Leila Sisic

Prognostic impact of lymph node involvement and the extent of lymphadenectomy (LAD) in adenocarcinoma of the esophagogastric junction (AEG)

BackgroundThe prognostic importance of lymph node (LN) involvement for patients with adenocarcinoma of the esophagogastric junction (AEG) is well-known. In the latest edition of the UICC staging system, the number of metastatic LNs was taken into account, while the extent of lymphadenectomy (LAD) remains unaddressed. Removal of at least six LNs is recommended, but there is no defined minimum number as to classify as (y)pN0. We examined the prognostic value of the number of positive LNs, number of LNs removed, and LN ratio (LNR) in order to determine the influence of an adequate LAD on overall survival (OS).MethodsWe analyzed data of 316 patients with AEG treated in our institution (2001–2011) regarding clinicopathological data, treatment, morbidity, mortality, and long-term prognosis. Univariate and multivariate analysis was performed using Cox regression to evaluate the prognostic impact of(y)pN category, number of LNs removed and LNR.ResultsOS decreased with higher count of positive LNs (p < 0.001) and higher LNR (p < 0.001). Whether >6, >15, or >30 LNs were removed did not influence OS, neither in the entire study population nor within individual (y)pT or (y)pN categories. Multivariate analysis revealed LNR (p < 0.001) besides M category (p = 0.015) and tracheotomy during the postoperative course (p = 0.005) as independent predictors of OS.ConclusionThe classification according to the number of involved LNs in the latest edition of the UICC staging system improves prognostication in patients with AEG. The importance of an adequate LAD is shown by the high prognostic relevance of the LNR rather than the absolute number of LNs removed.

Anti-angiogenic activity of VXM01, an oral T-cell vaccine against VEGF receptor 2, in patients with advanced pancreatic cancer: A randomized, placebo-controlled, phase 1 trial.

VEGFR-2 is expressed on tumor vasculature and a target for anti-angiogenic intervention. VXM01 is a first in kind orally applied tumor vaccine based on live, attenuated Salmonella bacteria carrying an expression plasmid, encoding VEGFR-2. We here studied the safety, tolerability, T effector (Teff), T regulatory (Treg) and humoral responses to VEGFR2 and anti-angiogenic effects in advanced pancreatic cancer patients in a randomized, dose escalation phase I clinical trial. Results of the first 3 mo observation period are reported. Locally advanced or metastatic, pancreatic cancer patients were enrolled. In five escalating dose groups, 30 patients received VXM01 and 15 placebo on days 1, 3, 5, and 7. Treatment was well tolerated at all dose levels. No dose-limiting toxicities were observed. Salmonella excretion and salmonella-specific humoral immune responses occurred in the two highest dose groups. VEGFR2 specific Teff, but not Treg responses were overall increased in vaccinated patients. We furthermore observed a significant reduction of tumor perfusion after 38 d in vaccinated patients together with increased levels of serum biomarkers indicative of anti-angiogenic activity, VEGF-A, and collagen IV. Vaccine specific Teff responses significantly correlated with reductions of tumor perfusion and high levels of preexisting VEGFR2-specific Teff while those showing no antiangiogenic activity had low levels of preexisting VEGFR2 specific Teff, showed a transient early increase of VEGFR2-specific Treg and reduced levels of VEGFR2-specific Teff at later time points – pointing to the possibility that early anti-angiogenic activity might be based at least in part on specific reactivation of preexisting memory T cells.

Surgery of gastric cancer and esophageal cancer: Does age matter?

In the past, elderly patients with upper GI cancers were excluded from surgery or multimodal treatment only due to their advanced age. In an aging society this way of patient selection seems to be questionable. The aim of this retrospective exploratory study was to investigate how patients with upper GI cancer over the age of 70 years differ from younger patients in the postoperative course and which parameters influence overall survival in older patient populations.

Serum microRNA profiles as prognostic/predictive markers in the multimodality therapy of locally advanced adenocarcinomas of the gastroesophageal junction

Neoadjuvant multimodality treatment is frequently applied to improve the poor prognosis of locally advanced adenocarcinomas of the gastroesophageal junction. This study aimed to asses if serum microRNA profiles are useable as response indicators in this therapeutic setting. Fifty patients with locally advanced adenocarcinomas of the gastroesophageal junction were included in the study. All patients received neoadjuvant therapy and subsequently underwent surgical resection. Histomorphologic regression was defined as major histopathological response when resected specimens contained less than 10% vital residual tumor cells. Circulating RNA was isolated from pretherapeutic/post‐neoadjuvant blood serum samples. RNA from nine patients was applied to PCR microarray analyses Based on these findings possible predictive miRNA markers were validated by quantitative RT‐PCR analyses. Depending on the histomorphologic regression, a differential serum microRNA profile was identified by microarray analyses. Based on the divergent miRNA pattern, miR‐21, miR‐192, miR‐222, miR‐302c, miR‐381 and miR‐549 were selected for further validation. During neoadjuvant therapy, there was a significant increase of miR 222 and miR‐549. Although on an expanded patient cohort, the six microRNAs could not be validated as markers for therapy response, there was a significant correlation between a high miR‐192 and miR‐222 expression with a high T‐category as well as miR‐302c and miR‐222 expression significantly correlated with overall survival. Comprehensive miRNA profiling showed a differential microRNA expression pattern depending on the histomorphologic regression in the multimodality therapy of locally advanced adenocarcinomas of the gastroesophageal junction. Moreover, using single RT‐PCR analyses a prognostic impact of miR‐222 and miR‐302c was detected.

Inflammatory cytokines are associated with response and prognosis in patients with esophageal cancer

Background Esophageal cancer is often marked by aggressive tumor growth and poor prognosis. Patient groups who benefit from perioperative therapy are not yet defined. The tumor microenvironment and circulating factors as possible predictors of response and prognosis gain interest. This study aimed to investigate cytokines in patients’ serum and tumor tissue with regard to response and prognosis. Results Median survival between SCC and AC was not different (published previously). Lower levels of CCL11 (Eotaxin-1) and CXCL10 (IP-10) in the tumor tissue were associated with a better prognosis (p = 0.022; p = 0.002). In the AC subgroup higher concentrations of TGF-β3 in serum and corresponding tumor tissue were associated with adverse prognosis (p = 0.035; p = 0.006). An association with histopathological response was found for IL-12(p70) and CXCL10 in patients’ sera (p = 0.041; p = 0.032). The tissue levels of TGF-β1 and TGF-β2 were significantly lower in histopathological responders than in nonresponders (p = 0.033; p = 0.007). A similar trend was seen for TGF-β3, without statistical significance (p = 0.097). Materials and Methods Preoperative serum samples and corresponding tumor tissue (n = 54), only serum (n = 20) or only tissue (n = 4) were collected from patients undergoing surgery for cT3/4 esophageal squamous cell cancer (SCC) (n = 34) and adenocarcinoma (AC) (n = 44). All samples were taken after neoadjuvant treatment. All patients received perioperative chemo(radio)therapy. Cytokine levels of 17 different cytokines were measured by multiplex immunoassay and correlated with clinicopathological factors. Conclusions Two chemokines (CCL11 and CXCL10) in posttherapeutic tumor tissue were associated with prognosis in patients with esophageal cancer, lower levels indicating a better prognosis. Lower levels of TGF-β were associated with better response and prognosis in patients with AC.

Clinically Staged cT2 Adenocarcinomas of the Gastroesophageal Junction: Accuracy of Staging and Therapeutic Consequences

Background: Multimodality treatment options in locally advanced adenocarcinomas of the esophagogastric junction (AEGs) have been established in the last years. However, the therapeutic approach in patients with clinically staged cT2 tumors remains controversial. The most important determinant is the accuracy of clinical staging. We aimed to evaluate the association of clinical and histopathological staging in patients with cT2 tumors in respect of possible therapeutic consequences. Patients and Methods: Between 2001 and 2011, 71 patients with AEG tumors were clinically staged as cT2 (cN0 = 48 (68%); cN+ = 23 (32%)) and underwent surgical resection. Results: A primary tumor resection was performed in 59 (83%) patients while 12 (17%) patients received neoadjuvant therapy. Primarily resected patients showed the following pT/pN categories: pT1: 13 (22%), pT2: 35 (59%), pT3: 11 (19%), pN0: 23 (39%), whereas the clinical/histopathological pN category included 55% of the patients. Neoadjuvantly treated patients showed the following pT/pN categories: ypT0: 3 (25%), ypT1: 3 (25%), ypT2: 6 (50%), ypN0: 6 (50%). The overall survival of primarily resected patients compared with patients undergoing neoadjuvant therapy was not significantly different. Conclusions: The accuracy of clinical staging in patients with cT2 tumors of the gastroesophageal junction is poor. As in primarily resected patients, over- and understaging balance each other; correct pretherapeutic staging occurs in just about 60% of the patients. Moreover, our study suggests that a radical surgical resection with adequate lymphadenectomy seems to be appropriate for cT2N0 and even in cT2N+ tumors, since down-categorizing and prognosis are not improved for neoadjuvantly treated patients. However, the data have to be interpreted with caution because of the small patient numbers.

[Salvage surgery in esophageal cancer : Feasibility in patients after definitive radiochemotherapy (> 50 Gy)].

BACKGROUND Salvage surgery as an additional therapy option is currently discussed for an increasing number of patients with esophageal cancer after definitive radio(chemo)therapy after tumor progression, recurrence or on explicit request of the patient. OBJECTIVES The objective of this study was an analysis of the surgical option of salvage esophagectomy after definitive radiation in patients with esophageal cancer. Additionally the current literature on this topic was evaluated. MATERIAL AND METHODS A total of 92 patients with esophageal cancer from a prospective database were included in this study who underwent esophagectomy either after neoadjuvant radio(chemo)therapy (< 50 Gy) or definitive radio(chemo)therapy (> 50 Gy) between 2002 and 2012. The analysis was performed retrospectively. RESULTS The median survival of the two groups of patients was not significantly different after initial diagnosis with 24.2 months (95 % CI 0.0-51.93) for patients undergoing definitive radio(chemo)therapy and 30.7 months (95 % CI 9.3-52.2) for patients after neoadjuvant therapy (p = 0.96). Both patient groups showed no differences in pretherapeutic characteristics and response to radio(chemo)therapy. Postoperative complications and perioperative mortality were not different. DISCUSSION Salvage esophagectomy is now an additional treatment option after definitive radio(chemo)therapy in patients with esophageal cancer. In preselected patients with tumor recurrence, progression or with a strong wish for surgical therapy, salvage surgery should be discussed in interdisciplinary tumor boards after exclusion of distant metastases.

Salvage-Chirurgie bei Ösophaguskarzinomen

BACKGROUND Salvage surgery as an additional therapy option is currently discussed for an increasing number of patients with esophageal cancer after definitive radio(chemo)therapy after tumor progression, recurrence or on explicit request of the patient. OBJECTIVES The objective of this study was an analysis of the surgical option of salvage esophagectomy after definitive radiation in patients with esophageal cancer. Additionally the current literature on this topic was evaluated. MATERIAL AND METHODS A total of 92 patients with esophageal cancer from a prospective database were included in this study who underwent esophagectomy either after neoadjuvant radio(chemo)therapy (< 50 Gy) or definitive radio(chemo)therapy (> 50 Gy) between 2002 and 2012. The analysis was performed retrospectively. RESULTS The median survival of the two groups of patients was not significantly different after initial diagnosis with 24.2 months (95 % CI 0.0-51.93) for patients undergoing definitive radio(chemo)therapy and 30.7 months (95 % CI 9.3-52.2) for patients after neoadjuvant therapy (p = 0.96). Both patient groups showed no differences in pretherapeutic characteristics and response to radio(chemo)therapy. Postoperative complications and perioperative mortality were not different. DISCUSSION Salvage esophagectomy is now an additional treatment option after definitive radio(chemo)therapy in patients with esophageal cancer. In preselected patients with tumor recurrence, progression or with a strong wish for surgical therapy, salvage surgery should be discussed in interdisciplinary tumor boards after exclusion of distant metastases.

Salvage-Chirurgie bei Ösophaguskarzinomen@@@Salvage surgery in esophageal cancer: Sinnvoll bei Patienten nach definitiver Radio(chemo)therapie (> 50 Gy)?@@@Feasibility in patients after definitive radiochemotherapy (> 50 Gy)

BACKGROUND Salvage surgery as an additional therapy option is currently discussed for an increasing number of patients with esophageal cancer after definitive radio(chemo)therapy after tumor progression, recurrence or on explicit request of the patient. OBJECTIVES The objective of this study was an analysis of the surgical option of salvage esophagectomy after definitive radiation in patients with esophageal cancer. Additionally the current literature on this topic was evaluated. MATERIAL AND METHODS A total of 92 patients with esophageal cancer from a prospective database were included in this study who underwent esophagectomy either after neoadjuvant radio(chemo)therapy (< 50 Gy) or definitive radio(chemo)therapy (> 50 Gy) between 2002 and 2012. The analysis was performed retrospectively. RESULTS The median survival of the two groups of patients was not significantly different after initial diagnosis with 24.2 months (95 % CI 0.0-51.93) for patients undergoing definitive radio(chemo)therapy and 30.7 months (95 % CI 9.3-52.2) for patients after neoadjuvant therapy (p = 0.96). Both patient groups showed no differences in pretherapeutic characteristics and response to radio(chemo)therapy. Postoperative complications and perioperative mortality were not different. DISCUSSION Salvage esophagectomy is now an additional treatment option after definitive radio(chemo)therapy in patients with esophageal cancer. In preselected patients with tumor recurrence, progression or with a strong wish for surgical therapy, salvage surgery should be discussed in interdisciplinary tumor boards after exclusion of distant metastases.

Metastatic esophagogastric adenocarcinomas (EGA): Treatment, prognosis, and pretherapeutic selection options.

142 Background: Nowadays an increasing number of patients (pts.) with metastatic disease (MD) are discussed in interdisciplinary tumor boards. Preliminary results of the FLOT-3 study suggest a benefit for pts. with limited MD after resection compared to pts. with chemotherapy (CTx) only. Own published data suggest that a subgroup of pts. may benefit from surgery (ESJO, 2013). Primary objective of this retrospective explorative study was the outcome of pts. with resected metastatic EGA and the evaluation of our preoperative prognosis score (PPS) in a larger patients`series. Methods: From 2001-2012 123/800 EGA were classified as cM1 either confirmed intraoperatively as pM1 or confirmed by imaging during follow-up. Response evaluation was performed clinically by endoscopy and CT-scan, histopathologically by the Becker regression score. The PPS for pts. treated with CTx contains grading, clinical response and presumed R-category. Analysis was performed retrospectively from a prospective database. Results: M1 ...