found that Memo-1 depletion negatively influenced the cellular actin network and that its expression is required for HER2-mediated cell migration and invasion. Moreover, analyses of Memo-1 expression in primary CRC revealed correlation with clinical parameters that point to Memo-1 as a new prognostic factor of aggressive disease in CRC patients. Altogether, these observations demonstrate that Memo-1 is an important downstream regulator of HER2-driven CRC cell migration and invasion through connecting extracellular signals from membrane to the cytoskeletal actin network.

[Pancreatic anastomosis in operative treatment of chronic pancreatitis]. / Pankreasanastomosen bei operativer Versorgung der chronischen Pankreatitis.

Chronic pancreatitis (CP) is an irreversible, inflammatory process, which is characterized by progressive fibrosis of the pancreas and leads to abdominal pain, endocrine and exocrine insufficiency. Surgical therapy is indicated by the absence of pain relief and local complications. The target of the surgical approach is to relieve the pancreatic and bile ducts and resection of the fibrotic and calcified parenchyma. Drainage procedures, such as the Partington-Rochelle method, are used in patients with isolated congestion of the pancreatic duct without further organ complications, such as inflammatory processes of the pancreatic head; however, patients with CP often have an inflammatory swelling of the pancreatic head. In this case classical pancreatoduodenectomy (PD) or organ-sparing duodenum-preserving pancreatic head resection (DPPHR) with its various techniques (e.g. Beger, Frey, Bern and V­shape) can be applied. Due to similar long-term results PD should be carried out in cases of suspicion or detection of malignancies and DPPHR for treatment of CP.

Non-trauma Emergency Pancreatoduodenectomies: A Single-Center Retrospective Analysis.

OBJECTIVE: To retrospectively assess the frequency and indications for emergency pancreatoduodenctomies in a tertiary referral center. METHODS: Pancreatoduodenectomies between January 2005 and January 2014 were retrospectively assessed for emergency indications defined as surgery following unplanned hospital admission in less than 24 h. Data on indications and on the intraoperative as well as the post-operative course were collected. RESULTS: Out of 583 pancreatoduodenectomies during the interval, a total of 10 (1.7 %) were performed as an emergency surgery. Indications included uncontrollable bleeding, duodenal and proximal jejunal perforations, and endoscopic retrograde cholangiopancreatography-related complications. Three of the 10 (30.0 %) patients died during the hospital course. In one patient, an intraoperative mass transfusion was necessary. No intraoperative death occurred. All but one patient were American Society of Anesthesiologists class three or higher. In two cases, the pancreatic remnant was left without anastomosis for second-stage pancreatojejunostomy. Median operation time was 326.5 min (SD 100.3 min). Hospital stay of the surviving patients was prolonged (median 43.0 days; SD 24.0 days). CONCLUSION: Emergency pancreatoduodenectomies are non-frequent, have a diverse range of indications and serve as an ultima ratio to cope with severe injuries and complications around the pancreatic head area.

[Perioperative CRP quantification for appendectomy: Clinically useful or a waste of money?]. / Perioperative CRP-Bestimmung bei der Appendektomie : Klinischer Nutzen oder Geldverschwendung?

BACKGROUND: Appendectomy is the most frequently performed non-elective surgical procedure in general surgery. Despite the questionable benefit, inflammatory markers, such as leukocyte count and C-related protein (CRP) are often determined before and after the surgical procedure. Clinicians are not infrequently confronted with the question whether a patient can be discharged despite an increase in inflammatory laboratory parameters. OBJECTIVES: The aim of the current study was to retrospectively evaluate the clinical course of patients after appendectomy and the correlation with inflammatory laboratory findings. MATERIAL AND METHODS: A total of 969 patients underwent a surgical procedure due to clinically suspected acute appendicitis. All clinical, laboratory and histopathological data were obtained from the patient records and a quality control database. Laboratory results were correlated with clinical and histopathological data (e.g. t-test, χ (2)-test, regression analysis and ROC curves). RESULTS: In patients without acute appendicitis operative trauma caused an increase in CRP up to a median of 31 mg/dl on the first postoperative day and up to 47 mg/dl on postoperative day 2. The overall morbidity was 6.2%. The strongest predictive parameter for complications was a CRP of more than 108 mg/l on the first postoperative day with an odds ratio of 16.6 (96% CI 6.4/42.8, p < 0.001, specificity 88% and sensitivity 69%). Patients with CRP values below the threshold suffered from complications in 1.1 % of cases in contrast to patients above the threshold in 16.8% of cases (p < 0.001). CONCLUSION: A moderate postoperative elevation of CRP values is not a general contraindication for discharge; however, postoperative determination of CRP serum values after appendectomy might be an effective predictor for complications and should therefore be measured in the clinical routine.

[Certification in surgical oncology : Relevance for the choice of hospital for treatment]. / Zertifizierungen in der onkologischen Chirurgie : Bedeutung für die Wahl der Behandlungsstätte.

BACKGROUND: Increasing requirements in quality management are leading to a rising number of certifications in the healthcare system. The certification of an institution should lead to this institution being chosen for treatment. OBJECTIVES: This study was carried out to evaluate this statement for surgical oncology. MATERIAL AND METHODS: A questionnaire was developed with which 100 patients, 40 general practitioners and 20 heads of oncology departments were surveyed with respect to the reasons for choosing a specific institution for oncological surgery. RESULTS: Of the patients 40 % followed the recommendations of their general practitioner while only 6 % considered certification as being relevant although 50 % believed certification was most important for their practitioner when choosing the surgical institution. Personal acquaintances were paramount for the choice of institution for 38.1 % of private practitioners, whereas none of the interviewees claimed that certification had had an influence. Of the heads of department 53.8 % answered that certification was irrelevant when referring a patient to another hospital. CONCLUSION: Despite widespread certification of surgical departments, patients, practitioners and heads of departments still rely on recommendations or personal experiences when choosing an institution for surgical oncology. The return rate of 16.4 % (41 received out of 250 questionnaires sent out) for practitioners shows the lack of interest in certification although 50 % of patients believed that the referral was based on this. Certification in surgical oncology has not yet been able to achieve the desired position as a strong quality factor showing that certification has not fulfilled one of the major goals and only plays an insignificant role in patient recruitment via referrals.

Expression of cancer testis antigens CT10 (MAGE-C2) and GAGE in gastrointestinal stromal tumors.

INTRODUCTION: Expression of cancer testis antigens (CTAs) has been associated with prognosis in gastrointestinal stromal tumors (GIST) and other malignancies. CTAs are currently being investigated for cancer immunotherapy. MATERIALS AND METHODS: We analyzed two CTAs, CT10/MAGE-C2 and GAGE, in 51 GIST by immunohistochemistry and correlated it with established histopathological criteria for malignancy. RESULTS: GAGE expression was found in 6/51 (12%) patients, whereas 5/51 (10%) patients expressed CT10/MAGE-C2. 7/51(14%) patients expressed at least one of both CTAs, in 4/51 (8%) patients both CTAs were positive. High-grade GIST are more likely to express GAGE (p = 0.002) and CT10/MAGE-C2 (p = 0.007) compared to less aggressive tumors. All patients with GAGE or CT10/MAGE-C2 expression had moderate- or high-risk of recurrence according to the established risk criteria. The presence of GAGE correlates with mitotic rate (p = 0.001) and tumor size (p = 0.02), but not with tumor location (p = 0.60). CT10/MAGE-C2 also significantly correlates with mitotic rate (p = 0.004) and tumor size (p = 0.002), whereas no correlation could be found with tumor location (p = 0.36). DISCUSSION: CT10/MAGE-C2 and GAGE should be explored together with other previously described CTAs as targets for immunotherapy of GIST in cases, which are refractory to conventional therapy.

Pancreatic cancer.

UNLABELLED: In recent years, it has become clear that the current standard therapeutic options for pancreatic cancer are not adequate and still do not meet the criteria to cure patients suffering from this lethal disease. Although research over the past decade has shown very interesting and promising new therapeutic options for these patients, only minor clinical success was achieved. Therefore, there is still an urgent need for new approaches that deal with early detection and new therapeutic options in pancreatic cancer. To provide optimal care for patients with pancreatic cancer, we need to understand better its complex molecular biology and thus to identify new target molecules that promote the proliferation and resistance to chemotherapy of pancreatic cancer cells. In spite of significant progress in curing cancers with chemotherapy, pancreatic cancer remains one of the most resistant solid tumour cancers and many studies suggest that drug-resistant cancer cells are the most aggressive with the highest relapse and metastatic rates. In this context, activated Notch signalling is strongly linked with chemoresistance and therefore reflects a rational new target to circumvent resistance to chemotherapy in pancreatic cancer. Here, we have focused our discussion on the latest research, current therapy options and recently identified target molecules such as Notch-2 and the heparin-binding growth factor midkine, which exhibit a wide range of cancer-relevant functions and therefore provide attractive new therapeutic target molecules, in terms of pancreatic cancer and other cancers also. LINKED ARTICLES: This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4.

Presence of the coxsackievirus and adenovirus receptor (CAR) in human neoplasms: a multitumour array analysis.

BACKGROUND: The Coxsackie- and Adenovirus Receptor (CAR) has been assigned two crucial attributes in carcinomas: (a) involvement in the regulation of growth and dissemination and (b) binding for potentially therapeutic adenoviruses. However, data on CAR expression in cancer types are conflicting and several entities have not been analysed to date. METHODS: The expression of CAR was assessed by immunohistochemical staining of tissue microarrays (TMA) containing 3714 specimens derived from 100 malignancies and from 273 normal control tissues. RESULTS: The expression of CAR was detected in all normal organs, except in the brain. Expression levels, however, displayed a broad range from being barely detectable (for example, in the thymus) to high abundance expression (for example, in the liver and gastric mucosa). In malignancies, a high degree of variability was notable also, ranging from significantly elevated CAR expression (for example, in early stages of malignant transformation and several tumours of the female reproductive system) to decreased CAR expression (for example, in colon and prostate cancer types). CONCLUSION: Our results provide a comprehensive insight into CAR expression in neoplasms and indicate that CAR may offer a valuable target for adenovirus-based therapy in a subset of carcinomas. Furthermore, these data suggest that CAR may contribute to carcinogenesis in an entity-dependent manner.

Altered PTEN function caused by deletion or gene disruption is associated with poor prognosis in rectal but not in colon cancer.

Colorectal cancer is the third most common malignancy worldwide. Anti-epidermal growth factor receptor (EGFR)-targeted therapy shows clinical evidence in this malignancy and improves outcome. The tumor suppressor gene phosphatase and tensin homologue (PTEN) is considered a potential predictor of nonresponse to anti-EGFR agents. The purpose of this study was to assess whether associations between PTEN alterations (PTEN gene deletion or PTEN gene disruption) and clinical outcome could be caused by a prognostic (and not predictive) effect of PTEN inactivation. Therefore, we analyzed 404 colorectal cancers not previously treated with anti-EGFR drugs in a tissue microarray format. PTEN deletion and PTEN gene rearrangements were analyzed by fluorescence in situ hybridization. Heterogeneity analysis of all available large tissue sections was performed in 6 cases with genomic PTEN alteration. Twenty-seven (8.8%) of 307 analyzable colorectal cancer spots showed genomic PTEN alterations including 24 hemizygous and 1 homozygous deletion as well as 2 PTEN gene disruptions. Genomic PTEN alterations were associated with reduced patient survival in rectal cancer in univariate and multivariate analyses (P = .012; hazard ratio, 2.675; 95% confidence interval, 1.242-5.759) but not in colon cancer. Large-section evaluation revealed a homogeneous distribution pattern in all 4 analyzed cases with PTEN deletion and in both cases with a PTEN gene disruption. In conclusion, genomic PTEN gene alterations caused by deletion or gene disruption characterize a fraction of rectal cancers with particularly poor outcome.

VEGFR-2, CXCR-2 and PAR-1 germline polymorphisms as predictors of survival in pancreatic carcinoma.

BACKGROUND: Hypoxic environment of pancreatic cancer (PC) implicates high vascular in-growth, which may be influenced by angiogenesis-related germline polymorphisms. Our purpose was to evaluate polymorphisms of vascular endothelial growth factor receptor 2 (VEGFR-2), CXC chemokine receptor 2 (CXCR-2), proteinase-activated receptor 1 (PAR-1) and endostatin (ES) as prognostic markers for disease-free (DFS) and overall survival (OS) in PC. PATIENTS AND METHODS: Genotyping of 173 patients, surgically treated for PC between 2004 and 2011, was carried out by TaqMan(®) genotyping assays or polymerase chain reaction. Chi-square test, Kaplan-Meier estimator and Cox regression hazard model were used to assess the prognostic value of selected polymorphisms. RESULTS: VEGFR-2 -906 T/T and PAR-1 -506 Del/Del genotypes predicted longer DFS (P = 0.003, P = 0.014) and OS (VEGFR-2 -906, P = 0.011). CXCR-2 +1208 T/T genotype was a negative predictor for DFS (P < 0.0001). Combined analysis for DFS and OS indicated that patients with the fewest number of favorable genotypes simultaneously present (VEGFR-2 -906 T/T, CXCR-2 +1208 C/T or C/C and PAR-1 -506 Del/Del) were at the highest risk for recurrence or death (P < 0.0001). CONCLUSION: VEGFR-2 -906 C>T, CXCR-2 +1208 C>T and PAR-1 -506 Ins/Del polymorphisms are potential predictors for survival in PC.

Surgical strategies in patients with advanced hilar cholangiocarcinoma (Klatskin tumor).

BACKGROUND: Surgical resection represents the only potentially curative treatment for hilar cholangicarcinoma. Because of the aggressive nature and the absence of effective adjuvant therapy treatment remains still a challenge. DISCUSSION: This manuscript reviews management of hilar cholangiocarcinoma with a focus on operative strategy.

Staging and outcome depending on surgical treatment in adenocarcinomas of the oesophagogastric junction.

BACKGROUND: Owing to controversial staging and classification of adenocarcinoma of the oesophago-gastric junction (AOG) before surgery, the choice of appropriate surgical approach remains problematic. In a retrospective study, preoperative staging of AOG and the impact of preoperative misclassification on outcome were analysed. METHODS: Data from patients with AOG were analysed from a prospectively collected database with regard to surgical treatment, preoperative and postoperative staging, and outcome. RESULTS: One-hundred and thirty patients with Siewert types I and II AOG who did not have neoadjuvant treatment were included in the study: 41 patients with an AOG type I who underwent oesophagectomy, 51 patients with an AOG staged before surgery as type I who underwent oesophagectomy but in whom the final histology showed a type II tumour, and 38 patients whose tumours were staged as AOG type II before and after operation who underwent gastrectomy. Among patients who had an oesophagectomy, lymph node metastases (P = 0.022), tumour relapse (P = 0.009) and recurrent distant metastases (P = 0.028) were significantly more frequent in patients with AOG type II; those with AOG type II had shorter overall survival than those with type I tumours (P = 0.024). Among those with AOG type II, recurrence-free survival was significantly shorter after oesophagectomy compared with extended gastrectomy (P = 0.019). Thoracoabdominal oesophagectomy had a favourable influence on outcome compared with the transhiatal approach. CONCLUSION: Accurate preoperative staging of AOG and appropriate surgical therapy are crucial for outcome. AOG type II is a more aggressive tumour with higher recurrence rates than AOG type I. These patients therefore benefit from more radical surgical treatment.

Arterial en bloc resection for pancreatic carcinoma.

BACKGROUND: Surgery for locally advanced pancreatic cancer with arterial involvement of the hepatic artery, coeliac trunk and superior mesenteric artery (SMA) is highly controversial. In a retrospective review, the benefits and harms of arterial en bloc resection (AEBR) for pancreatic adenocarcinoma with arterial involvement were analysed. METHODS: Patients were divided into three groups: 29 patients who had pancreatic resection and AEBR (group 1), 449 who had pancreatic resection with no arterial resection or reconstruction (group 2), and 40 with unresectable tumours who underwent palliative bypass (group 3). RESULTS: Eighteen patients underwent reconstruction of the hepatic artery, eight of the coeliac trunk and three of the SMA. Additional reconstruction of portal vein was required in 15 patients and of adjacent visceral organs in 19. Perioperative morbidity and mortality rates were higher in group 1 than in group 2 (P = 0·031 and P = 0·037 respectively). Additional portal vein resection was an independent predictor of morbidity (P < 0·001). Median overall survival was similar for groups 1 and 2 (14·0 versus 15·8 months; P = 0·152), and lower for group 3 (7·5 months; P = 0·028 versus group 1). CONCLUSION: In selected patients AEBR can result in overall survival comparable to that obtained with standard resection and better than that after palliative bypass. Nevertheless, AEBR is associated with significantly higher morbidity and mortality rates, counterbalancing the overall gain in survival and limiting the overall oncological benefit.

Major liver resections for primary liver malignancies in the elderly.

PURPOSE: The aim of our prospective study was to assess the results of major hepatic resections for primary liver tumours in patients 75 years of age or older. METHODS: From 10/1999 to 04/2006, 23 patients with non-cirrhotic livers > or = 75 years presented to our department to undergo curative resection for primary liver malignancies. Data were collected prospectively. Patients were assigned to two groups. Group A included those with resectable tumours, while Group B was made up of those with unresectable lesions. RESULTS: Fourteen patients had intrahepatic cholangiocarcinoma while 9 had hepatocellular carcinoma. Comorbidities were present in every case. Morbidity and hospital mortality rates for group A patients were 25% and 8%, respectively. The corresponding rates for group B patients were 9% and 9%. The 1-, 2-, and 3-year cumulative group A survival was 71%, 51% and 26% for cholangiocarcinoma and 80%, 60% and 60% for hepatocellular carcinoma, respectively. The corresponding group B survival was 45%, 18% and 0%. CONCLUSION: Advanced age does not seem to negatively affect the outcome of liver resections for malignancies. Hepatic resections in patients 75 years of age or older may be carried out with relative safety as long as patients are appropriately selected.

COX-2 expression in highly aggressive thyroid malignancies - indication for a possible therapeutic option?

Both anaplastic thyroid carcinoma (ATC) and angiosarcoma of the thyroid (AST) are highly aggressive malignancies with very limited therapeutic options. Since selective inhibition of COX-2, for example, by celecoxib has been shown to suppress both tumour formation and progression, we investigated COX-2 protein expression in a series of ATC and AST (26 cases each) using immunohistochemistry. COX-2 expression was demonstrated in 13 ATC (50%) and 11 AST (42%); a strong COX-2 expression in more than 50% of vital tumour cells was found in 5 ATC and 5 AST, respectively. Although a recently performed phase II trial applying celecoxib failed overall to halt tumour progression in differentiated thyroid carcinoma, the two cases with partial or complete remission noted in this study were related to tumours with immunohistochemically proven strong COX-2 expression. The strong COX-2 expression observed in approximately 20% of our ATC and AST samples may thus indicate selective patients with a possible therapeutic option for an otherwise fatal disease.