FOXO1 overexpression and loss of pSerine256-FOXO1 expression predicts clinical outcome in esophageal adenocarcinomas.

The function of Forkhead box O 1 (FOXO1) and pSerine256-FOXO1 immunostaining in esophageal cancer is unclear. To clarify the prognostic role of nuclear FOXO1 and cytoplasmic pSerine256-FOXO1 immunostaining, a tissue microarray containing more than 600 esophageal cancers was analyzed. In non-neoplastic esophageal mucosae, FOXO1 expression was detectable in low and pSerine256-FOXO1 expression in high intensities. Increased FOXO1 and decreased pSerine256-FOXO1 expression were linked to advanced tumor stage and high UICC stage in esophageal adenocarcinomas (EACs) (tumor stage: p = 0.0209 and p < 0.0001; UICC stage: p = 0.0201 and p < 0.0001) and squamous cell carcinomas (ESCCs) (tumor stage: p = 0.0003 and p = 0.0016; UICC stage: p = 0.0026 and p = 0.0326). Additionally, overexpression of FOXO1 and loss of pSerine256-FOXO1 expression predicted shortened survival of patients with EACs (p = 0.0003 and p = 0.0133) but were unrelated to outcome in patients with ESCCs (p = 0.7785 and p = 0.8426). In summary, our study shows that overexpression of nuclear FOXO1 and loss of cytoplasmic pSerine256-FOXO1 expression are associated with poor prognosis in patients with EACs. Thus, evaluation of FOXO1 and pSerine256-FOXO1 protein expression - either alone or in combination with other markers - might be useful for prediction of clinical outcome in patients with EAC.

Reduced RBM3 expression is associated with aggressive tumor features in esophageal cancer but not significantly linked to patient outcome.

BACKGROUND: RBM3 expression has been suggested as prognostic marker in several cancer types. The purpose of this study was to assess the prevalence and clinical significance of altered RBM3 expression in esophageal cancer. METHODS: RBM3 protein expression was measured by immunohistochemistry using tissue microarrays containing samples from 359 esophageal adenocarcinoma (EAC) and 254 esophageal squamous cell cancer (ESCC) patients with oncological follow-up data. RESULTS: While nuclear RBM3 expression was always high in benign esophageal epithelium, high RBM3 expression was only detectable in 66.4% of interpretable EACs and 59.3% of ESCCs. Decreased RBM3 expression was linked to a subset of EACs with advanced UICC stage and presence of distant metastasis (P = 0.0031 and P = 0.0024). In ESCC, decreased RBM3 expression was associated with advanced UICC stage, high tumor stage, and positive lymph node status (P = 0.0213, P = 0.0061, and P = 0.0192). However, RBM3 expression was largely unrelated to survival of patients with esophageal cancer (EAC: P = 0.212 and ESCC: P = 0.5992). CONCLUSIONS: In summary, the present study shows that decreased RBM3 expression is associated with unfavourable esophageal cancer phenotype, but not significantly linked to patient prognosis.

Prognostic Significant or Not? The Positive Circumferential Resection Margin in Esophageal Cancer: Impact on Local Recurrence and Overall Survival in Patients Without Neoadjuvant Treatment.

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.

Heterogeneity of amplification of HER2, EGFR, CCND1 and MYC in gastric cancer.

BACKGROUND: Intra-tumor heterogeneity is a potential cause for failure of targeted therapy in gastric cancer, but the extent of heterogeneity of established (HER2) or potential (EGFR, CCND1) target genes and prognostic gene alterations (MYC) had not been systematically studied. METHODS: To study heterogeneity of these genes in a large patient cohort, a heterogeneity tissue microarray was constructed containing 0.6 mm tissue cores from 9 different areas of the primary gastric cancers of 113 patients and matched lymph node metastases from 61 of these patients. Dual color fluorescence in-situ hybridization was performed to assess amplification of HER2, EGFR, CCND1 and MYC using established thresholds (ratio ≥ 2.0). Her2 immunohistochemistry (IHC) was performed in addition. RESULTS: Amplification was found in 17.4% of 109 interpretable cases for HER2, 6.4% for EGFR, 17.4% for CCND1, and 24.8% for MYC. HER2 amplification was strongly linked to protein overexpression by IHC in a spot-by-spot analysis (p < 0.0001). Intra-tumor heterogeneity was found in the primary tumors of 9 of 19 (47.3%) cancers with HER2, 8 of 17 (47.0%) cancers with CCND1, 5 of 7 (71.4%) cancers with EGFR, and 23 of 27 (85.2%) cancers with MYC amplification. Amplification heterogeneity was particularly frequent in case of low-level amplification (<10 gene copies). While the amplification status was often different between metastases, unequivocal intra-tumor heterogeneity was not found in individual metastases. CONCLUSION: The data of our study demonstrate that heterogeneity is common for biomarkers in gastric cancer. Given that both TMA tissue cores and clinical tumor biopsies analyze only a small fraction of the tumor bulk, it can be concluded that such heterogeneity may potentially limit treatment decisions based on the analysis of a single clinical cancer biopsy.

What should be the gold standard for the surgical component in the treatment of locally advanced esophageal cancer: transthoracic versus transhiatal esophagectomy.

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.

Prognostic impact of perineural, blood and lymph vessel invasion for esophageal cancer.

BACKGROUND: With a median survival of ⟨22 months esophageal cancer is one of the most aggressive tumors, up to 20% of node negative patients develop systemic relapse. Studies investigating the prognostic impact of tumor-micro-invasion in blood (AI) and lymphatic vessels (LVI) as well as perineural invasion (PNI) have shown inconsistent results. The aim of the present study was to investigate the prognostic value of the aforementioned factors in a large homogenously treated cohort of patients with esophageal cancer. METHODS: Data from 695 patients with surgically treated esophageal cancer were analyzed. AI, LVI and PNI were determined and data were statistically correlated with clinico-pathological parameters and survival of the patients. RESULTS: Thirteen percent of all specimens showed an AI, 35% a LVI and 5% a PNI. The invasion factors were mostly significantly correlated with the established prognostic parameter, including bone marrow micro-metastases. Kaplan-Meier analysis revealed a prognostic impact for LVI in both cancer subtypes, while AI and PNI were significant factors in adenocarcinoma only. In multivariate analysis, none showed statistical significance. However, sub-analysis of completely resected, node negative and non-metastasized patients showed a significant prognostic impact of LVI. CONCLUSION: The prognostic significance of AI, LVI and PNI seems to be limited compared to the established prognostic parameters of the UICC staging system. In completely resected, node negative and non-metastasized patients, LVI is an independent prognostic parameter for a worse outcome. Those patients might benfit from additional treatment or more intensive follow up.

EGFR intron-1 CA repeat polymorphism is a predictor of relapse and survival in complete resected only surgically treated esophageal cancer.

Basal transcription regulation of the epidermal growth factor receptor is dependent upon a CA simple sequence repeat polymorphism in the intron-1 (CA-SSR-1). Here, we evaluate the role of CA-SSR-1 in complete resected esophageal cancer (EC) patients without neoadjuvant or adjuvant treatment. Genomic DNA was extracted from peripheral blood leukocytes of 241 patients. To determine the number of the CA repeats in the CA-SSR-1, DNA was amplified by polymerase chain reaction and sequenced. The results were correlated with clinicopathological parameters and clinical outcome. Three genotypes were defined based on cut-off points for short allele (S) with ≤18 and long allele (L) >18 CA repeats. A steadily increasing risk was evident between LL, SL, and SS genotype for larger tumor size, presence of lymph node metastases, and disseminated tumor cells in bone marrow as well as tumor recurrence (P < 0.001, chi-square test). A gradual decrease in disease-free and overall survival (OS) was present among LL, SL, and SS patients (P < 0.001, log-rank test). The different outcomes were also evident in nodal status and histological type adjusted subgroup analyses. CA-SSR-1 was identified as the strongest independent prognosticator of tumor recurrence and OS (P < 0.001, Cox regression analysis). CA-SSR-1 is a strong predictive factor for tumor recurrence and overall survival in patients with complete resected esophageal cancer without neoadjuvant or adjuvant therapy.

Is the Whipple procedure harmful for long-term outcome in treatment of chronic pancreatitis? 15-years follow-up comparing the outcome after pylorus-preserving pancreatoduodenectomy and Frey procedure in chronic pancreatitis.

OBJECTIVE: The aim of this study was to report on 15-year long-term results of a randomized controlled trial comparing extended drainage procedure (Frey) and classical resectional procedure [pylorus-preserving pancreatoduodenectomy (PD)] in patients with chronic pancreatitis. BACKGROUND: Chronic pancreatitis is a common inflammatory disease with a prevalence of 10 to 30 cases per 100,000 inhabitants. It is characterized by the progressive conversion of pancreatic parenchyma to fibrous tissue. Different surgical procedures are used in treatment of persistent pain. METHODS: Sixty-four patients suffering from chronic pancreatitis with inflammatory mass in the pancreatic head were randomly assigned in 2 treatment groups (PD, n = 32) and (Frey, n = 32). The perioperative course of the randomized controlled trial and the 7 years follow-up have been previously published. All participating patients were contacted with a standardized, validated questionnaire (EORTC QLQ C30) to evaluate the long-term survival, quality-of-life pain, and exocrine and endocrine function. RESULTS: In the 15-year long-term follow-up, the pain control was good and comparable between both groups, but the quality of life was better after Frey procedure in regard of the physical status [PD: 100 (0-100) vs PD: 60 (0-100) (P = 0.011)]. No significant differences in terms of the Pain Score were detected between both groups [PD: 7 (0-100) vs Frey 4 (0-100) P = 0.258]. Seven patients after Frey OP and 6 patients after PD were free of pain. Analyzing the postoperative overall survival, a higher long-term mortality was found after PD (53%) than that found after Frey procedure (30%) resulting in a longer mean survival (14.5 ± 0.8 vs 11.3 ± 0.8 years; P = 0.037). No correlation between endocrine or exocrine pancreatic function and pain was found, whereas continuous alcohol consumption was associated with poorer outcome regarding quality of life (P < 0.001) and pain score (P < 0.001). CONCLUSIONS: PD and Frey procedure provide good and permanent pain relief and improvement of the quality of life in long-term follow-up. In addition, a longer survival was found after the organ sparing resection. Together with better short-term results, the organ-sparing procedure seems to be favorable in treatment of chronic pancreatitis.

Foudroyant Course of an Extensive Clostridium septicum Gas Gangrene in a Diabetic Patient with Occult Carcinoma of the Colon.

Background. Spontaneous gas gangrene is a rare disease in which Clostridium septicum frequently can be detected. After an incubation period of 5-48 hours, a very painful swelling is accompanied by a rapidly spreading toxic-infectious clinical picture ultimately leading to septic shock and multiple organ failure. We present a case of a completely documented rare infectious disease with triage findings including initial vital signs, initial medical findings, and the emergency lab., radiological, intraoperative, histopathological, microbiological, and postmortem results. After initial diagnosis of the underlying disease, the patient has been immediately transferred to the operating theatre. The laboratory findings reflect the devastating effect of toxin α which is a toxin typically produced by C. septicum. The patient presented both an anaemia and a manifest coagulopathy as well as an onset of multiple organ failure. Despite the aggressive medical and surgical measures that have been taken, this patient could not be saved. Discussion. The case presented vividly emphasises the difficulty to identify these cases early enough to save a patient. This documentation may help health care providers to identify this life threatening disease as early as possible in future cases.

Lymphatic invasion predicts survival in patients with early node-negative non-small cell lung cancer.

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.

Stapled hemorrhoidopexy versus Milligan-Morgan hemorrhoidectomy in circumferential third-degree hemorrhoids: long-term results of a randomized controlled trial.

BACKGROUND: The literature indicates higher recurrence rates for stapled hemorrhoidopexy than for conventional techniques. This could be due to inappropriate patient selection. OBJECTIVE: The aim of this study was to evaluate the short- and long-term outcome after stapled hemorrhoidopexy compared with the Milligan-Morgan procedure in a homogeneous patient population with circumferential third-degree hemorrhoids. DESIGN AND PATIENTS: One hundred thirty patients were enrolled into a randomized controlled study, of which 122 were clinically evaluated at weeks 1, 2, and 4, and thereafter each year for a minimum of 3 years. Patients completed a questionnaire for symptoms, function, and pain. Pain was assessed using a visual analog scale. Recurrences were determined by anoscopy and self-report. SETTINGS: The study was performed at the University Hospital Hamburg. MAIN OUTCOME MEASURES: Endpoints were pain, recurrence, bleeding, itching/burning, urinary retention, incontinence symptoms, and prolonged rate of wound healing. RESULTS: The cumulative recurrence rates after 5 years were 18 % (n = 11) in the stapled hemorrhoidopexy group and 23 % (n = 14) in the Milligan-Morgan group (p = 0.65). Patients who underwent stapled hemorrhoidopexy had significantly less postoperative pain with mean VAS scores at week 1: 3.1 vs. 6.2; week 2: 0.5 vs. 3; week 4: 0.05 vs. 0.6 (p < 0.001), and demonstrated less burning/itching sensation 4 weeks after surgery compared with the Milligan-Morgan group (4.9 vs. 19.7 %; p < 0.001). The postoperative bleeding rate was 4.9 % in both groups and the rate of urinary retention did not differ significantly (4.9 % vs. 1.6 %; p = 0.309). Postoperative incontinence symptoms (6.6 % versus 3.3 %; p = 0.40) resolved within the first 6 months. LIMITATIONS: Detailed measurement of incontinence was not possible because postoperative symptoms resolved between consultations, and pathological results were examined retrospectively. CONCLUSIONS: The results show a similar rate of recurrence in the long term and suggest increased patient comfort in the early postoperative course after stapled hemorrhoidopexy. In patients with circumferential third-degree hemorrhoids, stapled hemorrhoidopexy is as effective as the Milligan-Morgan procedure.

The T393C polymorphism of GNAS1 is a predictor for relapse and survival in resectable non-small cell lung cancer.

INTRODUCTION: The GNAS1 T393C single nucleotide polymorphism (T393C-SNP) correlates with Gαs mRNA stability and protein expression and augmented apoptosis. Genetic germ line variations as stable and reproducible markers potentially serve as prognostic marker in oncology. The aim of this study was to evaluate the potential prognostic value of T393C-SNP in complete resected non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In total 163 Caucasian patients, who had been surgically treated for NSCLC between 1998 and 2010, were included in this study. Genotyping of peripheral blood cells was performed by polymerase chain reaction and digestion using the restriction enzyme FokI. The T393C-SNP was correlated with clinic-pathological parameters and survival. Chi-square test, Kaplan-Meier estimator and cox regression hazard model were used to assess the prognostic value of the T393C-SNP. RESULTS: C-allele carriers had a higher recurrence rate (p=0.018) and a shorter disease-free survival compared to homozygous T-allele carriers (12.26 months vs. 44.65 months, p=0.009). The overall survival in homozygous C allele carriers was shorter (19.10 months vs. 53.95 months, p=0.019). Multivariate Cox regression identified the CC genotype as a negative independent prognostic factor for recurrence (hazard ratio 2.36, p=0.007) and survival (hazard ratio 2.51, p=0.008). CONCLUSION: Determination of T393C-SNP preoperatively potentially allows allocation of NSCLC patients into different risk profiles and may influence the therapeutic strategy.

Ultrasonic dissection versus conventional dissection techniques in pancreatic surgery: a randomized multicentre study.

OBJECTIVE: : This prospective randomized multicenter trial was performed to assess the potential benefits of ultrasonic energy dissection compared with conventional dissection techniques in pancreatic surgery. BACKGROUND: : Surgical procedures for tumors of the pancreatic head involve time-consuming manual dissection. The primary hypothesis was that use of ultrasonic tissue and vessel dissection would lead to substantial saving in operative time during pancreatic resection. METHODS: : Patients eligible for pancreaticoduodenectomy (PD) or pylorus-preserving PD (PPPD) were randomized to group A (dissection with ultrasonic device) or group B (conventional dissection) from March 2009 to May 2011. The primary endpoint was overall duration of operation time. Secondary endpoints were time to end of resection phase, intraoperative blood loss, number of transfused units of blood, and postoperative morbidity. RESULTS: : Analysis of primary and secondary endpoints included 101 patients, who received either PD or PPPD. Demographical characteristics and clinical parameters were similar in both groups. The use of an ultrasonic dissection device did not significantly reduce overall operation time (median 316 minutes in group A and 319 minutes in group B, P = 0.95) and did not significantly increase the costs of surgery. Analysis of secondary endpoints revealed no difference in postoperative course. CONCLUSIONS: : Tissue dissection and vessel closure using an ultrasonic device is equivalent to dissection with conventional techniques in pancreatic surgery.

Management of the difficult duodenal stump in penetrating duodenal ulcer disease: a comparative analysis of duodenojejunostomy with "classical" stump closure (Nissen-Bsteh).

BACKGROUND: Duodenal stump insufficiency after surgery for penetrating gastroduodenal ulcer is associated with substantial mortality. "Classical" technique of closing a difficult duodenal stump (Nissen-Bsteh) has, up to now, not been compared with duodenojejunostomy (DJ) in larger patient sets. This also refers to the potential benefit of a gastric and biliary diversion under such conditions. The aim of the present study was to compare classical duodenal closure (CC) with DJ and to evaluate the impact of gastric and biliary diversion on postoperative outcome after surgery for penetrating, high-risk duodenal ulcer in a matched control study. METHODS: Out of 321 patients, treated for penetrating duodenal ulcer disease, the perioperative outcome of 62 DJ patients was compared with 62 patients undergoing CC matched for age, gender, biliary diversion, and the operating surgeon collective. A total of 70 patients, equally distributed between DJ and CC subsets, received temporary biliary diversion. RESULTS: Overall perioperative mortality was 10.5%. However, DJ significantly reduced the mortality rate (4.8%) associated with penetrating duodenal ulcer compared to CC (16.1%, P < 0.04). The overall morbidity in DJ patients nearly equalled that in the CC group (P = 0.4). Differences in the prevalence of duodenal leakage rate between DJ (14.5%) and CC (29%) patients were of borderline significance (P = 0.05). Temporary biliary diversion was identified as a prognostic factor for closure consistency with lower duodenal leakage rates in both DJ (odds ratio 0.05, 95% confidence interval 0.005-0.42) and CC patients (odds ratio 0.2, 95% confidence interval 0.05-0.6). In contrast, gastric diversion performed in a subset of 35 DJ patients had no protective effect. CONCLUSION: Duodenojejunostomy combined with temporary biliary diversion substantially improves perioperative outcome in management of penetrating duodenal ulcer.

Goal-directed fluid therapy using stroke volume variation does not result in pulmonary fluid overload in thoracic surgery requiring one-lung ventilation.

Background. Goal-directed fluid therapy (GDT) guided by functional parameters of preload, such as stroke volume variation (SVV), seems to optimize hemodynamics and possibly improves clinical outcome. However, this strategy is believed to be rather fluid aggressive, and, furthermore, during surgery requiring thoracotomy, the ability of SVV to predict volume responsiveness has raised some controversy. So far it is not known whether GDT is associated with pulmonary fluid overload and a deleterious reduction in pulmonary function in thoracic surgery requiring one-lung-ventilation (OLV). Therefore, we assessed the perioperative course of extravascular lung water index (EVLWI) and p(a)O(2)/F(i)O(2)-ratio during and after thoracic surgery requiring lateral thoracotomy and OLV to evaluate the hypothesis that fluid therapy guided by SVV results in pulmonary fluid overload. Methods. A total of 27 patients (group T) were enrolled in this prospective study with 11 patients undergoing lung surgery (group L) and 16 patients undergoing esophagectomy (group E). Goal-directed fluid management was guided by SVV (SVV < 10%). Measurements were performed directly after induction of anesthesia (baseline-BL), 15 minutes after implementation OLV (OLVimpl15), and 15 minutes after termination of OLV (OLVterm15). In addition, postoperative measurements were performed at 6 (6postop), 12 (12postop), and 24 (24postop) hours after surgery. EVLWI was measured at all predefined steps. The p(a)O(2)/F(i)O(2)-ratio was determined at each point during mechanical ventilation (group L: BL-OLVterm15; group E: BL-24postop). Results. In all patients (group T), there was no significant change (P > 0.05) in EVLWI during the observation period (BL: 7.8 ± 2.5, 24postop: 8.1 ± 2.4 mL/kg). A subgroup analysis for group L and group E also did not reveal significant changes of EVLWI. The p(a)O(2)/F(i)O(2)-ratio decreased significantly during the observation period (group L: BL: 462 ± 140, OLVterm15: 338 ± 112 mmHg; group E: BL: 389 ± 101, 24postop: 303 ± 74 mmHg) but remained >300 mmHg except during OLV. Conclusions. SVV-guided fluid management in thoracic surgery requiring lateral thoracotomy and one-lung ventilation does not result in pulmonary fluid overload. Although oxygenation was reduced, pulmonary function remained within a clinically acceptable range.

Opposite roles of FOXA1 and NKX2-1 in lung cancer progression.

Gene copy number profiles of primary lung tumors were screened for high-level amplifications. We detected 22 high-level amplifications in various loci, including 14q13. This locus is known to harbor the adenocarcinoma (AC) lineage-specific target gene NKX2-1, which is not expressed in squamous cell carcinoma (SCC). As the 14q amplification was also found in SCC, we investigated whether or not FOXA1 might be the corresponding target gene for SCC. Focusing on these two target genes, we assessed gene amplifications and protein expression of NKX2-1 and FOXA1 in primary lung tumors (n = 554) and brain metastases (n = 68). Primary AC (n = 194) showed positive protein expression of NKX2-1 in 58.2% of the samples compared with 4.2% of primary SCC samples (n = 212). Positive staining for FOXA1 was seen in 34.7% of the SCC samples, which was comparable with 39.6% in the AC samples. For brain metastases, FOXA1 expression was slightly higher in the SCC samples (55.6%) compared with the non-matched primary SCC tumor samples (43.4%), whereas NKX2-1 expression was comparable in both primary tumors and brain metastases. Positive FOXA1 and NKX2-1 expression was associated with a gain or amplification in 34.6% and 28.6% of cases, respectively. The expression of NKX2-1 was associated with early stage and grade among the AC cases. In contrast, FOXA1 expression in SCC was associated with distant metastases as well as an unfavorable survival rate (P = 0.039). These results suggest that both FOXA1 and NKX2-1 may act as lineage-specific target genes within the 14q amplicon with opposite functions in lung cancer.

Vascular endothelial growth factor receptor 2 gene polymorphisms as predictors for tumor recurrence and overall survival in non-small-cell lung cancer.

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.

Heme oxygenase-1 germ line GTn promoter polymorphism is an independent prognosticator of tumor recurrence and survival in pancreatic cancer.

BACKGROUND: Heme oxygenase-1 (HO-1) correlates with aggressive tumor behavior and chemotherapy resistance in pancreatic cancer (PC). We evaluated the prognostic value of the basal transcription controlling germ line GTn repeat polymorphism (GTn) in the promoter region of the HO-1 gene in PC. PATIENTS AND METHODS: We determined the GTn in 100 controls and 150 PC patients. DNA was extracted from blood leukocytes and GTn determined by PCR, electrophoresis, and sequencing. Clinicopathological parameters, disease-free, and overall survival (DFS, OS) were correlated with GTn. RESULTS: Three genotypes were defined based on short (S) <25 and long (L) ≥25 GTn repeat alleles. In PC patients, a steadily increasing risk was evident between LL, SL, and SS genotype patients for larger tumor size, presence of lymph node metastasis, poor tumor differentiation and higher recurrence rate (P < 0.001 each). The SS genotype displayed the most aggressive tumor biology. The LL genotype had the best and the SS genotype the worst DFS and OS (P < 0.001 each). The GTn genotype was the strongest prognostic factor for recurrence and survival (P < 0.001 each). CONCLUSION: The GTn repeat polymorphism is a strong prognostic marker for recurrence and survival in PC patients.

The GNAS1 T393C single nucleotide polymorphism predicts the natural postoperative course of complete resected esophageal cancer.

BACKGROUND: Genetic variations in cancer patients may serve as important prognostic indicators of clinical outcome. The GNAS1 T393C single nucleotide polymorphism (SNP) diversely correlates with the clinical outcome in cancer. The aim of this study was to evaluate the potential prognostic value of T393C-SNP in complete resected only surgically treated esophageal cancer (EC). METHODS: Genomic DNA was extracted from peripheral blood leucocytes of 190 patients who underwent only complete surgical resection for EC. T393C-SNP was correlated with clinic-pathological parameters, tumor cell dissemination in bone marrow (DTC) and clinical outcome. RESULTS: T-allele carriers had more advanced disease due to presence of lymph node metastasis (P < 0.0001) and DTC (P = 0.01) and higher recurrence rate (P = 0.01) compared to CC genotype. The disease-free (P < 0.001) and overall survival (P < 0.001) was better in CC compared to TT and TC patients. In the multivariate Cox regression disease-stage adjusted analysis the T393C-SNP was identified as a strong independent prognostic factor for recurrence (hazard ratio 1.8, P = 0.01) and survival (hazard ratio 2.5, P < 0.001) in EC patients. CONCLUSION: Determination of T393C-SNP preoperatively will allow allocation of EC patients into different risk profiles which may help to stratify patients eligible for neoadjuvant and or adjuvant therapy.