[Rapid growth and malignant transformation of a mucinous cystic neoplasm during pregnancy - a case report]. / Massive Größenprogredienz und maligne Transformation einer muzinös-zystischen Neoplasie des Pankreas in der Schwangerschaft ­ ein Fallbericht.

BACKGROUND: Mucinous-cystic neoplasms (MCN) account for 10% of all pancreatic cystic lesions. They are found almost exclusively in females. MCN have an ovarian-like stroma and often estrogen and progesterone receptors. During pregnancy, they can massively increase in size and transform into malignancy. CASE REPORT: We report on a 29-year-old woman in whom a 35mm cyst in the pancreatic tail had been diagnosed several years ago. After workup the lesions had been classified as a pseudocyst. During pregnancy, the cyst massively increased in size and finally was resected. Histology showed a mucinous-cystic neoplasia with focal malignant transformation. CONCLUSION: Cystic neoplasms of the pancreas require a differentiated management. While overtreatment should be avoided, malignant transformation always merits consideration - in particular if the cystic lesion is located in the pancreatic tail. Women with suspected MCN or cystic pancreatic lesions of uncertain etiology should be informed about the (rare) risk of a malignant transformation of an MCN and should be closely monitored during pregnancy.

Sex- and gender-specific differences in symptoms and health-related quality of life among patients with gastroesophageal reflux disease.

Gastroesophageal Reflux Disease (GERD) is a common chronic gastrointestinal disorder affecting both men and women. Nonerosive reflux disease generally affects more women, whereas GERD complications such as Barrett's esophagus (BE) or esophageal cancer affect more men. The aim of this study was to evaluate sex- and gender-specific symptoms and health-related quality of life (HRQoL) among men and women with GERD. Patients with clinical signs of reflux and completion of 24-hour pH-Impedance testing at the University Hospital Cologne were included into the study. Evaluation of symptoms and HRQoL included the following validated questionnaires: GERD-Health-Related Quality of Life (GERD HRQL), Gastrointestinal Quality of Life Index (GIQLI), and Hospital Anxiety and Depression Scale (HADS). In all, 509 women and 355 men with GERD were included. Men had a significantly higher DeMeester score (60.2 ± 62.6 vs. 43 ± 49.3, P < 0.001) and a higher incidence of BE (18.6 vs. 11.2%, P = 0.006). Women demonstrated significantly higher levels of anxiety (30.9 vs. 14.5%, P = 0.001), more severely impacting symptoms (45.3 ± 11.3 vs. 49.9 ± 12.3, P < 0.001), as well as physical (14.2 ± 5.7 vs. 16.7 ± 5.6, P < 0.001) and social dysfunction (13.3 ± 4.8 vs. 14.8 ± 4.3, P = 0.002). Women further reported a lower HRQoL (85.3 ± 22.7 vs. 92.9 ± 20.8, P < 0.001). Men and women differ on biological, psychological, and sociocultural levels.

Assessment of Abrasion-Induced Visual Defects in Twin Screw Wet Granulation Using Wall Friction Measurements.

Starting point of the presented study were abrasion effects occurring during a twin screw wet granulation (TSG) process of a new chemical entity (NCE) formulation, resulting in gray spots on the final tablets. Several actions and systematic changes of equipment and process parameter settings of TSG process were conducted which reduced the visual defect rate of the tablets, i.e., gray spots on the surface, below the specification limit. To understand the rationale and mechanism behind these improvements, correlations of defect rates and wall friction measurements using a Schulze ring shear tester were evaluated. To check the suitability of the method, a broad range of wall materials as well as powder formulations at various moisture levels were investigated with regard to their wall friction angle. As differences in wall friction angle could be detected, further experiments were conducted using wall material samples made out of different screw materials for TSG. Evaluation of these screw wall material samples gave first hints, which screw materials should be preferred in regard of friction for TSG process. In the finally presented case study, wall friction measurements were performed using the above mentioned NCE formulation with known abrasion issues at TSG processing. The results confirmed that changes which led to a reduced visual defect rate of tablets correlated with a decreased wall friction angle. The results suggest wall friction measurements as a potent tool for equipment selection and establishment of a suitable process window prior to conducting TSG experiments.

Identification of risk factors for renal failure after cardiac surgery by RFILE classification.

OBJECTIVE: Acute kidney injury (AKI) is a major complication after cardiovascular surgery. The unclear etiology of this highly complex event challenges definition, diagnosis and prediction of AKI, and hence hampers adequate patient management. Identification of associated risk factors have the potential to overcome this limitation. METHODS: This retrospective study comprised 3574 patients who underwent cardiac surgery in a hospital in Germany. The patient cohort was interrogated for risk factors for AKI. RESULTS: The analysis identified risk factors for AKI development, such as type of surgery (particularly bypass surgery) (P = 0.02), previous coronary surgeries (P < 0.01), the application of intra-aortic balloon pump in surgery (P < 0.01), and blood loss during surgery (P < 0.01). In addition, old age, duration of surgery as well as ischemia, perfusion and reperfusion times contributed to AKI development (P < 0.01). Further, perioperative hypothermia also appeared as putative risk factor in the analysis (P < 0.01). CONCLUSIONS: This study identified several risk factors for the development of AKI after cardiac surgery. Further validation of these risk factors could allow the implementation of adequate patient management, and the appropriate implementation of risk-adverse interventions in cardiovascular surgery.

A linear scale-up approach to fluid bed granulation.

Fluid bed granulation (FBG) is used extensively in the pharmaceutical industry and it is known to be a complex process, because the final product quality of the FBG process is determined by a complex interplay between the process parameters, fluid dynamics, and material properties. Due to this complexity, the FBG process is inherently nonlinear and as such difficult to scale-up. The field of chemical engineering has shown that complex nonlinear processes can be assumed to be linear under limiting conditions. We leverage this idea and present a linear scale-up approach (LiSA) to the FBG process. We derive the key LiSA equation from first principles, and then use it in combination with the similarity principle for scale-up purposes. Furthermore, we present a novel regression-based LiSA. The regression-based LiSA is founded on the hypothesis that there is a linear relationship between the moisture content and a scaling parameter called the Maus factor. This hypothesis is based on our experience and it is shown to be plausible due to high R2 values ranging from 0.86 to 0.98. Moreover, we successfully demonstrate that LiSA is effective under typical industrial process settings by applying it to two different formulations during pharmaceutical drug product development.

Risk assessment of acute kidney injury following cardiopulmonary bypass.

BACKGROUND: Acute kidney injury (AKI) is a frequent and serious complication of cardiac surgery, associated with a high incidence of morbidity and mortality. Although the RIFLE criteria serve as a prominent tool to identify patients at high risk of AKI, an optimized diagnosis model in clinical practice is desired. METHODS: Based on the SOP-criteria, 365 patients (10%) developed AKI following surgery and were subjected to RRT. In contrast, the incidence of AKI, defined according to the RIFLE criteria, was only 7% (n = 251 patients). Prominent risk factors identified by SOP were patients' sex, valve and combined valve and bypass surgery, deep hypothermia, use of intra-aortic balloon pump (IABP) and previous coronary interventions. Ischemia, reperfusion, blood loss and surgery time also served as significant risk factors for patient evaluated by SOP. RESULTS: Risk assessment by RIFLE differed in as much as most patients with normothermia and those receiving only cardiovascular bypass developed AKI. However, patients' sex and valve surgery did not serve as a risk factor. CONCLUSION: Evaluation of patients by the RIFLE versus SOP criteria yielded different results with more AKI patients detected by SOP. Based on the present data, it is concluded that patients may not prone to AKI when surgery and ischemia time will be kept short, when blood loss is mitigated to a minimum and when surgery is performed under non-hypothermic conditions.

Continuous twin screw granulation and fluid bed drying: A mechanistic scaling approach focusing optimal tablet properties.

This study provides the results of investigation on scaling approaches for three differently-sized continuous granulation lines, each consisting of a twin screw wet granulation process and a continuous fluid bed drying process. To check the initial scaling approach with regard to granule and tablet properties, a process parameter Design of experiment (DoE) was performed on each of the three equipment scales. The processed formulation did not contain cellulose to allow a high overall flowrate through the directly connected granulation and drying sections. Enhanced scaling aspects showed the influence of Froude number [-] at different twin screw granulator scales and screw speeds on the overgranulated particle fraction [% (V/V] as well as on the scale-dependent drying performance of the continuous fluid bed dryers. Scale-independent, specification limits of the two granule material attributes particle fine fraction [%] and residual water content [%] could be defined, resulting in high tableting performance in terms of tabletability and compressibility. Based on these specification limits and the statistical evaluation of the process parameter DoE, a process design space for the continuous granulation and drying process for each scale was calculated. It came up, that this process design space was decreasing in range with increasing equipment scale. The applicability of the presented scaling approach in terms of granule and tablet properties could successfully be demonstrated by three control experiments performed on the different equipment scales. In sum, this work delivers a basis for a smooth transition of scales within process development on the investigated continuous twin screw granulation and drying lines.

A semi-theoretical model for simulating the temporal evolution of moisture-temperature during industrial fluidized bed granulation.

Moisture plays a major role in determining the attributes of granules prepared by fluidized bed granulation (FBG). Here, a semi-theoretical droplet-based evaporation rate model was developed and incorporated into moisture mass-enthalpy balances to simulate the temporal evolution of bed moisture-temperature. Experimental data from a GPCG30 unit were used to fit the model parameters. With only two fitting parameters, the model demonstrated excellent capability to describe the moisture-temperature evolution for a wide range of operating conditions. Then, in a global process model (GPM) approach, the evaporation parameters were fitted to multi-linear functions of inlet air temperature, binder concentration, and spray rate. The GPM was validated successfully by simulating a different data set which was not used in its calibration. As the GPM demonstrated a good predictive capability, it was further used to investigate the impacts of process parameters. Numerical simulations suggest that the proposed GPM predicts the experimentally well-established trends of moisture-temperature profiles in previously published data, proving the applicability of the GPM approach. This study has demonstrated the capabilities of simple process models as a practical approach to predict time-wise evolution of bed moisture-temperature profiles in industrial FBG modeling, while also pointing out their limitations.

Dickkopf-2 (DKK2) as Context Dependent Factor in Patients with Esophageal Adenocarcinoma.

Dickkopf-2 (DKK2) has been described as Wnt/beta-catenin pathway antagonist and its expression is mediated by micro RNA-221 (miRNA-221). So far, there is only limited data characterizing the role of DKK2 expression in esophageal cancer. A tissue micro array of 192 patients with esophageal adenocarcinoma was analyzed immunohistochemically for DKK2, miRNA-221 expression by RNA scope, and GATA6 amplification by fluorescence in-situ hybridization. The data was correlated with clinical, pathological and molecular data (TP53, HER2, c-myc, GATA6, PIK3CA, and KRAS amplifications). DKK2 expression was detectable in 21.7% and miRNA-221 expression in 33.5% of the patients. We observed no correlation between DKK2 or miRNA-221 expression and clinico-pathological data DKK2 expression was correlated with TP53 mutations and amplification of GATA6. We did not detect a survival difference in dependence of DKK2 for the total cohort, however, in patients without neoadjuvant treatment DKK2 expression correlated with a prolonged survival (median overall-survival 202 vs. 55 months, p = 0.012) which turned opposite in patients that underwent neoadjuvant treatment. High amounts of miRNA-221 were in trend associated with a prolonged overall-survival (p = 0.070). DKK2 as a Wnt antagonist is associated with prolonged survival in patients without neoadjuvant treatment and changes its prognostic value to the contrary in patients after neoadjuvant therapy. The modulatory effects of neoadjuvant treatment in connection with DKK2 expression are not fully understood, but when considering DKK2 as a tumor marker, it is necessary to see it in the context of neoadjuvant therapy.

Mechanistic modelling of fluid bed granulation, Part I: Agglomeration in pilot scale process.

The present study aims to develop a mechanistic model to predict the performance of a fluid bed granulation process. Therefore, the behavior of the bed was investigated experimentally for various operating conditions. It was observed that the granule Loss on Drying (LoD) and granule size are strongly interrelated. In detail, the maximum final granule size was observed at an intermediate final LoD. Consequently, there is an optimum spray rate and inlet temperature with respect to the granule size. Besides, it was demonstrated that the experiments delivering lower LoD result in a more elongated final granule. Aimed at enabling the prediction of the bed performance numerically, a single-compartment, population-balance-based model was developed and validated against experimental data. The model parameters associated with the growth rate of granule were estimated and mechanistically correlated to the relevant operating conditions. Detailed analysis of the experimental results suggested that these model parameters may be partially connected to the granule LoD. Subsequently, in order to examine the accuracy of the developed model, a simulation was performed for a new set of operating conditions not previously accounted for in the correlations. The comparison of the simulated bed performance, when compared to the experimental results, proved with reasonable accuracy the reliability of the developed model in predicting the temporal evolution of granule size. Therefore, this study can be a step forward in developing a stand-alone granulation model, via modeling heat and mass transfer, to simulate evaporation and drying in a fluid bed granulator.

Mechanistic modelling of fluid bed granulation, Part II: Eased process development via degree of wetness.

The performance of a fluid bed granulator was investigated through experimental and numerical study to develop a stand-alone fluid bed granulation model. The single-compartment model proposed in part I (for agglomeration modeling) was extended to account for i) evaporation of freely-flowing droplets, and ii) particle drying. This model enables us to predict the granule liquid content and temperature besides the granule size. Accurately, the equations of heat and mass conservation were solved in parallel to the population balance calculation of the agglomeration. In the same manner as for the agglomeration model, the model parameters associated with the drying model were estimated and correlated to the relevant quantities. The analysis of the experimental results revealed the significant contribution of the system "degree of wetness" to the bed performance, i.e., granule size and loss on drying (LoD). As the agglomeration model parameters were partially correlated to LoD in Part I, the presented model was revisited by inclusion of the degree of wetness. The reliability of the developed model in predicting the temporal evolution of granule size, liquid content, and temperature was proven through comparing the bed performance between simulation and experiment. Subsequently, to lowering the costs associated with experimental run, an approach was proposed based on the degree of wetness, aimed at reducing the number of experiments required for the design of experiment (DoE). The results of our simulation using reduced experiments demonstrated that the degree of wetness can be a promising indicator for the performance of the fluid bed granulator as well as for more efficient design of experiment.

Endoscopic Treatment of Transesophageal Echocardiography-Induced Esophageal Perforation.

BACKGROUND: Perforation of the esophagus is the most severe complication of transesophageal echocardiography (TEE) and can lead to mediastinitis, pleural empyema, or peritonitis. Currently, the majority of patients receive operative treatment with only 6% treated endoscopically. We report our experience with endoscopic and conservative approaches. METHODS: We retrospectively reviewed all patients treated for esophageal perforation and included all patients with perforation caused by TEE. All patients with perforation of the esophagus by TEE probe underwent conservative or endoscopic treatment, drainage of pleural and mediastinal retentions, and adjusted to antibiotic therapy. RESULTS: From January 2004 to December 2014 a total of 109 patients were treated for esophageal perforation in our department. In 6 patients (5.5%) the perforation was caused by TEE. Location was cervical and midthoracic in 2 and 4 cases, respectively. All patients underwent successful endoscopic treatment and no further surgical procedure, such as esophageal suture or resection was necessary. The mean time between TEE and therapy of the perforation was 7.3 days. In all patients closure of the leakage could be achieved within 30 days. Mortality rate was 0%. CONCLUSIONS: Esophageal perforations caused by TEE are typically small, in the cervical and mid esophagus, and minimally contaminated. These are good prognostic factors for successful endoscopic treatment with preservation of the esophagus. Operative treatment should only be considered in cases of failed endoscopic treatment.

Results of endoscopic vacuum-assisted closure device for treatment of upper GI leaks.

BACKGROUND: Esophageal perforations and postoperative leakage of esophagogastrostomies are considered to be life-threatening conditions due to the potential development of mediastinitis and consecutive sepsis. Vacuum-assisted closure (VAC) techniques, a well-established treatment method for superficial infected wounds, are based on a negative pressure applied to the wound via a vacuum-sealed sponge. Endoluminal VAC (E-VAC) therapy as a treatment for GI leakages in the rectum was introduced in 2008. E-VAC therapy is a novel method, and experience regarding esophageal applications is limited. In this retrospective study, the experience of a high-volume center for upper GI surgery with E-VAC therapy in patients with leaks of the upper GI tract is summarized. To our knowledge, this series presents the largest patient cohort worldwide in a single-center study. METHODS: Between October 2010 and January 2017, 77 patients with defects in the upper gastrointestinal tract were treated using the E-VAC application. Six patients had a spontaneous perforation, 12 patients an iatrogenic injury, and 59 patients a postoperative leakage in the upper gastrointestinal tract. RESULTS: Complete restoration of the esophageal defect was achieved in 60 of 77 patients. The average duration of application was 11.0 days, and a median of 2.75 E-VAC systems were used. For 21 of the 77 patients, E-VAC therapy was combined with the placement of self-expanding metal stents. CONCLUSION: This study demonstrates that E-VAC therapy provides an additional treatment option for esophageal wall defects. Esophageal defects and mediastinal abscesses can be treated with E-VAC therapy where endoscopic stenting may not be possible. A prospective multi-center study has to be directed to bring evidence to the superiority of E-VAC therapy for patients suffering from upper GI defects.

Percutaneous Endoscopic Gastrostomy in Direct Puncture Technique: When, Why and How?

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) placed in the pull through (PT) technique is a common procedure to restore enteral feeding in patients with swallowing disorders. Limitations of this technique are patients with obstruction of the pharynx or esophagus or with an esophageal stent. We report our experience with the direct puncture (DP) PEG device. METHODS: We included 154 patients (55 women). One hundred forty patients had cancer. After passing the endoscope into the stomach, 4 gastropexies were performed with a gastropexy device and the PEG was placed with the introducer method. After 1 month, the sutures were removed and a constant gastrocutaneous fistula had been created and the new catheter could be placed safely. RESULTS: The DP PEG was successfully placed in all patients. Overall complication rate was 11% (minor: 6%, major: 5%). The most common event was tube dislocation (40 cases). In 5 cases of dislocation, this resulted in a major complication with injuring the gastric wall and the necessity for surgical treatment. CONCLUSIONS: The DP PEG system is safe, and can be used in cases in which a standard PT PEG is not feasible. To avoid dislocation, strict adherence to a post-interventional protocol is highly recommended.

Gastric Outlet Obstruction After Esophagectomy: Retrospective Analysis of the Effectiveness and Safety of Postoperative Endoscopic Pyloric Dilatation.

BACKGROUND AND AIMS: Delayed gastric emptying after esophagectomy with gastric replacement can pose a significant postoperative problem, often leading to aspiration and pneumonia. The present study analyzes retrospectively the effectiveness of endoscopic pyloric dilatation for post-surgical gastric outlet obstruction. METHODS: Between March 2006 and March 2010, 403 patients underwent a transthoracic en-bloc esophagectomy and reconstruction with a gastric tube and intrathoracic esophagogastrostomy. In patients with postoperative symptoms of an outlet dysfunction and the confirmation by endoscopy, pyloric dilatations were performed without preference with either 20- or 30-mm balloons. RESULTS: A total of 89 balloon dilatations of the pylorus after esophagectomy were performed in 60 (15.6 %) patients. In 21 (35 %) patients, a second dilatation of the pylorus was performed. 55 (61.8 %) dilatations were performed with a 30-mm balloon and 34 (38.2 %) with a 20-mm balloon. The total redilatation rate for the 30-mm balloon was 20 % (n = 11) and 52.9 % (n = 18) for the 20-mm balloon (p < 0.001). All dilatations were performed without any complications. CONCLUSIONS: Pylorus spasm contributes to delayed gastric emptying leading to postoperative complications after esophagectomy. Endoscopic pyloric dilatation after esophagectomy is a safe procedure for treatment of gastric outlet obstruction. The use of a 30-mm balloon has the same safety profile but a 2.5 lower redilatation rate compared to the 20-mm balloon. Thus, the use of 20-mm balloons has been abandoned in our clinic.

Web-Based Immersive Virtual Patient Simulators: Positive Effect on Clinical Reasoning in Medical Education.

BACKGROUND: Clinical reasoning is based on the declarative and procedural knowledge of workflows in clinical medicine. Educational approaches such as problem-based learning or mannequin simulators support learning of procedural knowledge. Immersive patient simulators (IPSs) go one step further as they allow an illusionary immersion into a synthetic world. Students can freely navigate an avatar through a three-dimensional environment, interact with the virtual surroundings, and treat virtual patients. By playful learning with IPS, medical workflows can be repetitively trained and internalized. As there are only a few university-driven IPS with a profound amount of medical knowledge available, we developed a university-based IPS framework. Our simulator is free to use and combines a high degree of immersion with in-depth medical content. By adding disease-specific content modules, the simulator framework can be expanded depending on the curricular demands. However, these new educational tools compete with the traditional teaching OBJECTIVE: It was our aim to develop an educational content module that teaches clinical and therapeutic workflows in surgical oncology. Furthermore, we wanted to examine how the use of this module affects student performance. METHODS: The new module was based on the declarative and procedural learning targets of the official German medical examination regulations. The module was added to our custom-made IPS named ALICE (Artificial Learning Interface for Clinical Education). ALICE was evaluated on 62 third-year students. RESULTS: Students showed a high degree of motivation when using the simulator as most of them had fun using it. ALICE showed positive impact on clinical reasoning as there was a significant improvement in determining the correct therapy after using the simulator. ALICE positively impacted the rise in declarative knowledge as there was improvement in answering multiple-choice questions before and after simulator use. CONCLUSIONS: ALICE has a positive effect on knowledge gain and raises students' motivation. It is a suitable tool for supporting clinical education in the blended learning context.

Both GLUT-1 and GLUT-14 are Independent Prognostic Factors in Gastric Adenocarcinoma.

BACKGROUND: The role of glucose transporter 14 (GLUT-14/SLC2A14) in tumor biology is entirely unknown, and the significance of hypoxia inducible factor 1-alpha (HIF1-α) for gastric adenocarcinoma is controversial. The impact of GLUT-1/SLC2A1 has never been confirmed in a Caucasian cohort. METHODS: Between 1996 and 2007, 124 patients underwent gastrectomy for gastric adenocarcinoma. Tumor sections were incubated with GLUT-1, GLUT-14, and HIF1-α antibodies. Expression was analyzed for correlations with histopathology, marker coexpression, and patient survival by uni- and multivariate analyses. RESULTS: Expressions of GLUT-1, GLUT-14, and HIF1-α were detectable in 50, 77.4, and 27.1 %, respectively. Expression of GLUT-1 was associated with pT-category (p = 0.019), pN-category (p = 0.019), tubular (WHO, p = 0.008), and intestinal (Lauren classification; p = 0.002) histologic subtypes. Expression of GLUT-14 was correlated with pT category (p = 0.043), whereas HIF1-α did not show any correlation with histopathology or survival. The median survival period was 14 months (95 % confidence interval [CI] 9.2-18.8 months) for GLUT-1-positive patients and 55 months (95 % CI 25.8-84.2; p = 0.01) for GLUT-1-negative patients. An inferior prognosis also was seen for GLUT-14-positive cases compared with GLUT-14-negative cases (p = 0.004). Thus, worst survival was seen with both GLUT-1- and GLUT-14-positive expression followed by single-positive and then double-negative cases (p = 0.004). In multivariate analysis including International Union Against Cancer (UICC) stages, R category, Lauren classification, surgery alone versus neoadjuvant/perioperative chemotherapy, and marker expression as covariates, GLUT-1 (p = 0.011) and GLUT-14 (p = 0.025) kept their prognostic independence. CONCLUSIONS: The study findings suggest that detection of GLUT-1 and GLUT-14 is of high prognostic value. It gives additional information to UICC stages and identifies patients with inferior prognosis. If confirmed in prospective studies, these markers need to be considered for future classification systems.

Prognostic impact of blood biomarkers TS and DPD in neoadjuvant-treated esophageal cancer patients.

BACKGROUND/AIM: The prognostic value of TS (thymidylate synthase) and DPD (dihydropyrimidine dehydrogenase) RNA expression in the blood of patients with esophageal cancer is not known. The aim of the present study was to evaluate the significance of these molecular alterations in the blood as a prognostic marker for patients with neoadjuvant-treated esophageal cancer. PATIENTS AND METHODS: A total of 29 patients with locally advanced esophageal cancer (cT3-T4, Nx, M0) were enrolled in this prospective study. All patients received neoadjuvant chemoradiation followed by a transthoracic resection (curative transthoracic en bloc esophagectomy, RO). Peripheral blood samples were drawn before initiation of therapy. The analysis was performed using quantitative real-time-polymerase chain reaction (RT-PCR). The histomorphological regressions grading after neoadjuvant therapy was defined as follows: major response (MaR)=less than 10% vital tumor tissue, minor response (MiR)=more than 10% vital tumor tissue. RESULTS: Nineteen out of 29 patients (65.5%) had a MiR and 10 (34.5%) had a MaR. The median survival of patients was 2.08 years (range=0.15-4.53). Among the tested genes, the RNA expression of TS was significantly associated with prognosis of patients. Patients with TS expression above 0.78 had a median survival of 1.1 years (range=0.21-3.96) compared to 2.6 years (range=0.15 to 4.53) in patients with TS expression lower than 0.78 (p=0.031, log rank test). There was no association between clinical variables (e.g., tumor stage, gender, age, etc.) and the RNA expression of TS in the serum. CONCLUSION: The RNA expression of TS in the blood is a potential prognostic marker in patients with neoadjuvant-treated esophageal cancer. The significance of these molecular alterations as non-invasive prognostic marker for esophageal cancer should be evaluated in prospective studies.

Primary tumor location as a prognostic factor in metastatic colorectal cancer.

BACKGROUND: We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC). METHODS: We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided. RESULTS: Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location. CONCLUSIONS: These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.

Validation of 2-mm tissue microarray technology in gastric cancer. Agreement of 2-mm TMAs and full sections for Glut-1 and Hif-1 alpha.

BACKGROUND/AIM: Tissue Microarray (TMA) is a widely used method to perform high-throughput immunohistochemical analyses on different tissues by arraying small sample cores from paraffin-fixed tissues into a single paraffin block. TMA-technology has been validated on numerous cancer tissues and also for gastric cancer studies, although it has not been validated for this tumor tissue so far. The objective of this study was to assess, whether the 2-mm TMA-technology is able to provide representative samples of gastric cancer tissue. MATERIALS AND METHODS: TMA paraffin blocks were constructed by means of 220 formalin-fixed and paraffin-embedded gastric cancer samples with a sample diameter of 2 mm. The agreement of immunohistochemical stainings of Glut-1 and Hif-1 alpha in TMA sections and the original full sections was calculated using kappa statistics and direct adjustment. RESULTS: The congruence was substantial for Glut-1 (kappa 0.64) and Hif-1 alpha (kappa 0.70), but with an agreement of only 71% and 52% within the marker-positive cases of the full-section slides. CONCLUSION: Due to tumor heterogeneity primarily, the TMA technology with a 2-mm sample core shows relevant limitations in gastric cancer tissue. Although being helpful for tissue screening purposes, the 2-mm TMA technology cannot be recommended as a method equal to full-section investigations in gastric cancer.