Predictive Value of Preoperative Endoscopic Ultrasound (EUS) After Neoadjuvant Chemotherapy in Locally Advanced Esophagogastric Cancer - Data From a Randomized German Phase II Trial.

PURPOSE: The role of EUS before or after neoadjuvant chemotherapy (nCTX) in advanced esophagogastric cancer (EGC) is still unclear. The phase II NEOPECX trial evaluated perioperative chemotherapy with or without panitumumab in this setting. The aim of this sub-study was to investigate the prognostic value of EUS-guided preoperative staging before and after nCTX. MATERIALS AND METHODS: Preoperative yuT/yuN stages by EUS were compared with histopathological ypT/ypN stages after curative resection. Reduction in T-stage from baseline to preoperative EUS was defined as downstaging (DS+) and compared to progression-free (PFS) and overall survival (OS) of patients without downstaging (DS-). In addition, preoperative EUS N-stages (positive N+ or negative N-) were correlated with clinical data. RESULTS: The preoperative yuT-stage correlated with the ypT-stage in 48% of cases (sensitivity 48%, specificity 52%), while the preoperative yuN-stage correlated with the ypN-stage in 64% (sensitivity 76%, specificity 52%). Within DS+ patients who were downstaged by ≥ 2 T-categories, a trend towards improved OS was detected (median OS DS+: not reached (NR), median OS DS-: 38.5 months (M), p=0.21). Patients with yuN+ at preoperative EUS had a worse outcome than yuN- patients (median OS yuN-: NR, median OS yuN+: 38.5 M, p = 0.013). CONCLUSION: The diagnostic accuracy of EUS to predict the response after nCTX in patients with advanced EGC is limited. In the current study the endosonographic detection of lymph node metastasis after nCTX indicates a poor prognosis. In the future, preoperative EUS with sectional imaging procedures may be used to tailor treatment for patients with advanced EGC.

Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program.

BACKGROUND: To date, the cornerstone of treatment in patients with advanced or metastatic cholangiocarcinoma (CCA) is systemic chemotherapy based on a combination of gemcitabine and a platinum derivative. Other therapeutic approaches including targeted agents and tyrosine kinase inhibitors (TKI) have demonstrated disappointing results, highlighting the complexity of CCA. Recently, drugs aiming at the inhibition of HER-receptors have shown first therapeutic benefit in patients with late stage disease. The aim of this phase I study was to test the dose level toxicities (DLTs), safety and efficacy of afatinib, a highly specific panErbB family receptor TKI, in chemotherapy naive patients with advanced CCA in conjunction with an extensive biomarker program. METHODS: Afatinib was administered continuously p. o. as add-on in patients with advanced CCA who received conventional chemotherapy with gemcitabine/cisplatin. A classical 3 + 3 phase I study was employed, while the maximum tolerated dose (MTD) of oral afatinib was determined in a 2 step dose escalation. Safety, overall survival (OS) and progression free survival (PFS) were evaluated for all patients. Finally, a translational biomarker analysis was conducted for the EGFR and VEGF signalling cascades. RESULTS: Overall, 9 patients were enrolled. Further recruitment was discontinued due to lack of efficacy results of the tested drug in other indications. 30 mg afatinib could be safely administered as add-on to 80% of standard dose gemcitabine/cisplatin. The mOS and mPFS were 7.7 and 6.0 months, respectively. Diarrhoea and haematological disorders were the most common observed AEs. Almost all patients overexpressed EGFR on their tumour tissues, whereas none of them expressed mutations in Exons 18, 19 and 21. Non-responders showed a higher variation of VEGF-C, -D, leptin and sEGFR in their sera. CONCLUSIONS: Afatinib failed to show survival benefits in combination with gemcitabine/cisplatin in patients with advanced CCA. Mutational analysis of EGFR and pathways associated with VEGF-C, -D and leptin might show promising results in future studies. CLINICAL TRIALS REGISTRATION: NCT01679405 August, 2012.

Cytokeratin-18 fragments predict treatment response and overall survival in gastric cancer in a randomized controlled trial.

BACKGROUND: Gastric cancer is common malignancy and exhibits a poor prognosis. At the time of diagnosis, the majority of patients present with metastatic disease which precludes curative treatment. Non-invasive biomarkers which discriminate early from advanced stages or predict the response to treatment are urgently required. This study explored the cytokeratin-18 fragment M30 and full-length cytokeratin-18 M65 in predicting treatment response and survival in a randomized, placebo-controlled trial of advanced gastric cancer. METHODS: Patients enrolled in the SUN-CASE study received sunitinib or placebo as an adjunct to standard therapy with leucovorin (Ca-folinate), 5-fluorouracil, and irinotecan in second or third line. Treatment response rates, progression-free survival and overall survival were assessed during a follow-up period of 12 months. Cytokeratin-18 fragments were analyzed in 52 patients at baseline and day 14 of therapy. RESULTS: Levels of M30 correlated with the presence of metastasis and lymph node involvement and decreased significantly during chemotherapy. Importantly, baseline levels of M30 were significantly higher in patients who failed therapy. In addition, patients who did not respond to treatment were also identifiable at day 14 based on elevated M30 levels. By stepwise regression analysis, M30 at day 14 was identified as independent predictor of treatment response. Likewise, serum levels of full-length cytokeratin-18 M65 at baseline also correlated with treatment failure and progression-free survival. The addition of sunitinib did not exert any effects on serum levels of M30 or M65. CONCLUSION: The cytokeratin-18 fragment M30 at day 14 identifies patients that fail to second- or third-line therapy for advanced gastric cancer. Validation of this non-invasive biomarker in gastric cancer is warranted.

Feasibility Trial of the Newly Introduced Optical Enhancement Technology in Patients with Gastroesophageal Reflux Disease.

BACKGROUND: Optical Enhancement technology (OE) combines bandwidth-limited light and image enhancement processing technology to enhance subtle mucosal and vascular details. This is the first study assessing the new technology for the diagnosis of gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: Consecutive patients with GERD and controls were prospectively included. The distal esophagus was examined in all quadrants with high definition white-light endoscopy (HD-WLE) followed by OE and biopsies for histopathological analysis. Features observed only by OE were compared between controls and patients with GERD. RESULTS: A total of 100 areas were evaluated. About 56% of patients had a diagnosis of GERD. The mean age of patients was 53 years (range 27-89 years), 60% were female. Compared to controls, patients with diagnosis of GERD showed significantly more often tortuosity (p = 0.042), dilation (p = 0.0003), and increased number (p = 0.001) of intrapapillary capillary loops (IPCLs). In addition, increased vascularity and mucosal breaks were significantly more often found in patients with GERD as compared to controls (p < 0.05). On multivariate analysis, increased number and dilation of IPCL were the best predictors of GERD. CONCLUSIONS: The newly introduced OE technology significantly improves the diagnosis of GERD compared to HD-WLE. The results should be confirmed in a multicenter trial.

Understanding of headache patterns modification in an emergency department during the economic crisis of Greece.

Very few neurological research is published regarding health effects of global economic crisis. Our aim was to assess the impact of economic recession on frequency and severity of headaches. We also tested if depression, anxiety and experiences associated with crisis, such as unemployment, were reflected in headaches. This is a retrospective observational study in the Emergency setting of tertiary Clinic from 1 January 2008 until 31 December 2009 and from 1 January 2010 until 31 December 2011. Demographic data were collected of 1094 consecutive adult patients with headache. Multinomial logistic regression performed to examine if hospital anxiety depression (HAD), HAD anxiety, experience of serious life events, year of survey had influence on type of headache. The total number of headache cases increased significantly from 2008 to 2011 (p < 0.001). Tension type and medication overuse headaches remained unchanged over time (p > 0.05), while migraines decreased. Secondary and not otherwise specified (NOS) increased significantly (p < 0.05). The most common, overtime, was Tension type headache, followed by migraines (in 2008, 2011) and NOS (2010). Chi square test showed significant correlation between type of headache and year, as well medication type and year (p < 0.05). Common analgesics, the most common medication, increased five times during survey period (77 % 2008 to 87.6 % 2011). Multivariate analysis revealed stronger association for experience serious events with NOS vs. tension type headache [odds ratio (OR) 0.13; 95 % confidence interval (CI) 0.03, 0.7]. This is the first study showing that the prolonged economic crisis affected headache frequency accompanied by a higher use of analgesics.

VEGFR-3 and CXCR4 as predictive markers for treatment with fluorouracil, leucovorin plus either oxaliplatin or cisplatin in patients with advanced esophagogastric cancer: a comparative study of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

BACKGROUND: Combination of fluoropyrimidines and a platinum derivative are currently standards for systemic chemotherapy in advanced adenocarcinoma of the stomach and gastroesophageal junction (GEJ). Nevertheless, individual likelihood for response to these therapeutic regimes remains uncertain. Even more, no predictive markers are available to determine which patients may benefit more from oxaliplatin versus cisplatin or vice versa. The new invasion and stem cell markers VEGFR-3 and CXCR4 have been linked prognostically with more aggressive esophagogastric cancer types. Thus, we aimed to assess correlations of VEGFR-3 and CXCR4 expression levels with clinical outcome in a randomized phase III study of patients with oxaliplatin/leucovorin/5-FU (FLO) versus cisplatin/leucovorin/5-FU (FLP). METHODS: The patients data examined in this study (n = 72) were from the collective of the FLO vs. FLP phase III AIO trial. Tumour tissues were stained via immunohistochemistry for VEGFR-3 and CXCR4 expression and results were evaluated by two independent, blinded investigators.Outcome parameter: Survival analysis was calculated for patients receiving FLO vs. FLP in relation to VEGFR-3 and CXCR4 expression. RESULTS: 54% and 36% of the examined tumour tissues showed strong positive expression of VEGFR-3 and CXCR4 respectively. No superiority of each regime was detected in terms of overall survival (OS) in the whole population. Patients with strong expression of CXCR4 on their tumour tissues profited more in terms of OS under the treatment of FLP (mOS: 28 vs 15 months, p = 0.05 respectively). Patients with negative VEGFR-3 and CXCR4 expression had a trend to live longer when FLO regime was applied (mOS: 22 vs. 9 months, p = 0.099 and 20 vs. 10 months, p = 0.073 respectively). In an exploratory analysis of patients older than 60 years at diagnosis, we observed a significant benefit in overall survival for VEGFR-3 and CXCR4-positive patients when treated with FLP (p = 0.002, p = 0.021 respectively). CONCLUSIONS: CXCR4 positive patients profited in terms of OS from FLP, whereas FLO proved to be more effective in CXCR4 and VEGFR-3 negative patients. Our results suggest, despite the limited size of the study, a predictive value of these biomarkers concerning chemotherapy with FLP or FLO in advanced esophagogastric cancer.

Erythropoietin treatment in chemotherapy-induced anemia in previously untreated advanced esophagogastric cancer patients.

BACKGROUND: The impact of erythropoiesis-stimulating agents in chemotherapy-induced anemia has been a constant topic of debate over recent years. We prospectively assessed the efficacy of epoetin beta (Epo-b) in improving hemoglobin (Hb) levels and outcome in patients within an open label, randomized clinical phase II trial with advanced or metastatic gastric/esophagogastric cancer. METHODS: Previously untreated patients were randomized to receive 3-weekly cycles of capecitabine (1000 mg/m(2) bid) for 14 days plus on day 1 either irinotecan 250 mg/m(2) or cisplatin 80 mg/m(2). Epo-b (30000 IU once weekly) was initiated in patients with Hb <11 g/dl and continued until Hb ≥12 g/dl was reached. If after 4 weeks the Hb increase was <0.5 g/dl, Epo-b was increased to 30000 IU, twice weekly. RESULTS: Of 118 patients enrolled, 32 received Epo-b treatment; of these, 65 % achieved an increase in Hb levels of at least 2 g/dl, with 74 % achieving the target Hb of ≥12 g/dl. Within the study population, patients receiving Epo-b showed better overall survival (median 14.5 vs. 8.0 months, P = 0.056) as well as a significantly improved disease control rate (78 vs. 55 %, P = 0.025). Patients in the irinotecan group profited significantly (P < 0.05) in terms of progression-free survival and overall survival under Epo-b treatment (median 6.5 vs 4.1 months and median 15.4 vs 8.4 months, respectively). CONCLUSIONS: Epo-b was effective in raising Hb levels in patients with advanced esophagogastric cancer. Patients receiving Epo-b had a significantly increased response to chemotherapy and a clear trend to improved survival.

Prospective, open, multi-centre phase I/II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and oxaliplatin in patients with adenocarcinoma of the oesophagogastric junction.

BACKGROUND: This phase I/II-trial assessed the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of neoadjuvant radiochemotherapy (RCT) with docetaxel and oxaliplatin in patients with locally advanced adenocarcinoma of the oesophagogastric junction. METHODS: Patients received neoadjuvant radiotherapy (50.4 Gy) together with weekly docetaxel (20 mg/m(2) at dose level (DL) 1 and 2, 25 mg/m(2) at DL 3) and oxaliplatin (40 mg/m(2) at DL 1, 50 mg/m(2) at DL 2 and 3) over 5 weeks. The primary endpoint was the DLT and the MTD of the RCT regimen. Secondary endpoints included overall response rate (ORR) and progression-free survival (PFS). RESULTS: A total of 24 patients were included. Four patients were treated at DL 1, 13 patients at DL 2 and 7 patients at DL 3. The MTD of the RCT was considered DL 2 with docetaxel 20 mg/m(2) and oxaliplatin 50 mg/m(2). Objective response (CR/PR) was observed in 32% (7/22) of patients. Eighteen patients (75%) underwent surgery after RCT. The median PFS for all patients (n = 24) was 6.5 months. The median overall survival for all patients (n = 24) was 16.3 months. Patients treated at DL 2 had a median overall survival of 29.5 months. CONCLUSION: Neoadjuvant RCT with docetaxel 20 mg/m2 and oxaliplatin 50 mg/m(2) was effective and showed a good toxicity profile. Future studies should consider the addition of targeted therapies to current neoadjuvant therapy regimens to further improve the outcome of patients with advanced cancer of the oesophagogastric junction. TRIAL REGISTRATION: NCT00374985.

Convolutional Neural Networks for Optical Discrimination Between Histological Types of Colorectal Polyps Based on White Light Endoscopic Images.

The objective of this study was to compare different convolutional neural networks (CNNs), as employed in a Python-produced deep learning process, used on white light images of colorectal polyps acquired during the process of a colonoscopy, in order to estimate the accuracy of the optical recognition of particular histologic types of polyps. The TensorFlow framework was used for Inception V3, ResNet50, DenseNet121, and NasNetLarge, which were trained with 924 images, drawn from 86 patients.

Outcomes in patients receiving palliative chemotherapy for advanced biliary tract cancer.

BACKGROUND & AIMS: Advanced biliary tract cancer (ABTC) is associated with a poor prognosis. Real-world data on the outcome of patients with ABTC undergoing sequential chemotherapies remain scarce, and little is known about treatment options beyond the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX. This study aimed to evaluate the outcome of patients with regard to different oncological therapies and to identify prognostic factors. METHODS: From January 2010 until December 2019, 142 patients started palliative chemotherapy at our tertiary care liver center. Overall survival (OS) was calculated using Kaplan-Meier plots. Prognostic factors were evaluated using cox proportional-hazards. RESULTS: Patients received a median number of 2 lines of chemotherapy. Median OS was 6.7, 15.2 and 18.2 months for patients who received 1, 2 and 3 lines of chemotherapy, respectively. Patients treated with FOLFIRINOX had a significantly extended OS of 23.8 months (log-rank test: p = 0.018). The univariate cox regression analysis identified several clinical parameters associated with survival (e.g. albumin, bilirubin, carcinoembryonic antigen, carbohydrate antigen 19-9 levels). CONCLUSIONS: Our study provides real-world data on the prognosis of ABTC including survival times for patients receiving third and later lines of chemotherapy. LAY SUMMARY: Real-world data depicting the outcome of patients with advanced biliary tract cancer outside the framework of controlled trials remain rare despite being extremely important for clinical decision-making. This study therefore provides important real-world data on the established first- and second-line treatments with gemcitabine + cisplatin and FOLFOX, as well as on other chemotherapy regimens or later lines of chemotherapy. It further demonstrates that the use of FOLFIRINOX is associated with promising survival and that there is an association between various clinical parameters such as pre-therapeutic albumin, bilirubin or carbohydrate antigen 19-9 levels and survival.

Comparative aspects of murine proteinase 3.

The neutrophilic granule protein proteinase 3 (PR3) is the preferred target antigen of anti-neutrophil cytoplasmic antibodies (ANCA) found in the serum of patients with Wegener's granulomatosis, a systemic small-vessel vasculitis. Due to the lack of data concerning the murine homologue of human PR3, we assessed the neutrophil marker polypeptide PR3 in mice by generating a murine-specific PR3 antibody. In contrast to humans, peripheral blood leukocytes are not the main resource of murine PR3. Interestingly, we could show that the mouse bone marrow is the main PR3 source, indicating that it is a large reservoir for functional neutrophils. This pool of neutrophils could be rapidly mobilized after injection of IL-8. The development of the new PR3 antibody provides a new tool for studying the maturation processes of the murine hematopoietic system and will also support the generation of infectious disease or vasculitis mouse models.

The Addition of Transarterial Chemoembolization to Palliative Chemotherapy Extends Survival in Intrahepatic Cholangiocarcinoma.

Incidence and mortality of intrahepatic cholangiocarcinoma (iCCA) have been increasing continuously. Recent studies suggest that the combination of palliative chemotherapy (pCTX) and transarterial chemoembolization (TACE) improves overall survival (OS). This study aimed to evaluate the outcome of patients treated with TACE and pCTX in unresectable iCCA at our tertiary care center. A group of 14 patients was treated with both pCTX and TACE. The non-randomized control group of 59 patients received pCTX alone. Patients received a median of two pCTX lines in both groups. Those treated with TACE underwent a median number of 3.5 sessions. Median OS from the time of unresectability was 26.2 months in the pCTX + TACE group versus 13.1 months in the pCTX group (p = 0.008). Controlling for albumin, bilirubin, ECOG (Eastern Cooperative Oncology Group) performance status, and UICC (Union for International Cancer Control) stage, the addition of TACE still conferred an OS benefit of 12.95 months (p = 0.014). A propensity score matching analysis yielded an OS benefit of 14 months from the time of unresectability for the pCTX + TACE group (p = 0.020). The addition of TACE to pCTX may provide an OS benefit for patients with unresectable iCCA. Thus, patients with liver-dominant iCCA undergoing standard-of-care pCTX should be considered for additional treatment with TACE.

Terminal Ileitis due to Yersinia Infection: An Underdiagnosed Situation.

Endoscopy is currently the gold standard for the diagnosis of inflammatory bowel disease (IBD). The presence of macroscopic lesions along with the microscopic detection of inflammatory infiltration in the terminal ileum often leads the gastroenterologist to the diagnosis of Crohn's disease (CD). However, some of these cases could be, in fact, an infection caused by Yersinia spp., accompanied or not with CD, which could be easily diagnosed with the identification of serum antibodies against Yersinia outer protein antigens (YOP antigens). Since Yersiniosis is considered to be an uncommon situation, food and water are not usually checked for the possibility of contamination by Yersinia. Therefore, it is reasonable to assume that the true prevalence of Yersinia infection in patients with terminal ileitis is probably underestimated. In this article, we review the most important data regarding the various aspects of Yersinia infection with special focus on its pathophysiology and diagnosis. We recommend testing for serum antibodies against YOP antigens in all patients with an endoscopic and histological image of terminal ileitis in order to identify Yersiniosis in conjunction or not with terminal ileum CD.

Advances in the endoscopic management of malignant biliary obstruction.

Biliary obstruction is common in pancreatobiliary malignancies and has a negative impact on the patient's quality of life, postoperative complications, and survival rates. Particularly in the last decade, there has been enormous progress regarding the diagnostic and therapeutic options in patients with malignant biliary obstruction. Endoscopy has given a new insight in this direction and novel techniques have been developed for the better characterization and treatment of malignant strictures. We herein summarize the available data on the different endoscopic techniques, and clarify their role in the diagnosis and treatment of malignant biliary obstructive disease. Finally, we propose an algorithm that can facilitate management decisions in these patients.

Downregulation of alpha-galactosidase A upregulates CD77: functional impact for Fabry nephropathy.

Anderson-Fabry disease, an inherited deficiency in the lysosomal enzyme alpha-galactosidase A, is characterized by the progressive accumulation of globotriaosylceramide (Gb3), also known as CD77. We sought to clarify the pathogenesis of Fabry disease by establishing a cell model of this disorder. The expression of alpha-galactosidase A was transiently silenced by RNA interference in HK2 and primary human renal epithelial cells and stably silenced in HK2 cells by retroviral transfection with small hairpin RNA. All of the silenced cells had histological similarities to cells of patients with Fabry disease. The cells had reduced viability, significant accumulation of intracellular Gb3, and a modest but significant increase in membranous Gb3 expression compared to nonsilenced cells. When silenced HK2 cells were reconstituted with agalsidase-alpha, a protein used for enzyme replacement therapy, they decreased their membranous CD77 expression to levels indistinguishable from those of nonsilenced cells. Because plasma and urinary Gb3 levels are not reliable biomarkers for Fabry disease, our study suggests that membranous CD77 levels mirror Gb3 tissue load and that CD77 expression levels may be used to monitor the efficacy of enzyme replacement therapy.

Immunoadsorption with tryptophan columns: a therapeutic option for the treatment of rheumatoid arthritis with septic complications.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting multiple organs and tissues. Although there is a wide range of therapeutic applications, the coexistence of severe side effects and contraindications outlines the necessity of new therapeutic options in the treatment of severe RA. We report on the case of a 71-year-old patient with successful treatment of a complicated RA with tryptophan immunoadsorption combined with low-dose steroids. Bacterial spondylitis developed in this patient during long-term treatment with infliximab and methotrexate. Weekly immunoadsorption sessions with tryptophan columns resulted in continuous suppression of RA activity over a period of more than 5 months, as indicated by laboratory findings, the disease activity score, and the visual analog scale. This is the first report of successful treatment of a refractory and complicated RA using tryptophan immunoadsorption columns. In conclusion, immunoadsorption is a safe and effective therapeutic alternative, which should be considered to bridge infectious complications in patients with severe RA.