• Pancho trial (p53-adapted neoadjuvant chemotherapy for resectable esophageal cancer) completed-mutation rate of the marker higher than expected.

BACKGROUND: In operable esophageal cancer patients, neoadjuvant therapy benefits only those who respond to the treatment. The • Pancho trial represents the first prospective randomized trial evaluating the relevance of the mark53 status for predicting the effect of two different neoadjuvant chemotherapies. METHOD: Biomarker analysis was conducted using the mark53 analysis. Calculation of patient number needed was based on a 60% rate of marker positivity, deduced from the results of a phase II pilot study. RESULTS: From 2007-2012, the • Pancho trial recruited 235 patients with operable esophageal cancer in Austria. A total of 181 patients were eligible and could be subjected to mark53 analysis and randomization. After randomizing 74 patients, the overall TP53 mutation rate was 79%. However, due to the high prevalence of marker positivity, the number of projected patients was increased to 181 patients in order to ensure a sufficient number of marker-negative patients. After completion of the trial, the overall TP53 mutation rate was 77.9%. CONCLUSION: Due to high medical need, the recruitment for the academic trial was excellent. Mark53 analysis clearly detected more mutations in the TP53 gene as compared to the cancer-specific p53 literature. Final analysis examining the interaction between the mark53 status and the effect of chemotherapies applied in the • Pancho trial is now awaited.

Subclinical involvement of the liver is associated with prognosis in treatment naïve cancer patients.

BACKGROUND: Routinely tested liver biomarkers as alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), butyryl-cholinesterase (BChE), albumin and bilirubin are altered in distinct malignancies and hepatic metastases. This study aimed to investigate whether all liver parameters have the ability to predict long-term mortality in treatment naïve cancer patients but without a malignant hepatic involvement. METHODS: We prospectively enrolled 555 consecutive patients with primary diagnosis of cancer without prior anticancer therapy. BChE, albumin, AST, ALT, GGT and bilirubin as well as the inflammatory makers C-reactive protein (CRP), serum amyloid A (SAA) and interleukin-6 (IL-6) were determined. All-cause mortality was defined as primary endpoint. RESULTS: During a median follow-up of 25 (IQR16-31) months 186 (34%) patients died. All liver parameters were significantly associated with all-cause mortality (p < 0.001 for all). However, for patients without a malignant primary or secondary hepatic involvement (82%) only the functional parameters BChE and albumin remained significantly associated with the primary endpoint (crude HR per 1-IQR increase 0.61, 95%CI:0.49-0.77; p < 0.001 for BChE and 0.58, 95%CI:0.47-0.70; p < 0.001 for albumin). This e ect was persistent after multivariate adjustment (adj.HR per 1-IQR increase 0.65, 95%CI:0.50-0.86; p = 0.002 for BChE and 0.63, 95%CI:0.50-0.79; p < 0.001 for albumin). BChE and albumin correlated inversely with CRP (r = -0.21, p < 0.001 and r = -0.36, p < 0.001), SAA (r = -0.19, p < 0.001 and r = -0.33, p < 0.001) and IL-6 (r = -0.13, p = 0.009 and r = -0.17, p = 0.001). CONCLUSIONS: Decreased serum BChE and albumin levels are associated with increased all-cause mortality in treatment-naïve cancer patients without a manifest malignant hepatic involvement irrespective of tumor entity or stage. This association may reflect progressing systemic inflammation and metabolic derangement with subclinical involvement of the liver.

Oxaliplatin/Irinotecan/Bevacizumab Followed by Docetaxel/Bevacizumab in Inoperable Locally Advanced or Metastatic Gastric Cancer Patients - AGMT_GASTRIC-3.

BACKGROUND/AIM: Although high response rates using the doublet-chemotherapy of oxaliplatin and irinotecan as well as its combination with cetuximab in advanced gastric cancer were shown in previous trials, time to progression was short, suggesting acquired chemotherapy resistance. PATIENTS AND METHODS: Sequential chemotherapy (oxaliplatin and irinotecan followed by docetaxel) combined with bevacizumab was investigated in the GASTRIC-3 trial. Patients achieving at least stable disease were continued on maintenance bevacizumab. RESULTS: Objective response rate was available in 33 patients: Complete response (CR) 12.1%, partial response (PR) 39.4%, stable disease (SD) 27.3%. Median time to progression was 7.0 months (95%CI=5.0-11.0) and median overall survival was 11 months (95%CI=9.0-15.0). Of note, two patients continue to receive bevacizumab maintenance therapy for more than 5 years with ongoing CR. CONCLUSION: Combining sequential chemotherapy with oxaliplatin/irinotecan and docetaxel with bevacizumab followed by bevacizumab maintenance is feasible and clinically active in advanced gastric cancer.

Cutaneous paraneoplastic disorders in stomach cancer: Collaboration between oncologically active dermatologists and clinical oncologists.

To our knowledge this is the first systemic review that provides an overview of the cutaneous paraneoplastic syndromes (CPS) (i.e., clinical manifestations, pathomechanisms, and treatment modalities) occurring in stomach cancer. CPS are caused by substances produced by stomach cancer and may precede, coincide with, or follow the diagnosis of this malignancy. More than 20 possible CPS in association with stomach cancer have been identified. CPS mostly compromises the patient's quality of life by skin impairment plus discomfort and are often associated with a dismal prognosis on survival. Studies of these CPS not only in stomach cancer have partially contributed to the understanding of pathomechanism and since CPS may be the presenting sign of an occult cancer, cognizance of their features and clinical implications are of considerable importance. Patients with these syndromes should have an appropriate work-up for a possibly occult malignancy with consecutive successful early treatment.

Change in volume parameters induced by neoadjuvant chemotherapy provide accurate prediction of overall survival after resection in patients with oesophageal cancer.

OBJECTIVES: To assess the prognostic value of volumetric parameters measured with CT and PET/CT in patients with neoadjuvant chemotherapy (NACT) and resection for oesophageal cancer (EC). METHODS: Patients with locally advanced EC, who were treated with NACT and resection, were retrospectively analysed. Data from CT volumetry and (18) F-FDG PET/CT (maximum standardized uptake [SUVmax], metabolic tumour volume [MTV], and total lesion glycolysis [TLG]) were recorded before and after NACT. The impact of volumetric parameter changes induced by NACT (MTVRATIO, TLGRATIO, etc.) on overall survival (OS) was assessed using a Cox proportional hazards model. RESULTS: Eighty-four patients were assessed using CT volumetry; of those, 50 also had PET/CT before and after NACT. Low post-treatment CT volume and thickness, MTV, TLG, and SUVmax were all associated with longer OS (p < 0.05), as were CTthicknessRATIO, MTVRATIO, TLGRATIO, and SUVmaxRATIO (p < 0.05). In the multivariate analysis, only MTVRATIO (Hazard ratio, HR 2.52 [95% Confidence interval, CI 1.33-4.78], p = 0.005), TLGRATIO (HR 3.89 [95%CI 1.46-10.34], p = 0.006), and surgical margin status (p < 0.05), were independent predictors of OS. CONCLUSIONS: MTVRATIO and TLGRATIO are independent prognostic factors for survival in patients after NACT and resection for EC. KEY POINTS: • Change in PET parameters shows close correlation to survival in oesophageal cancer. • Association with OS is independent of changes in SUVmax and CT volume. • Metabolic parameters after NACT correlate with pathologic response and nodal status. • Metabolic parameters may be better suited than SUVmax for response assessment.

Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality.

OBJECTIVE: Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer. METHODS: We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint. RESULTS: During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP. CONCLUSIONS: Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

A pilot study of the endomicroscopic assessment of tumor extension in Barrett's esophagus-associated neoplasia before endoscopic resection.

BACKGROUND AND STUDY AIMS: Barrett's esophagus (BE) - associated neoplasia can be treated endoscopically, but accurate assessment before intervention is challenging. This study aimed to investigate the role of confocal laser endomicroscopy (CLE) as an adjunct in the endoscopic treatment of BE-associated neoplasia by assessing lateral tumor and subsquamous tumor (SST) extension. PATIENTS AND METHODS: In the context of a prospective, single-arm pilot clinical trial, patients referred for endoscopic resection of BE-associated neoplasia (high grade dysplasia and esophageal adenocarcinoma) underwent high definition, white light endoscopy with narrow-band imaging (NBI). Then, CLE mapping of suspected neoplastic lesions was performed by another endoscopist, partially blinded to the previous findings, before the patients underwent endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD), depending on lesion size and anticipated histology. RESULTS: In 7 of 38 patients (18 %), CLE revealed additional neoplastic tissue compared with prior white light endoscopy and NBI: 2 concomitant lesions, 2 cases of lateral tumor extension within the Barrett's epithelium, and 3 cases of previously undetected SST extension. Overall, en bloc resection (tumor-free lateral margin) was achieved in 28 of 34 neoplastic lesions (82 %), and complete resection (tumor-free lateral and basal margins) in 21 of 34 neoplastic lesions (62 %). CONCLUSIONS: CLE-assisted endoscopic resection of BE-associated neoplasia was safe and effective in this study, as proved by a high additional diagnostic yield of CLE (including visualization of occult SST extension) and a favorable rate of en bloc resection. The clinical value of CLE for assisting endoscopic therapy of BE-associated neoplasia deserves further evaluation in randomized controlled trials.

The biomarker TP53 divides patients with neoadjuvantly treated esophageal cancer into 2 subgroups with markedly different outcomes. A p53 Research Group study.

BACKGROUND: Fluorouracil and cisplatin have been used most frequently as neoadjuvant therapy for esophageal cancer. Both drugs are believed to act via a p53-dependent apoptosis pathway. The TP53 gene is frequently mutated in esophageal cancer. OBJECTIVE: To test the value of TP53 as a biomarker prognosing outcome in patients with neoadjuvantly treated esophageal cancer. PATIENTS AND METHODS: The investigation included 36 patients with primary operable esophageal cancer who were treated neoadjuvantly with cisplatin and fluorouracil. The TP53 genotype was assessed from paraffin-embedded diagnostic tumor biopsies using a standardized gene-specific TP53 sequencing protocol (mark53 kit; mark53 Ltd, Vienna, Austria). RESULTS: Mutations in the TP53 gene were present in 50% of tumors. Two-year overall survival rates were 55.6% in patients with a normal TP53 marker status, compared with 16.7% in those with a mutant TP53 gene. In patients with normal TP53, neoadjuvant treatment resulted in significant advantages in terms of tumor-associated survival (P=.0049) and overall survival (P=.0304) compared with those with mutant TP53. The median tumor-associated survival was 34.2 months for patients with normal TP53, compared with 8.9 months for those with mutant TP53. The latter had a 3-fold higher risk of dying (hazard ratio, 3.01; 95% confidence interval, 1.359-6.86). CONCLUSIONS: The biomarker TP53 divides esophageal cancer patients into 2 categories with markedly different outcomes: patients with a normal TP53 marker status may experience notable benefits from neoadjuvant chemotherapy with cisplatin/fluorouracil, whereas those with a mutant TP53 marker status appear to be at risk for lack of response.

Comparison between DCF (Docetaxel, Cisplatin and 5-Fluorouracil) and modified EOX (Epirubicin, Oxaliplatin and Capecitabine) as palliative first-line chemotherapy for adenocarcinoma of the upper gastrointestinal tract.

BACKGROUND: The efficacy of triple-drug combination regimens such as docetaxel, cisplatin and 5-fluorouracil (DCF), and epirubicin, oxaliplatin and capecitabine (EOX), is superior to standard cisplatin/5-fluorouracil in patients with upper gastrointestinal adenocarcinoma. In this analysis, we compare DCF and EOX regarding toxicity and efficacy. PATIENTS AND METHODS: Patients received either intravenous docetaxel at 75 mg/m(2), cisplatin at 75 mg/m(2), both given on day 1, and 5-fluorouracil at 750 mg/m(2), on days 1 to 5, or epirubicin at 50 mg/m(2) i.v. on day 1, oxaliplatin at 130 mg/m(2) i.v. on day 1 and capecitabine at a twice-daily dose of 1000 mg/m(2) p.o. for two weeks; both regimens were repeated every three weeks. RESULTS: Response rates for DCF and EOX were 28% and 10%, time-to-progression was 26 and 20 weeks, and overall survival were 54 and 52 weeks, respectively. CONCLUSION: We conclude that further investigations within comparative prospective clinical trials of these regimens are warranted.

The implementation of minimally-invasive esophagectomy does not impact short-term outcome in a high-volume center.

BACKGROUND: Esophagectomy represents the gold standard in the treatment of resectable esophageal cancer. Despite significant improvements in perioperative care, postoperative morbidity and mortality rates remain high. Minimally-invasive surgical techniques introduced to the surgical treatment of esophageal malignancies have been shown to successfully diminish surgical trauma and postoperative morbidity. AIM: In the present report we present the stepwise implementation of minimally-invasive techniques in the treatment of esophageal cancer at a high-volume center and its influence on overall patient outcome. PATIENTS AND METHODS: A total of 165 consecutive patients with esophagectomy, in two 4-year periods, namely that before (period A) and that after (period B) the implementation of minimally-invasive esophagectomy (MIE) for cancer, were compared. Patients' characteristics, and perioperative, surgical, oncological and survival outcomes were compared. RESULTS: In time period A, 73 patients were treated with open esophagectomy (OE), whereas in time period B 37 patients (40.2%) underwent an OE and 55 (59.8%) a minimally-invasive esophagectomy. Surgical and non-surgical complications did not differ significantly between groups (B: 44.6% vs. A: 54.8%; B: 38% vs. A: 35.6%; p>0.05). Duration of ventilation (B: 1.8 days vs. A: 6.7 days), ICU (B: 5.7 days vs. A: 12.2 days) and hospital stay (B: 20.5 days vs. A: 28.4 days) were significantly reduced in patients of time period B. The number of lymph nodes removed and complete resection rates were comparable (mean=18.1 ± 10.1 lymph nodes; B: 87% R0 vs. A: 93.2% R0). No significant differences between the groups were detectable regarding short-term disease-free or overall survival. CONCLUSION: The implementation of minimally-invasive esophagectomy is feasible, safe and has the potential to reduce perioperative morbidity without compromising oncological outcome.

Modified EOX (Epirubicin, Oxaliplatin and Capecitabine) as palliative first-line chemotherapy for gastroesophageal adenocarcinoma.

BACKGROUND: The efficacy of triple-drug combination regimens such as epirubicin, oxaliplatin and capecitabine (EOX) is superior to standard cisplatin/5-fluorouracil, but considerable toxicity needs to be taken into account in patients with upper gastrointestinal adenocarcinoma. Therefore, we aimed to establish a modified version of the EOX regimen with improved tolerability for these patients. PATIENTS AND METHODS: Patients received palliative first-line chemotherapy with a modified EOX regimen repeated every three weeks (epirubicin 50 mg/m(2) i.v., day 1; oxaliplatin 130 mg/m(2) i.v., day 1; capecitabine at a twice-daily dose of 1000 mg/m(2) p.o. for two weeks). RESULTS: Out of 51 patients, partial remission was observed in five (10.2%) and stable disease in 31 (60.8%). Progression-free survival was four months, and overall survival twelve months. CONCLUSION: Modified EOX was generally well-tolerated and, therefore, further investigation within prospective clinical trials is warranted.

Brain metastases of gastro-oesophageal cancer: evaluation of molecules with relevance for targeted therapies.

BACKGROUND: Brain metastases (BM) of gastro-oesophageal cancer are exceedingly rare and only limited data exist on their pathobiology. MATERIALS AND METHODS: We identified tissue samples of BM of gastro-oesophageal cancer and analyzed the expression of human epidermal growth factor receptor-2 (HER2), phosphorylated signal transducer and activator of transcription-3 (pSTAT3), epithelial growth factor receptor (EGFR), V600E point mutation of the v-raf murine sarcoma viral oncogene homolog-B1 (BRAF V600E), cluster of differentiation molecule-34 (CD34), hypoxia inducible factor-1α (HIF 1-α) and Ki-67 by immunohistochemical methods. RESULTS: Our series comprised of twenty adenocarcinomas and one oesophageal squamous cell carcinoma. Three (14%), 7 (33%), 9 (43%), 18 (86%) and 0 BM specimens were scored positively for HER2, EGFR, pSTAT3, HIF1-α and BRAF V600E expression. The median Ki-67 index was 59%. The microvascular density was moderate-to-high and active intratumoral microvascular sprouting was evident in 20/21 (95%) of BMs. The HER2 and EGFR expression status were consistent between primary tumors and BM in all three assessable cases. HIF1-α and pSTAT3 expression were significantly higher in HER2-positive cases. CONCLUSION: Therapeutic use of agents targeting HER2, pSTAT3, EGFR and angiogenesis may be feasible for selected BM of gastro-esophageal cancer. HER2 positivity does not seem to predispose to brain colonization in gastro-esophageal cancer.

No evidence for BRAF-V600E mutations in gastroeosophageal tumors: results from a high-throughput analysis of 534 cases using a mutation-specific antibody.

BACKGROUND: BRAF-V600E mutations are found in a broad spectrum of cancer types and can be successfully targeted by specific therapeutic compounds. Little data on the prevalence of BRAF-V600E mutations in tumors of the upper gastrointestinal tract are available. MATERIALS AND METHODS: We constructed tissue microarrays of formalin-fixed and paraffin-embedded specimens of 534 gastroesophageal tumors (119 squamous cell cancers and 72 adenocarcinomas of the esophagus, 63 cancers of the gastroesophageal junction/cardia, 199 gastric cancers of the corpus or antrum, 81 gastric gastrointestinal stromal tumors) and performed anti-BRAF-V600E immunostaining using the mutation-specific antibody VE1. As control tissue we used 3 melanoma cases with confirmed BRAF-V600E mutation and distinct VE1 immunostaining. RESULTS: None of the gastroesophageal tumor cases showed a positive immunostaining signal. CONCLUSIONS: BRAF-V600E mutation is not a relevant oncogenic driver in gastroesophageal tumors. Immunohistochemical analysis using mutation-specific antibodies on tissue microarrays is a feasible, time-efficient and cost-efficient approach to high-throughput screening for specific mutations in large tumor series.

Lack of correlation between blood group and HER-2 status in adenocarcinomas of the upper gastrointestinal tract.

The assessment of the human epidermal growth factor receptor-2 (HER-2) status has become a routine diagnostic procedure for patients with advanced-stage gastroesophageal adenocarcinoma. The aim of this study was to evaluate the possible correlation between the HER-2 status and the ABO blood group. HER-2 status determination and routine ABO typing was performed according to current standards. We evaluated the correlation between the HER-2 status and the ABO and Rhesus (Rh) system in 100 consecutive patients with adenocarcinoma of the upper gastrointestinal tract. There were no significant differences between HER-2 status and ABO and Rh system. Furthermore, no correlation was observed between the HER-2 status and the ABO and Rh type in patients with adenocarcinoma of the upper gastrointestinal tract.

Pre- and postoperative treatment modalities for esophageal squamous cell carcinoma.

BACKGROUND: The objective of this article was to review randomized clinical trials (RCTs) utilizing pre- and postoperative treatment modalities for esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: A computerized (MEDLINE) and manual search was performed to identify articles published on this topic between 1984 and 2012. RESULTS: We identified a total of 49 published RCTs, which included a total of 8,785 patients with ESCC. Treatment modalities consisted of pre- (n=38) and postoperative (n=11) chemo-, radio- and chemoradiotherapy. While both preoperative chemotherapy and chemoradiotherapy apparently improve R0 resection, they often result in substantial postoperative morbidity and mortality. Only for preoperative chemoradiotherapy does there seem to be a significant benefit in overall survival. CONCLUSION: R0 resection remains the only curative therapy for patients with ESCC. While preoperative chemoradiotherapy may improve overall survival, there is still the need for well-designed RCTs, which should include a homogeneous patient collective, to clarify the question of definitive benefit.

Her-2/neu gene amplification and over-expression in stomach and esophageal adenocarcinoma: from pathology to treatment.

Discovery of the over-expression of Her-2/neu or the amplification of its regulatory gene in stomach and esophageal cancer has resulted in targeted treatment directed at this protein. The fact itself and its consequences have been the topic of an abundance of studies and clinical trials. In the present report we review the current state of the art as regards diagnosis of the over-expression and amplification of Her-2/neu, its inhibition as a new therapeutic concept, treatment toxicity, and the development of resistance to Her-2/neu as a limiting factor in stomach and esophageal adenocarcinoma.

Esophageal cancer: a critical evaluation of systemic second-line therapy.

The objective of this article was to review clinical trials that used antineoplastic second-line chemotherapy and/or targeted therapies in patients with esophageal cancer after first-line therapy. Computerized (MEDLINE) and manual searches were performed to identify articles published on this topic between 1996 and 2011. Twenty-five published trials and four abstracts presented at scientific meetings were identified. A total of 10 trials included only patients with squamous cell carcinomas (SCCs), four focused exclusively on adenocarcinoma (AC), the remaining 15 studies included both SCC and AC. The majority of trials (17 of 29) used docetaxel in combination with platinum analogs, eight used single-agent cytotoxic chemotherapy, and six evaluated targeted therapies. The numbers of patients were relatively small, ranging from eight to 55 patients. The response rates were generally low (between 0% and 39%), with only two small studies reporting objective responses of 50% and 63%, respectively. Time to progression ranged from 1.4 to 6.2 months, and the overall survival was disappointing at 4.0 to 11.4 months. Approximately 40% of patients who experience progressive disease after first-line chemotherapy are able to undergo second-line treatment. On the basis of data published so far, no standard second-line therapy has emerged. Future research will need to focus on individual therapy strategies such as genetic receptor mutations to increase the therapeutic outcome.

Docetaxel, cisplatin and 5-fluorouracil plus granulocyte colony-stimulating factor prophylaxis in patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction: experience at the Medical University of Vienna.

BACKGROUND: A retrospective analysis was carried out to evaluate toxicity and efficacy of the combination chemotherapy of docetaxel, cisplatin and 5-fluorouracil (DCF) plus granulocyte colony-stimulating factor prophylaxis (G-CSF) in patients with metastatic gastric and gastroesophageal junction adenocarcinoma. PATIENTS AND METHODS: Eighteen patients received intravenous 75 mg/m2 docetaxel, 75 mg/m2 cisplatin, both given on day 1 and 750 mg/m2 5-fluorouracil, on days 1 to 5 plus G-CSF on day 6, all repeated every 3 weeks. RESULTS: Response rate was 28%, time to progression and overall survival were 26 and 54 weeks, respectively. The most common hematological WHO toxicities were anemia and leukocytopenia, which occurred in 18/18 and in 12/18 patients. WHO Grade 4 neutropenia occurred in one patient whereas nonhematological toxicity was generally mild. CONCLUSION: We conclude that DCF combination plus G-CSF prophylaxis is a safe and active regimen for patients with metastatic gastric and gastroesophageal junction adenocarcinoma.

Accuracy of hydro-multidetector row CT in the local T staging of oesophageal cancer compared to postoperative histopathological results.

OBJECTIVE: To evaluate the accuracy of multidetector computed tomography with water filling (Hydro-MDCT) in the T-staging of patients with oesophageal cancer. MATERIALS AND METHODS: There were 131 consecutive patients who were preoperatively and prospectively examined in the prone position on arterial phase contrast-enhanced MDCT, after ingestion of 1,000-1,500 ml tap water and effervescent granules. Two readers staged the local tumour growth (T-staging) independently. They assessed tumour location, size, presence of stenosis, and morphology of the outer border of the oesophageal wall and perioesophageal fat planes on CT. CT findings were compared with histopathological results from resected specimens. Data were analyzed using the SPSS statistical package. RESULTS: Both readers obtained a high sensitivity of 95% and a high positive predictive value of 96%. Accurate local staging was achieved in 76.3% and 68.7% for readers 1 and 2, respectively. Inter-reader agreement was excellent (weighted κ value of 0.93 and un-weighted κ of 0.89). CONCLUSION: Using the hydro-technique and applying specific assessment criteria, MDCT appears to be an accurate, non-invasive diagnostic tool for local tumour staging of oesophageal cancer.

Gastric cancer growth control by BEZ235 in vivo does not correlate with PI3K/mTOR target inhibition but with [18F]FLT uptake.

PURPOSE: In this study, we tested the antitumor activity of the dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor BEZ235 against gastric cancer in vitro and in vivo. EXPERIMENTAL DESIGN: Gastric cancer cell lines (N87, MKN45, and MKN28) were incubated with BEZ235 and assessed for cell viability, cell cycle, and PI3K/mTOR target inhibition. In vivo, athymic nude mice were inoculated with N87, MKN28, or MKN45 cells and treated daily with BEZ235. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) uptake was measured via small animal positron emission tomography (PET). RESULTS: In vitro, BEZ235 dose dependently decreased the cell viability of gastric cancer cell lines. The antiproliferative activity of BEZ235 was linked to a G(1) cell-cycle arrest. In vivo, BEZ235 treatment resulted in PI3K/mTOR target inhibition as shown by dephosphorylation of AKT and S6 protein in all xenograft models. However, BEZ235 treatment only inhibited tumor growth of N87 xenografts, whereas no antitumor effect was observed in the MKN28 and MKN45 xenograft models. Sensitivity to BEZ235 in vivo correlated with downregulation of the proliferation marker thymidine kinase 1. Accordingly, [(18)F]FLT uptake was only significantly reduced in the BEZ235-sensitive N87 xenograft model as measured by PET. CONCLUSION: In conclusion, in vivo sensitivity of gastric cancer xenografts to BEZ235 did not correlate with in vitro antiproliferative activity or in vivo PI3K/mTOR target inhibition by BEZ235. In contrast, [(18)F]FLT uptake was linked to BEZ235 in vivo sensitivity. Noninvasive [(18)F]FLT PET imaging might qualify as a novel marker for optimizing future clinical testing of dual PI3K/mTOR inhibitors.