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Objective To identify the prognostic significance of the location of lymph node metastases in patients with esophageal or gastroesophageal junction (GEJ) adenocarcinoma treated with neoadjuvant therapy followed by esophagectomy. Background Detection of lymph node metastases in the upper mediastinum and around the celiac trunk after neoadjuvant therapy and resection does not alter the TNM classification of esophageal carcinoma. The impact of these distant lymph node metastases on survival remains unclear. Methods Between March 2003 and September 2013, 479 consecutive patients with adenocarcinoma of the distal esophagus or GEJ who underwent transthoracic esophagectomy with en bloc 2-field lymphadenectomy after neoadjuvant therapy were included, and survival was analyzed according to the location of positive lymph nodes in the resection specimen. Results Two hundred fifty-three patients had nodal metastases in the resection specimen. Of these patients, 92 patients had metastases in locoregional nodes, 114 patients in truncal nodes, 21 patients in the proximal field of the chest, and 26 patients had both positive truncal and proximal field nodes. Median disease-free survival was 170 months in the absence of nodal metastases, 35 months for metastases limited to locoregional nodes, 16 months for positive truncal nodes, 15 months for positive nodes in the proximal field, and 8 months for nodal metastases in both truncal and the proximal field. On multivariate analysis, location of lymph node metastases was independently associated with survival. Conclusions Location of lymph node metastases is an independent predictor for survival. Relatively distant lymph node metastases along the celiac axis and/or the proximal field have a negative impact on survival. Location of lymph node metastases should therefore be considered in future staging systems of esophageal and GEJ adenocarcinoma.

Background Anastomotic leakage is one of the most severe complications following esophageal surgery, leading to significant morbidity, prolonged hospital stay, considerable costs, decreased quality of life, and increased mortality. Management of anastomotic leakage is complicated and has currently not been standardized. The objective of this research is to gain insight into the different opinions on anastomotic leakage management among upper gastrointestinal surgeons and verify the need for diagnostic and treatment guidelines. Methods Surgeons with interest in esophageal surgery were invited to participate in an international online questionnaire. The survey consisted of questions pertaining to the surgeons' experience, operation techniques, management routine, and opinion on future international guidelines on the treatment of anastomotic leakage. Results Of the 331 invited surgeons, 40% participated in the survey. Among the 129 responders, 90.7% use laboratory diagnostics and 62.8% use imaging or endoscopy postoperatively on a routine basis to detect anastomotic leakage. In case of suspected anastomotic leakage, the most chosen diagnostic imaging modalities were computed tomography scan (35.7%) or dynamic swallow investigation (33.3%). Independent from the clinical manifestations, participants of this survey treat patients very differently. More than 70% of the responders agreed that there is a need for diagnostic and therapeutic international guidelines on anastomotic leakage management. Conclusions This survey shows that there is no standardized guideline for diagnostic workup or management of anastomotic leakage and that there is a need for an international guideline regarding the optimal management of anastomotic leakage.

Background Goal-directed therapy (GDT) can reduce postoperative complications in high-risk surgery patients. It is uncertain whether GDT has the same benefits in patients undergoing esophageal surgery. Goal of this Quality Improvement study was to evaluate the effects of a stroke volume guided GDT on post-operative outcome. Methods and findings We compared the postoperative outcome of patients undergoing esophagectomy before (99 patients) and after (100 patients) implementation of GDT. There was no difference in the proportion of patients with a complication (56% vs. 54%, p = 0.82), hospital stay and mortality. The incidence of prolonged ICU stay (>48 hours) was reduced (28% vs. 12, p = .005) in patients treated with GDT. Secondary analysis of complication rate showed a decrease in pneumonia (29 vs. 15%, p = .02), mediastinal abscesses (12 vs. 3%, p = .02), and gastric tube necrosis (5% vs. 0%, p = .03) in patients treated with GDT. Patients in the GDT group received significantly less fluids but received more colloids. Conclusions The implementation of GDT during esophagectomy was not associated with reductions in overall morbidity, mortality and hospital length of stay. However, we observed a decrease in pneumonia, mediastinal abscesses, gastric tube necrosis, and ICU length of stay.

Background For patients with locally advanced esophageal cancer, radical esophageal resection with gastric tube reconstruction preceded by chemo(radio)therapy offers the best chance for cure. Anastomotic leakage (AL) is one of the most severe complications following esophageal surgery, leading to significant morbidity, prolonged hospital stay, considerable costs, decreased quality of life and increased mortality. Management is complicated and not standardized. The objective is to gain insight into the different opinions on AL management among upper gastrointestinal surgeons and to verify the need for a diagnostic and treatment guideline. Methods Surgeons with particular interest in esophageal surgery, were invited to participate in an online questionnaire. The survey consisted of questions pertaining to the surgeons’ experience, operation characteristics, management routine and their opinion on international guidelines on the diagnosis and therapy of AL. Results Of the 331 invited physicians, 40% participated in the survey. 90.7% Use laboratory diagnostics and 62.8% imaging and/or endoscopy postoperatively on routine basis. In case of suspected AL, the first choice of diagnostic imaging modalities was mostly a CT scan (35.7%) or a dynamic swallow investigation (33.3%). In case of AL, indepently of the clincal manifestations (local symptoms only, medianstinal manifestations or In case of gastric conduit necrosis) the treatment strategies differed widely between surgeons (table 1). Over 70% of the responders agree that there is a need for a solid international guideline on AL management. Conclusion There is no general consensus in the management of AL. There is a need for an international guideline regarding the optimal management of AL. Disclosure All authors have declared no conflicts of interest.

BACKGROUND: A globally accepted standard first-line chemotherapy regimen in advanced esophagogastric cancer (AEGC) is not clearly established. We conducted a systematic review to investigate the efficacy and safety of first-line chemotherapy using Network meta-analysis (NMA). METHODS: Medline, EMBASE, CENTRAL, and conferences were searched until June 2015 for randomized controlled trials that compared regimens containing: fluoropyrimidine (F), platinum (cisplatin [C] and oxaliplatin [Ox]), taxane (T), anthracycline (A), irinotecan (I), or methotrexate (M). Direct and indirect evidence for overall survival (OS) and progression-free-survival (PFS) were combined using random-effects NMA on the hazard ratio (HR) scale and calculated as combined hazard ratios and 95% credible intervals (CrIs). RESULTS: The NMA incorporated 17 chemotherapy regimens with 37 direct comparisons between regimens for OS (50 studies, n = 10 249) and 29 direct comparisons for PFS (34 studies, n = 7795). Combining direct and indirect effects showed increased efficacy for fluoropyrimidine noncisplatin doublets (F-doublets) over cisplatin doublets (C-doublets): FI vs CF (combined HR = 0.85, 95% CrI = 0.71 to 0.99), FOx vs CF (combined HR = 0.83, 95% CrI = 0.71 to 0.98) in OS and FOx vs CF (combined HR = 0.82, 95% CrI = 0.66 to 0.99) in PFS. Anthracycline-containing triplets (A-triplets: ACF, AFOx, AFM) and TCF triplet showed no benefit over F-doublets in OS and PFS. The triplet FOxT showed increased PFS vs F-doublets FT (combined HR = 0.61, 95% CrI = 0.38 to 0.99), FI (combined HR = 0.62, 95% CrI = 0.38 to 0.99), and FOx (combined HR = 0.67, 95% CrI = 0.44 to 0.99). Increased grade 3 to 4 toxicity was found for CF vs F-doublets, for ACF vs FI for TCF vs CF, and for FOxT vs FOx. CONCLUSIONS: Based on efficacy and toxicity, F-doublets FOx, FI, and FT are preferred as first-line treatment for AEGC compared with C-doublets, A-triplets, and TCF. FOxT is the most promising triplet.

Worldwide an increasing part of oncologic oesophagectomies is performed in a minimally invasive way. Over the past decades multiple reports have addressed the perioperative outcomes and oncologic safety of minimally invasive oesophageal surgery. Although many of these (retrospective) case-control studies identified minimally invasive oesophagectomy as a safe alternative to open techniques, the clear benefit remained subject to debate. Recently, this controversy has partially resolved due to the results of the first randomized controlled trial that compared both techniques. In this trial short-term benefits of minimally invasive oesophagectomy were demonstrated in terms of lower incidence of pulmonary infections, shorter hospital stay and better postoperative quality of life. However, the current lack of long-term data on recurrence rate and overall survival precludes a comprehensive comparison of minimally invasive and open oesophagectomy. Proclaiming minimally invasive oesophagectomy as the standard of care for patients with resectable oesophageal cancer would therefore be a premature decision.

Mesenchymal stem cells (MSC) are emerging as novel cell-based delivery agents; however, a thorough investigation addressing their therapeutic potential in medulloblastomas (MB) has not been explored to date. In this study, we engineered human MSC to express a potent and secretable variant of a tumor specific agent, tumor necrosis factor-apoptosis-inducing ligand (S-TRAIL) and assessed the ability of MSC-S-TRAIL mediated MB killing alone or in combination with a small molecule inhibitor of histone-deacetylase, MS-275, in TRAIL-sensitive and -resistant MB in vitro and in vivo. We show that TRAIL sensitivity/resistance correlates with the expression of its cognate death receptor (DR)5 and MSC-S-TRAIL induces caspase-3 mediated apoptosis in TRAIL-sensitive MB lines. In TRAIL-resistant MB, we show upregulation of DR4/5 levels when pre-treated with MS-275 and a subsequent sensitization to MSC-S-TRAIL mediated apoptosis. Using intracranially implanted MB and MSC lines engineered with different combinations of fluorescent and bioluminescent proteins, we show that MSC-S-TRAIL has significant anti-tumor effects in mice bearing TRAIL-sensitive and MS-275 pre-treated TRAIL-resistant MBs. To our knowledge, this is the first study that explores the use of human MSC as MB-targeting therapeutic-vehicles in vivo in TRAIL-sensitive and resistant tumors, and has implications for developing effective therapies for patients with medulloblastomas.

The resistance of glioma cells to a number of antitumor agents and the highly invasive nature of glioma cells that escape the primary tumor mass are key impediments to the eradication of tumors in glioma patients. In this study, we evaluated the therapeutic efficacy of a novel PI3-kinase/mTOR inhibitor, PI-103, in established glioma lines and primary CD133+ glioma-initiating cells and explored the potential of combining PI-103 with stem cell–delivered secretable tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) both in vitro and in orthotopic mouse models of gliomas. We show that PI-103 inhibits proliferation and invasion, causes G0–G1 arrest in cell cycle, and results in significant attenuation of orthotopic tumor growth in vivo. Establishing cocultures of neural stem cells (NSC) and glioma cells, we show that PI-103 augments the response of glioma cells to stem cell–delivered S-TRAIL. Using bimodal optical imaging, we show that when different regimens of systemic PI-103 delivery are combined with NSC-derived S-TRAIL, a significant reduction in tumor volumes is observed compared with PI-103 treatment alone. To our knowledge, this is the first study that reveals the antitumor effect of PI-103 in intracranial gliomas. Our findings offer a preclinical rationale for application of mechanism-based systemically delivered antiproliferative agents and novel stem cell–based proapoptotic therapies to improve treatment of malignant gliomas. Cancer Res; 71(1); 154–63. ©2010 AACR.

Background Prognosis of esophageal cancer patients can be significantly improved by neoadjuvant chemoradiotherapy (nCRT). Given the aggressive nature of esophageal tumors, it is conceivable that in a significant portion of patients treated with nCRT, dissemination already becomes manifest during the period of nCRT. The aim of this retrospective study was to determine the value and diagnostic accuracy of PET-CT after neoadjuvant chemoradiotherapy to identify patients with metastases preoperatively in order to prevent non-curative surgery. Methods From January 2011 until February 2013 esophageal cancer patients deemed eligible for a curative approach with nCRT and surgical resection underwent a PET-CT after completion of nCRT. If abnormalities on PET-CT were suspected metastases, histological proof was acquired. A clinical decision model was designed to assess the cost-effectiveness of this diagnostic strategy. Results 156 patients underwent a PET-CT after nCRT. In 31 patients (19.9%) PET-CT showed abnormalities suspicious for dissemination, resulting in 17 cases of proven metastases (10.9%). Of the patients without proven metastases 133 patients were operated. In 6 of these 133 cases distant metastases were detected intraoperatively, corresponding to 4.5% false-negative results. The standard introduction of a post-neoadjuvant therapy PET-CT led to a reduction of overall health care costs per patient compared to a scenario without restaging with PET-CT ($34,088 vs. $36,490). Conclusion In 10.9% of esophageal cancer patients distant metastases were detected by standard PET-CT after neoadjuvant chemoradiotherapy. To avoid non-curative resections we advocate post-neoadjuvant therapy PET-CT as a cost-effective step in the standard work-up of candidates for surgery.

4066 Background: The tumor regression grade (TRG) is used to define the response to preoperative chemoradiotherapy for esophageal carcinoma. The aim of this study was to determine whether inclusion...

e15024 Background: Recurrent disease (RD) after potentially curative treatment for esophageal or junctional cancer is common and survival after recurrence is poor. Potentially curative strategies are possible in limited occasions and palliative systemic therapy or supportive care are often the only therapies possible. Little is known about survival after recurrence and factors influencing treatment success. We aimed to assess the recurrence patterns and overall survival (OS) of patients who developed RD after curative treatment. Methods: Patients with RD of esophageal or junctional cancer between 1994 and 2014 after potentially curative esophagectomy preceded by neoadjuvant chemo(radio)therapy were included in this retrospective cohort study. A logistic regression analysis was performed to assess predictive factors for receiving treatment aimed at radical tumor eradication. Results: Recurrence was diagnosed in 219 of 503 patients (43.5%). 212 of 219 patients (96.8%) were evaluable for dissemination patter...

e15083 Background: Recently, there has been an increasing interest in the potential role of statins on pCR rates and survival in different types of cancer. However, no studies explored the role of ...

Gliomas are difficult to eradicate due to several factors: a) the lack of efficient delivery of anti-tumor agents to the tumors without affecting the normal brain tissue; b) the inherent or acquired resistance of tumor cells to anti-tumor agents; and c) the highly invasive nature of tumor cells that escape the primary tumor mass and subsequently cause recurrence. We previously established that a secreted form of tumor necrosis factor-related apoptosis inducing ligand (S-TRAIL) specifically eradicates glioma cells when delivered by various stem cell types in culture and in orthotopic glioma models. However, recent evidence has shown that a number of established and primary glioma lines have varying degrees of resistance to TRAIL, due to the heterogeneity of genetic alterations and possibly due to the over-activation of phosphatidylinositol 3 kinase (PI3K) pathway. In this study, we report the effect of a novel PI3K inhibitor, PI-103, alone or in combination with neural stem cell (NSC)-delivered S-TRAIL in mouse models of malignant and invasive gliomas. Using established and primary CD133+ glioma initiating cells engineered to express fluorescent and bioluminescent markers, we show that PI-103 alone inhibits proliferation and invasion, and causes G0-G1 arrest in cell cycle of most of the glioma cells tested. Furthermore, PI-103 augments the response of glioma cells to stem cell delivered S-TRAIL in co-cultures of NSCs and glioma cells suggesting that it can synergize with S-TRAIL-induced apoptosis. Using orthotopic malignant glioma models and bioluminescence imaging, PI-103 treatment in combination with NSC-derived S-TRAIL was shown to result in significant reduction in tumor volumes compared to either treatment alone in vivo. Our results reveal that combination of the novel PI3K inhibitor, PI-103, and stem cell delivered TRAIL might represent a novel therapy for malignant gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3495.