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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA loads in patient specimens may act as a clinical outcome predictor in critically ill patients with coronavirus disease 2019 (COVID-19)., Methods: We evaluated the predictive value of viral RNA loads and courses in the blood compared with the upper and lower respiratory tract loads of critically ill COVID-19 patients. Daily specimen collection and viral RNA quantification by reverse transcription quantitative polymerase chain reaction were performed in all consecutive 170 COVID-19 patients between March 2020 and February 2021 during the entire intensive care unit (ICU) stay (4145 samples analyzed). Patients were grouped according to their 90-day outcome as survivors (n=100) or nonsurvivors (n=70)., Results: In nonsurvivors, blood SARS-CoV-2 RNA loads were significantly higher at the time of admission to the ICU ( P =.0009). Failure of blood RNA clearance was observed in 33/50 (66%) of the nonsurvivors compared with 12/64 (19%) survivors ( P <.0001). As determined by multivariate analysis, taking sociodemographic and clinical parameters into account, blood SARS-CoV-2 RNA load represents a valid and independent predictor of outcome in critically ill COVID-19 patients (odds ratio [OR; log 10 ], 0.23; 95% CI, 0.12-0.42; P <.0001), with a significantly higher effect for survival compared with respiratory tract SARS-CoV-2 RNA loads (OR [log 10 ], 0.75; 95% CI, 0.66-0.85; P <.0001). Blood RNA loads exceeding 2.51×103 SARS-CoV-2 RNA copies/mL were found to indicate a 50% probability of death. Consistently, 29/33 (88%) nonsurvivors with failure of virus clearance exceeded this cutoff value constantly., Conclusions: Blood SARS-CoV-2 load is an important independent outcome predictor and should be further evaluated for treatment allocation and patient monitoring., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

In this study, we directly compared coronavirus disease 2019 (COVID-19) patients hospitalized during the first (27 February-28 July 2020) and second (29 July-31 December 2020) wave of the pandemic at a large tertiary center in northern Germany. Patients who presented during the first ( n = 174) and second ( n = 331) wave did not differ in age (median [IQR], 59 years [46, 71] vs. 58 years [42, 73]; p = 0.82) or age-adjusted Charlson Comorbidity Index (median [IQR], 2 [1, 4] vs. 2 [0, 4]; p = 0.50). During the second wave, a higher proportion of patients were treated as outpatients (11% [ n = 20] vs. 20% [ n = 67]), fewer patients were admitted to the intensive care unit (43% [ n = 75] vs. 29% [ n = 96]), and duration of hospitalization was significantly shorter (median days [IQR], 14 [8, 34] vs. 11 [5, 19]; p < 0.001). However, in-hospital mortality was high throughout the pandemic and did not differ between the two periods (16% [ n = 27] vs. 16% [ n = 54]; p = 0.89). While novel treatment strategies and increased knowledge about the clinical management of COVID-19 may have resulted in a less severe disease course in some patients, in-hospital mortality remained unaltered at a high level. These findings highlight the unabated need for efforts to hamper severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) transmission, to increase vaccination coverage, and to develop novel treatment strategies to prevent mortality and decrease morbidity.

Background: Resection margin status and lymph node (LN) involvement are known prognostic factors for patients who undergo pancreatoduodenectomy for pancreatic ductal adenocarcinoma (PDAC). This study aimed to compare overall survival (OS) and disease-free survival (DFS) by resection margin status in patients with PDAC and LN involvement., Methods: A retrospective international multicentric study was performed including four Western centers. Multivariable Cox analysis was performed to identify prognostic factors of OS and DFS. Median OS and DFS were calculated using Kaplan-Meier curves and compared using log-rank tests., Results: A cohort of 814 PDAC patients with pancreatoduodenectomy were analyzed. A total of 651 patients had LN involvement (80%). On multivariable analysis R1 resection was not an independent factor of worse OS and DFS in patients with LN involvement (HR 1.1, p = 0.565; HR 1.2, p = 0.174). Only tumor size, grade, and adjuvant chemotherapy were associated with OS and DFS. Median OS and DFS were similar between patients with R0 and R1 resections (23 vs. 20 months, p = 0.196; 15 vs. 14 months, p = 0.080)., Conclusion: Resection status was not identified as predictor of OS or DFS in PDAC patients with LN involvement. Extensive surgery to achieve R0 resection in such patients might not influence the disease course., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Outbreaks of infectious diseases pose particular challenges for hospitals and intensive care units., Objectives: Typical infectiological scenarios and their significance for modern intensive care medicine are presented., Materials and Methods: Selected pathogens/infectious diseases that have significantly strained the resources of intensive care units are described., Results: Intensive medical care is necessary in severe cases of many infectious diseases. In the context of epidemics/pandemics, many critically ill patients have to be admitted within a short time. Examples are the 2009 H1N1 influenza pandemic, the 2011 enterohemorrhagic Escherichia coli (EHEC) outbreak in northern Germany, the 2014/2015 Ebola fever outbreak and the 2020 coronavirus disease 19 (COVID-19) pandemic. Multidisciplinary teams, protocol development, adequate staffing, and training are required to achieve optimal treatment outcomes, including prevention of healthcare worker infections., Conclusions: Pandemics and epidemics are unique challenges for intensive care unit preparedness planning.

The aim of the present review was to analyze the current data on surgery of synchronous liver metastases in pancreatic ductal adenocarcinoma (PDAC) in curative intent. A review of the literature was carried out to identify the current international concepts regarding surgery of liver metastases of PDAC and, furthermore, we addressed the current challenges of resection of liver metastases of PDAC. Resection of liver metastases in PDAC may provide survival benefit without compromising safety and quality of life in a highly selected group of patients., Competing Interests: Conflicts of Interest: Authors declare no conflicts of interest for this article.

Development and progression of malignant tumors is in part characterized by the ability of a tumor cell to overcome cell-cell and cell-matrix adhesion and to disseminate in organs distinct from that in which they originated. This study was undertaken to analyze the clinical significance of the expression of the following cell-cell and cell-matrix adhesion molecules in pancreatic ductal adenocarcinomas (PDACs) and synchronous liver metastases: intercellular adhesion molecule 1 (ICAM-1), E-cadherin, periostin, and midkine (MK). ICAM-1, E-cadherin, periostin and MK expression was analyzed by immunohistochemistry on a tissue microarray containing 34 PDACs and 12 liver metastasis specimens. ICAM-1 expression was predominantly localized in the membranes of the cells and was found in weak to moderate intensities in PDACs and liver metastases. E-cadherin expression was absent in the majority of PDACs and corresponding liver metastases. The secreted proteins periostin and MK were expressed in various intensities in primary cancers and liver metastases. Statistical analysis demonstrated that the expression levels of the analyzed markers were neither significantly associated with metastasis in PDACs nor with clinical outcome of patients. Our study shows that the expression of the cell-cell and cell-matrix adhesion molecules ICAM-1, E-cadherin, periostin and MK was not significantly linked to metastatic disease in PDACs. Moreover, our study excludes the analyzed markers as prognostic markers in PDACs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The aim of this study is to investigate the impact of the circumferential resection margin (CRM) in esophageal cancer on survival and recurrence in patients without pretreatment., Background: Whereas the infiltration of the proximal or distal resection margin is associated with poor survival and higher recurrence, studies looking at the role of the circumferential resection margin on survival and local recurrence after esophagectomy are conflicting., Methods: Influence of CRM infiltration according to the College of American Pathologists (CAP) and Royal College of Pathologists (RCP) on long-term survival of 180 patients with resected pT3 tumors and without neoadjuvant therapy was analyzed., Results: A positive CRM was found in 76 (42.4%) patients according to RCP and 44 (24.4%) patients according to CAP. The CRM status had neither according to CAP nor according to RCP a significant impact on overall survival (P = 0.317 and 0.655, respectively), local recurrence (P = 0.716 and 0.900, respectively), or distant tumor relapse (P = 0.303 and 0.471, respectively).Lymphatic tumor spread found in 129 (71.7%) patients was an independent prognosticator (P = 0.002). In 137 (76.1%) patients who had a transthoracic esophagectomy a CRM infiltration was significantly lower according to CAP compared with 43 (23.9%) patients who had a transhiatal esophagectomy (P = 0.026)., Conclusions: CRM was found to have no impact on survival and recurrence in esophageal cancer. Therefore, the possible impact of neoadjuvant pretreatment in locally advanced tumors should be considered with caution in terms of an improved resectability.

Background: The aim of this study was to establish a new preoperative staging classification and evaluate its comparability to the post-operative tumour stage, lymph node invasion and metastasis (TNM) classification. To date, adequate, preoperative staging in patients with oesophageal carcinoma (EC) is still missing but urgently needed. Systemic inflammation and disseminated tumour load have a pivotal role in recurrence and oncological outcome. To improve the clinical staging, we merged the Glasgow Prognostic Score (GPS) and disseminated tumour cells (DTC) into a new sufficient preoperative staging classification, the Hamburg-Glasgow classification (HGC)., Methods: In this prospective, single-centre study, 326 patients following curative oesophagectomy were included. From all patients preoperative bone marrow was aspirated from the iliac crest to detect DTCs by immunostaining with the pan-keratin antibody A45-B/B3. HGC was subdefined into four prognostic groups on the basis of C-reactive protein (CRP), albumin and DTC. The three prognostic groups of the GPS were supplemented by DTC detection status. Results were correlated with clinicopathological parameters and clinical outcome., Results: Increasing HGC significantly correlated with lymph node invasion (P=0.022), post-operative pathohistological TNM staging (P=0.001) and tumour recurrence (P=0.001). The four HGC prognostic groups displayed a gradual decrease in overall as well as disease-free survival (P<0.001, each). Hamburg-Glasgow classification was a strong, significant independent predictor of overall survival and disease-free survival (P<0.001, both) in multivariate analysis., Conclusions: Hamburg-Glasgow classification seems to be a promising preoperative additive staging classification for accurate and simple outcome stratification.

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., (Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

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.

Background: Post-pancreatic surgical morbidity is frequent but often manageable by less invasive means than re-operation. Yet, some complications can become hazardous and life threatening. Herein, the results of a completion pancreatectomy (CP) to cope with severe post-operative pancreatic fistulas (POPF) and bleeding complications after major pancreatic resections for suspected pancreatic malignancy are presented., Methods: CPs to treat severe post-pancreatic index-surgery complications between January 2002 and January 2012 were selected out of a prospective database. Indications for CP as well as perioperative data were prospectively collected and retrospectively assessed., Results: In 20 of 521 Kausch-Whipple Resections (3.8%), a CP was necessary to treat post-index surgery morbidity. Indications included insufficiency of the pancreaticojejunal anastomosis with resulting POPF in 14 (70.0%) patients, severe bleeding complications in 6 (30.0%) patients, and a severe portal vein thrombosis in 1 (5.0%) patient. In 7 (35.0%) of the 20 patients, the course was complicated by remnant pancreatitis. Eleven (55.0%) of the 20 patients died during the hospital stay. Median time to re-operation did not significantly differ between survivors and in-hospital deaths (10.0 vs. 8.0 days; p = 0.732). Median hospital stay of the surviving patients was 31.0 (range 10-113) days. Re-operations following CPs were necessary in 5 (55.6%) of the 9 patients who survived and in 9 (81.8%) out of 11 patients who died., Conclusions: Post-pancreatic resection complications can become hazardous and result in severely ill patients requiring maximum therapy. CP in these cases has a high mortality but serves as an ultima ratio to cope with deleterious complications.

Objective: The aim of this study is to evaluate the impact of upfront surgery without neoadjuvant pretreatment on survival in patients with clinically staged locally advanced esophageal carcinoma before the new era of neoadjuvant therapy regimes., Material and Methods: This is a retrospective analysis of prospectively collected data of patients with clinically advanced esophageal cancer (cT3) and without neoadjuvant treatment who underwent transthoracic esophagectomy (TTE) in curative intent between 1992 and 2009. Locally advanced esophageal cancer was defined based on presurgical computertomography, endoscopy, and endosonography findings as a tumor infiltrating the paraesophageal tissue or the adjacent structures, with or without lymph node affection., Results: Histological subtypes included 131 squamous cell carcinomas (SCC) and 81 adenocarcinomas (AC). Complete resection (R0) was achieved in 84.0% of all 212 patients. Thirty-day mortality rate was 7.1%. Final pathology revealed 50 patients (23.5%) with pT1 or pT2 carcinomas which were preoperatively overstaged. Median overall survival following TTE for SCC was 13.7 months (95% CI; 10.1-17.2 months) and 24.8 months (95% CI; 14.5-35.1 months) for AC, respectively (p = 0.007). The 5-year survival rates were 14% for SCC and 26% for AC, respectively. In median, 27 lymph nodes were resected. On multivariable analyses, histological type, tumor localization, tumor grading, and resection status remained independent factors influencing overall survival., Conclusion: Our results in the treatment of patients with locally advanced esophageal carcinoma undergoing primary TTE are comparable to the results reported for patients undergoing neoadjuvant chemo-radio-therapy followed by surgery in the pre-CROSS-study era. Histological subtypes show different survival rates and should therefore be separately examined in future trials.

Background and Objective: Cyclin D1 is an important regulator protein for the G1-S cell cycle phase transition. The aim of this trial was to evaluate the impact of the CCND1 polymorphism G870A and corresponding protein expression and CCND1 amplification on the survival of the patients., Methods: 425 patients with ductal pancreatic adenocarcinoma who underwent resection were included after histopathological confirmation. DNA was analyzed for Cyclin D1 polymorphisms, immunhistochemical examination and fluorescence in situ hybridization analysis of the tumor were performed., Results: Overall, the mean survival was 22.9 months (20.5-25.3). The survival in patients with Cyclin D1 G870A polymorphism Adenine/Adenine was 15.1 months (95% CI 11.3-18.9), 21.5 months (17.4-25.6) for Adenine/Guanine, and 29.4 months (95% CI 23.8-35.0) for Guanine/Guanine (P = 0.003). A shorter survival was associated with strong/moderate protein expression in immunohistochemistry (IHC) compared to weak/no expression (P = 0.028). Additionally, a significant coherency between unfavourable polymorphism (AA/AG) and increased protein expression was detected (P = 0.005)., Conclusions: A strong impact on survival of Cyclin D1 G870A polymorphism and the detected corresponding protein expression was found. The biological mechanism of CCND1 in carcinogenesis has not been fully examined; but at present Cyclin D1 seems to be an interesting biomarker for the prognosis of ductal adenocarcinoma., (© 2014 Wiley Periodicals, Inc.)

Knowledge about hereditary eye diseases has been substantially increased by means of genetic testing during the last decade. This has resulted in a new classification of a number of disease patterns, which are characterised by non-progressive restrictive disorders of the oculomotor system, formerly classified as "congenital fibrosis syndromes". Based on the results of genetic testing, these ocular motility disorders are now referred to as "congenital cranial dysinnervation disorders" (CCDDs). They are caused by an impaired innervation of extraocular muscles because of a dysgenesis of the nuclei of the affected cranial nerves in the brainstem and pons and not by primary fibrosis of the extraocular muscles. In this review, congenital fibrosis of the extraocular muscles (CFEOM), Duane syndrome, horizontal gaze palsy with progressive scoliosis, congenital ptosis and Moebius syndrome are presented and basic principles of intracellular transport mechanisms and kinesins are discussed., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To analyze survival differences between transthoracic esophagectomy (TTE) and limited transhiatal esophagectomy (THE) in clinically (cT3) and pathologically (pT3) staged advanced tumors without neoadjuvant treatment., Background: Debate exists whether in the type of resection in locally advanced cancer plays a role in prognosis and whether THE is a valuable alternative to TTE regarding oncological doctrine and overall survival., Methods: In a retrospective study of 2 high-volume centers, 468 patients with cT3NXM0 esophageal cancer, including 242 (51.7%) squamous cell carcinomas (SCCs) and 226 (48.3%) adenocarcinomas (ACs), were analyzed. A total of 341 (72.9%) TTE and 127 (27.1%) THE were performed. We used the propensity score matching to build comparable groups. Primary endpoint was the overall survival; secondary endpoints included resection status and lymph node yield., Results: TTE achieved a higher rate of R0 resections (86.2% vs 73.2%; P = 0.001) and a higher median lymph node yield (27.0 ± 12.4 vs 17.0 ± 6.4; P < 0.001) than THE. Thirty-day mortality rate was 6.6% (8/121) for TTE and 7.4% (9/121) for THE (P = 0.600). In the matched groups, TTE was beneficial for pT3 SCC (P = 0.004), pT3 AC (P = 0.029), cT3 SCC (P = 0.018), and cT3 AC (P = 0.028) patients. TTE was either beneficial in pN2 disease for cT3 AC + SCC or pT3 SCC but not for pT3 AC patients, without nodal stratification in pT3 and cT3 SCC node-positive patients. On multivariable analysis, TTE remained an independent factor for survival., Conclusions: Extended TTE achieved a higher rate of R0 resections, a higher lymph node yield, and resulted in a prolonged survival than THE in pT3, cT3, and node-positive patients.

Objectives: Development of a simple preoperative risk score to predict morbidity related to pancreatic surgery., Background: Pancreatic surgery is standardized with little technical diversity among institutions and unchanging morbidity and mortality rates in recent years. Preoperative identification of high-risk patients is potentially one of the rare avenues for improving the clinical course of patients undergoing pancreatic surgery., Methods: Using a prospectively collected multicenter database of patients undergoing pancreatic surgery (n=703), surgical complications were classified according to the Clavien-Dindo classification. A new scoring system for preoperative identification of high-risk patients that included only objective preoperatively assessable variables was developed using a multivariate regression model. Subsequently, this scoring system was prospectively validated from 2011 to 2013 (n=429) in a multicenter setting., Results: Eight independent preoperatively assessable variables were identified and included in the scoring system: systolic blood pressure, heart rate, hemoglobin level, albumin level, ASA (American Society of Anesthesiologists) score, surgical procedure, elective surgery or not, and disease of pancreatic origin or not. On the basis of 3 subgroups (low risk, intermediate risk, high risk), the proposed scoring system reached an accuracy of 75% for correctly predicting occurrence or nonoccurrence of major surgical complications in 80% of all analyzed patients within the validation cohort (c-statistic index=0.709, P<0.001, 95% confidence interval=0.657-0.760)., Conclusions: We present an easily applied scoring system with convincing accuracy for identifying low-risk and high-risk patients. In contrast to other systems, the score is exclusively based on objective preoperatively assessable characteristics and can be rapidly and easily calculated.

Pancreatic cancer patients often present in an already advanced state of disease and the therapeutic approach is an interdisciplinary challenge. Surgery is an integral part in a potentially curative setting, yet in such advanced disease surgery can reach its limits. The technical feasibility has to be weighted against potential harms and the oncological reasonableness. In locally advanced disease, limits of surgery could be pushed as evidence grew. A venous vascular tumor infiltration nowadays does not preclude patients from surgery, as venous resections can be safely performed and survival rates are not inferior to patients with standard resections. Multivisceral resections have an increased risk of morbidity and mortality, but can improve overall survival. The resection and reconstruction of tumor infiltrated arteries is technically feasible, but these procedures have a high rate of associated morbidity and mortality with an unclear oncological benefit and therefore are generally not recommended. This also holds true for intentional palliative R2-resections, which do not offer a survival benefit but decrease the quality of life and have higher morbidity and mortality rates than palliative bypass procedures. A synchronous resection of the primary tumor and intraabdominal metastases in an olgiometastatic disease only offers a questionable oncological benefit and the evidence for this approach is scarce. Therefore, surgery in a metastatic disease is generally not recommended and has to be discussed interdisciplinary on a highly individual basis.Key words: pancreatic cancer multivisceral resection staging.

Background: Surgery for early esophageal carcinoma has been challenged by less invasive endoscopic approaches. Selecting patients in need for surgical intervention according to their risk of lymphatic spread is mandatory., Objective: The aim of this study was to evaluate risk factors for lymphatic metastasis formation in T1b esophageal carcinomas., Methods: Histopathological specimens following surgical resection for T1b esophageal carcinomas were reevaluated for overall submucosal layer thickness, depth of submucosal tumor infiltration, tumor length as well as lymphatic and vascular infiltration. Depth of tumor infiltration to overall submucosal thickness was divided in thirds (SM1, SM2, and SM3) and factors influencing lymphatic metastasis formation were assessed., Results: A total of 67 patients with pT1b tumors were analyzed, including 36 adenocarcinomas (53.7 %) and 31 squamous cell carcinomas (46.3 %). Lymph node involvement was seen in 22.4 % (15/67) patients without significant differences between SM1 3/11 (27.3 %), SM2, 4/18 (22.2 %), and SM3 (8/38) (21.8 %) (p = 0.909) carcinomas. On binomial log-regression models, only lymphangioinvasion and tumor length >2 cm was significantly associated with lymph node involvement., Conclusion: As depth of submucosal tumor infiltration did not correlate with the formation of lymph node metastases and in regard of the risk of lymphatic spread in these cases, surgical resection is warranted in pT1b carcinomas.

Objective: The aim of this study was to assess the influence of lymphatic and vascular invasion on overall survival in patients with surgically resected non-small cell lung cancer (NSCLC) without lymph node and distant metastases., Methods: From January 1999 to December 2009, a total of 190 NSCLC patients with node-negative pT1-pT4 disease underwent radical resection with lymphadenectomy. Pathologic reports were reclassified to the TNM-7 version, and the influence of lymphatic and vascular invasion on overall survival was examined using Kaplan-Meier and adjusted Cox proportional hazards analyses., Results: Lymphatic invasion was present in 34 (17.9%) and vascular invasion in 28 (14.7%) of 190 cases. Lymphatic and vascular invasions were correlated with higher Union for International Cancer Control stages (P = .056 and P = .011, respectively) and poor differentiated tumors (P = .051 and P = .012, respectively). There was no difference between pT1a and pT1b tumors in the presence of lymphatic (P = .912) or vascular (P = .134) invasion. Survival analyses revealed lymphatic (P < .001) and vascular (P = .008) invasion as statistically significant for the entire study population. Multivariable Cox analysis adjusted for age, Union for International Cancer Control stage, and lymphatic and vascular invasion confirmed lymphatic, but not vascular, invasion as an independent prognostic factor (P < .001; hazard ratio, 3.002; 95% confidence interval, 1.780-5.061). Especially in early stages, lymphatic invasion was associated with poorer overall survival in pT1a (P < .001), pT1b (P = .019), and pT2a (P = .028) tumors., Conclusions: Lymphatic invasion represents an independent risk factor for node-negative NSCLC. Its implications on therapy decision making should be further evaluated, especially in early stages., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

The progress of non-small cell lung cancer (NSCLC) is dependent on sufficient angiogenesis. Thrombin induced activation of proteinase-activated receptor 1 (PAR-1) on platelets leads to platelet secretion and aggregation. This influences cell survival, apoptosis and angiogenesis by the release of VEGF and Endostatin (ES), a potent angiogenesis inhibitor. Interleukin-8 (IL-8) induces tumor angiogenesis independent of the VEGF pathway through the chemokine C-X-C motif receptor 2 (CXCR-2). Our purpose was to evaluate germline polymorphisms of these potential therapy targets as prognostic markers for disease free survival (DFS) and overall survival (OS) in surgically treated NSCLC patients. In total 209 Caucasian patients, treated between 1996 and 2011, were included in this study. Genomic DNA was extracted from peripheral blood leucocytes. Genotyping of CXCR-2 +1208 C > T and +785 C > T, PAR-1 -506 Ins/del and -14 Ivs A > T and ES +4349 G > A was performed by TaqMan(®) genotyping assays or by polymerase chain reaction (PCR) followed by capillary electrophoresis. Chi-square test, Kaplan-Meier estimator and cox regression hazard model were used to assess the prognostic value of selected polymorphisms. The PAR-1 -14 Ivs A/A genotype was associated with advanced tumor stages (p = 0.024) and, in univariate analysis, with shorter median OS in squamous cell lung carcinoma (SqCC, p = 0.035). The CXCR-2 + 1208T/T genotype was associated with aggressive tumor biology (p = 0.038), and shorter DFS and OS (p = 0.018, p = 0.021) in NSCLC and especially in SqCC a negative predictor for DFS and OS (p = 0.045, p = 0.041). Genotyping of the CXCR-2 +1208 C >T polymorphism could be a useful tool to identify high-risk SqCC subgroups., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background and Objective: E- and P-selectins expressed on the luminal surface of mesodermally derived endothelial cells play a crucial role in the formation of haematogenous metastases in a number of malignancies. As peritoneal mesothelial cells are also derived form the mesoderm, it was hypothesised that selectins are also of importance in peritoneal tumour spread., Methods: Immunohistochemistry was used to identify selectin expression on normal human peritoneum and isolated mesothelial cells. E- and P-selectin interactions with human pancreatic adenocarcinoma cells were investigated in dynamic flow assays and flow cytometry; the latter was also used to determine the main selectin ligands on pancreatic adenocarcinoma cell lines PaCa 5061, BxPC-3 and PaCa 5072, and selectin expression on human mesothelial cells. All cell lines were xenografted into the peritoneum of E- and P-selectin-deficient pfp/rag2 mice and selectin wild-type controls. Peritoneal carcinomatosis was quantified using MRI or a scoring system., Results: E- and P-selectin were constitutively expressed on human mesothelial and endothelial cells in the peritoneum. PaCa 5061 and BxPC-3 cells interacted with E- and P-selectins in dynamic flow assays and flow cytometry, with CA19-9 (Sialyl Lewis a) being the main E-selectin ligand. For xenografted PaCa 5061 and BxPC-3 cells, peritoneal metastasis was significantly reduced in E- and P-selectin double knockout mice compared with wild-type pfp/rag2 animals. In contrast, PaCa 5072 cells were almost devoid of selectin binding sites and no intraperitoneal tumour growth was observed., Conclusion: Interactions of tumour cells with peritoneal selectins play an important role in the peritoneal spread of pancreatic adenocarcinoma.

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.

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., (Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Purpose: VEGFR-2 gene displays several functional germline polymorphisms with impact on VEGFR-2 mediated angiogenesis. Our purpose was to evaluate VEGFR-2 polymorphisms as prognostic markers for tumor recurrence and overall survival (OS) in non-small-cell lung cancer (NSCLC)., Methods: In total, 209 Caucasian patients who had been surgically treated for NSCLC between 1996 and 2010 were included in this study. Genotyping of peripheral blood cells was performed by TaqMan® genotyping assays or polymerase chain reaction for five VEGFR-2 polymorphisms. Chi- square test, Kaplan-Meier estimator, and Cox regression hazard model were used to assess the prognostic value of VEGFR-2 polymorphisms., Results: VEGFR-2+4422 (AC)10-14 polymorphism was identified as a positive prognostic marker for time to metastasis (11/12 vs. 11/11 (AC) repeats: hazard ratio (HR), 0.28; 95% confidence interval (CI), 0.11-0.75; p=0.012) and OS (11/12 vs. 11/11 (AC) repeats: HR, 0.41; 95% CI, 0.21-0.82; p=0.012) in squamous cell carcinoma. For adenocarcinoma, VEGFR-2-906 C>T (C/T vs. CC: HR, 0.19; 95% CI, 0.43-0.82; p=0.027) and VEGFR-2-271 G>A (G/A vs. G/G: HR, 0.25; 95% CI, 0.07-0.86; p=0.027) predicted longer time to local recurrence and VEGFR-2-906 C>T was a predictor for better OS (T/T vs. C/C: HR, 0.28; 95% CI, 0.09-0.84; p=0.024)., Conclusions: VEGFR2 germline polymorphisms predict tumor recurrence and OS in NSCLC.

Due to the late onset of symptoms in pancreatic cancer, patients are often presented with an already advanced or metastatic state of disease. Only in a minority of patients is a tumor resection indicated, e.g. in general tumor encasement of major vessels, while the presence of metastatic disease excludes patients from curative-intended surgery. Limitations for pancreatic resections have been debated and re-thought after more experience has gained over time. This holds true for en-bloc vascular resections, total pancreatectomies, intentional R2 pancreatic resections and synchronous resection of liver metastases. These issues are addressed in this review.

Background: The aim of our study was to investigate the ability of the Seventh edition of the classification by the International Union Against Cancer (UICC) to identify patients at higher risk and to predict the overall survival in patients with esophageal carcinoma., Methods: Demographic and clinical data of 605 patients, who underwent esophagectomy for esophageal carcinoma between 1992 and 2009, were analyzed. Tumor stage and grade were classified according to the sixth and seventh editions of the UICC classification., Results: Tumor depth (T), lymph node affection (N), and metastasis (M) status according to the seventh edition of the UICC classification showed significant differences in survival of each single status. Kaplan-Meier analysis of overall survival by the seventh edition of the UICC classification showed poor discrimination between stages Ib and IIa (p=0.098), stages IIIa and IIIb (p=0.672), and stages IIIc and IV (p=0.799). Further, the estimated median survival time between stages IIa and IIb was discordant., Conclusions: The seventh edition of the UICC TNM classification cannot satisfactorily distinguish among different risk groups of patients with resected esophageal carcinoma. The new subgroups do not unify the different TNM stages with similar survival. We strongly propose that the next revision of the UICC classification should reduce the stages to groups with similar survival, without defining complex subgroups., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: To establish xenograft mouse models of metastatic and nonmetastatic human prostate cancer and to apply these models to the search for aberrant glycosylation patterns associated with tumor progression in vivo and in patients., Experimental Design: Prostate cancer cells (LNCaP, PC-3, LuCaP 23.1, and DU-145) were xenografted subcutaneously into immunodeficient pfp(-/-)/rag2(-/-) mice. Tumor growth and metastasis formation were quantified and as altered glycosylation patterns have been associated with metastasis formation in several other malignancies, prostate cancer cells were profiled by a quantitative real-time PCR (qRT-PCR) glycosylation array and compared with normal human prostate cells. The activity of upregulated glycosyltransferases was analyzed by their sugar residues end products using lectin histochemistry on primary tumors and metastases in the animal experiments and on 2,085 clinical samples., Results: PC-3 cells produced the largest number of spontaneous lung metastases, followed by LNCaP and LuCaP 23.1, whereas DU-145 was nonmetastatic. qRT-PCR revealed an upregulation of β1,6-N-acetylglucosaminyltransferase-5b (Mgat5b) in all prostate cancer cell lines. Mgat5b products [β(1,6)-branched oligosaccharides] were predominantly detectable in metastatic xenografts as shown by increased binding of Phaseolus vulgaris leukoagglutinin (PHA-L). The percentage of prostate cancer patients who were PHA-L positive was 86.5. PHA-L intensity correlated with serum prostate-specific antigen and a cytoplasmic staining negatively affected disease-free survival., Conclusion: We show a novel xenograft mouse model for human prostate cancer respecting the complete metastatic cascade. Specific glycosylation patterns reveal Mgat5b products as relevant markers of both metastatic competence in mice and disease-free survival in patients. This is the first description of Mgat5b in prostate cancer indicating a significant biologic importance of β(1,6)-branched oligosaccharides for prostate cancer progression.

HER-2/neu over-expression occurs in 10-40% of patients with esophageal adenocarcinoma. Therefore, inhibitory effects of trastuzumab on proliferation, neoangiogenesis and metastatic spread of the esophageal adenocarcinoma cell line PT1590 were investigated (subcutaneous xenograft model). PT1590 revealed an amplified copy number of c-erbB2 and HER-2/neu over-expression occured in xenograft tumors and spontaneous lung metastases. PT1590 proliferation was significantly inhibited by trastuzumab in vitro. In vivo, tumor weight, volume, microvessel density and number of lung metastases decreased significantly after three weeks of treatment. These data suggest the importance of HER-2/neu for metastatic spread in esophageal adenocarcinoma and encourages clinical trials., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: High surgical morbidity following distal pancreatectomy, especially pancreatic fistula, remains an unsolved problem. The aim of this study was to identify potential risk factors for surgical morbidity with a focus on the development of pancreatic fistula., Methods: Clinicopathologic parameters were collected for 283 patients who underwent distal pancreatectomy between January 2000 and May 2010. Logistic regression analyses were performed to identify potential risk factors for surgical morbidity and pancreatic fistula., Results: Spleen-preserving pancreatectomy was carried out in 12% of all cases and multivisceral resections were performed in 37.8%. For closure of the pancreatic remnant, three different techniques were used: hand-sewn suture in 44.5%, pancreaticojejunal anastomosis in 24%, and closure by stapler in 31.5%. Overall morbidity and mortality were 53 and 3.5%. Surgical morbidity was observed in 50.2% of all cases and pancreatic fistula in 24%. The stapling group had significantly higher surgical morbidity at 65.2% (p=0.001) and the most pancreatic fistulas, though this did not reach statistical significance (p=0.189). Univariate and multivariate logistic analyses indicated that closure by stapler [odds ratio (OR)=3.61; p<0.001] is a risk factor for surgical morbidity., Conclusion: Closure of the pancreatic remnant by using a stapling device was associated with an increased risk of surgical morbidity. With an increasing number of laparoscopic distal pancreatectomies being performed, further studies analyzing the use of stapling devices and newer closure techniques are needed.