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Quantitative Analysis of Survivin RNA Expression in Blood as a Non-Invasive Predictor of Response to Neoadjuvant Radiochemotherapy in Esophageal Cancer
Abstract
Analysis of survivin RNA expression in peripheral blood as a non-invasive molecular predictor of response to neoadjuvant radiochemotherapy in patients with locally advanced cancer of the esophagus.
Blood samples were drawn from 29 patients with esophageal cancer prior to neoadjuvant radiochemotherapy. After extraction of cellular tumor-RNA from blood samples, quantitative expression analysis of survivin was done by quantitative real-time RT-PCR.
Twenty of 29 (69%) of patients showed a minor histopathological response and 9 of 29 (31%) showed a major-response to neadjuvant radiochemotherapy. RNA expression in blood of patients was detectable for survivin in 27.6%, and in 100% for beta-actin. The mean survivin expression was not significantly different between minor- and major-responders. No significant associations were detected between survivin expression levels and patients clinical variables. A high expression level for survivin was significantly associated with a minor-response to neoadjuvant treatment (P = 0.042). Relative survivin expression levels above 0.15 were not associated with major histopathological response (sensitivity: 35%; specificity: 100%).
Minor-response to the applied therapy was significantly associated with a high survivin RNA expression level in patient's blood. Survivin appears to be a specific non-invasive predictor of response to neoadjuvant therapy in esophageal cancer.
... Esophageal cancer is currently the eighth most common cancer worldwide; with esophageal adenocarcinoma (EAC) accounting for 50% of esophageal cancer cases12345. The five-year survival for esophageal cancer is less than 20% and its incidence has increased by almost three fold in the western hemisphere in the past 20 years [6,7]. ...
... The efficacy of current regimens has reached a plateau and further intensification of cytotoxic agents or radiation dose escalation has been shown to be associated with significant adverse side effects. Consequently, the need for the development of effective targeted therapies aimed at treating specific mechanisms of carcinogenesis are required in order to improve survival23410,11]. Survivin, also known as Baculoviral Inhibitor of apoptosis Repeat-Containing 5 or BIRC5, is an inhibitor of apoptosis or programmed cell death10111213. ...
... Studies have reported increased expression of survivin in a number of cancers including breast, lung, melanoma, leukemia, lymphoma, colon, pancreas, and etc. [15]. Evidence also supports over expression of survivin in esophageal squamous cell carcinoma and its association with a poor prognosis [3,4,8,10,11,20]. Because survivin is not expressed in the majority of healthy tissues, it represents an ideal target for the development of novel cancer agents [3,4,8,10,11,13,20,21]. ...
Survivin is an inhibitor of apoptosis and its over expression is associated with poor prognosis in several malignancies. While several studies have analyzed survivin expression in esophageal squamous cell carcinoma, few have focused on esophageal adenocarcinoma (EAC) and/or cancer-adjacent squamous epithelium (CASE). The purpose of this study was 1) to determine the degree of survivin up regulation in samples of EAC and CASE, 2) to evaluate if survivin expression in EAC and CASE correlates with recurrence and/or death, and 3) to examine the effect of survivin inhibition on apoptosis in EAC cells.
Fresh frozen samples of EAC and CASE from the same patient were used for qRT-PCR and Western blot analysis, and formalin-fixed, paraffin-embedded tissue was used for immunohistochemistry. EAC cell lines, OE19 and OE33, were transfected with small interfering RNAs (siRNAs) to knockdown survivin expression. This was confirmed by qRT-PCR for survivin expression and Western blot analysis of cleaved PARP, cleaved caspase 3 and survivin. Survivin expression data was correlated with clinical outcome.
Survivin expression was significantly higher in EAC tumor samples compared to the CASE from the same patient. Patients with high expression of survivin in EAC tumor had an increased risk of death. Survivin expression was also noted in CASE and correlated with increased risk of distant recurrence. Cell line evaluation demonstrated that inhibition of survivin resulted in an increase in apoptosis.
Higher expression of survivin in tumor tissue was associated with increased risk of death; while survivin expression in CASE was a superior predictor of recurrence. Inhibition of survivin in EAC cell lines further showed increased apoptosis, supporting the potential benefits of therapeutic strategies targeted to this marker.
... In general clinical practice, a pathological complete response is characterized by a lack of vital residual tumor cells in both the resected primary tumor and resected lymph nodes. Alternatively, a cut-off of 10% or less remaining vital cells in the resection specimen after chemo(radio)therapy is frequently used to define responders in historic biomarker studies [17][18][19][20][21][22][23][24][25]. A pathological complete response is seen in only 23% of patients with EAC treated according to the CROSS regimen [5], and even more disappointing, patients with EAC treated with FLOT have a complete pathological response in 16% [9]. ...
Esophageal cancers confer a major health challenge and are highly aggressive malignancies with poor prognosis. Esophageal adenocarcinoma (EAC) is one of the two major histopathological subtypes of esophageal cancer. Despite advances in treatment modalities, the prognosis of patients with EAC remains poor, with a 5-year survival rate that rarely exceeds 30% in patients treated with curative intent. Chemoradiotherapy followed by resection is the treatment of choice for EAC patients, which are deemed to be curable. Current patient stratification and treatments are based on outcomes from clinical trials. Unfortunately, the molecular heterogeneity of EAC which determines the chemo- and radiosensitivity of these cancers are not taken into account. A more personalized approach in the treatment of EAC could improve patient outcomes. This review aims at summarizing literature on translational and clinical research in the field of EAC which could be of importance to develop personalized approaches. As suggested by the TCGA, expression data features molecular classifications by different platforms, including miRNA, genomic mutations and reverse-phase protein arrays. Here, we summarize literature on transcriptomic, data-driven approaches to identify distinct subtypes of EAC associated with molecular features. These novel classifications may determine the responsiveness to chemo(radio)therapy and help to identify novel molecular targets within cell signaling pathways. Moreover, we discuss the current clinical research efforts on tailored treatment regimens for patients with EAC taking into account the heterogeneous response to chemoradiotherapy. We summarize the evidence regarding active surveillance instead of immediate surgical resection after application of neoadjuvant chemo(radio)therapy in EAC. We consider that in future patients with complete response to chemo(radio)therapy, predicted by (transcriptomic) biomarkers, might benefit most from this approach. Finally, challenges to overcome for current findings to be implemented in clinical practice and move the field forward are being discussed.
... In recent years, researchers have tried to identify indicators that could be used to predict the efficacy of neoadjuvant chemotherapy so that these indicators can be considered biomarkers; however, despite these research efforts [12][13][14][15][16][17][18][19][20][21], no unanimously recognized molecular biomarkers are currently available for use in clinical practice. Along with the development of high-throughput gene sequencing technology, genetic tests have been widely applied to screen for genes associated with complicated diseases and to predict the efficacy of treatment and estimate the prognosis of the disease. ...
Background:
Heterogeneous efficacy of neoadjuvant chemotherapy has led to controversies that have limited its application in clinical practice. Thus, we aimed to identify potential biomarkers predicting esophageal squamous cell carcinoma (ESCC) chemo-responsiveness by gene expression profiling.
Methods:
CCK8 assay was used to evaluate the growth inhibitory effect of different concentrations of cisplatin and paclitaxel on the ESCC cell lines EC109, KYSE450, KYSE410, KYSE510, and KYSE150 to differentiate between chemosensitive and chemoresistant cell lines. Gene expression profiling and Real-time PCR were applied to analyze and validate the gene expression differences between chemosensitive and chemoresistant cell lines. IHC was conducted to examine the expression of selected target markers MUC4, MUC13, and MUC20 in 186 ESCC resection samples and the relationships between their expression and tumor regression grade was analyzed. Moreover, RNAi was conducted to instantly block the expression of MUC4, MUC13, and MUC20 to observe their influences on chemo-responsiveness.
Results:
EC109 was found to be relatively sensitive to both cisplatin and paclitaxel, while KYSE410 was relatively resistant to cisplatin, KYSE510 was relatively resistant to paclitaxel. Gene expression profiling analysis showed that 2018 genes were differentially expressed in sensitive cell line compared to resistant cell lines. The expression patterns of MUC4, MUC13, MUC20 were validated. Low expression of MUC4 and MUC20 in resection samples was significantly correlated with better TRG. Blockage of MUC20 and MUC13 decreased the drug-resistance capacity and chemosensitivity, respectively.
Conclusions:
MUC4 and MUC20 were identified as potential biomarkers for predicting the efficacy of neoadjuvant chemotherapy in ESCC patients.
... In the present study, we found that survivin correlates with lymph node metastasis and late clinical stage, but has no correlation with the overall survival. The lack of prognostic significance is contradictory with the previous findings that over-expression of survivin in ESCC correlates with poor prognosis [27][28][29]. The reasons for this discrepancy may be due to the small sample size and a relatively short follow up. ...
We recently found evidence that STAT1 in esophageal squamous carcinoma (ESCC) cells exerts tumor suppressor function, and it regulates five key regulators of apoptosis or cell-cycle progression, including Bcl-2, Bcl-xL, survivin, cyclin D1 and p21. In this study, we confirmed these findings in four ESCC cell lines. Using immunohistochemistry, we also assessed the expression of these proteins in 62 primary tumors. The expression of these markers was heterogeneous, ranging 39 to 69% of the cohort. Significant correlation was found between STAT1 and three proteins (p21, Bcl-xL and survivin), whereas only a trend was identified for cyclin D1 and Bcl-2. We then correlated the expression of these proteins with several clinicopathologic parameters including lymph node metastasis, depth of invasion, clinical stage and overall survival. Significant correlations were found between Bcl-2 and deep invasion (p = 0.033), survivin and lymph node metastasis (p = 0.006), as well as cyclin D1 and clinical stage (p = 0.014). Patients with p21-positive tumors had a significantly longer survival compared to those with p21-negative tumors (p = 0.031). To conclude, our findings support the concept that STAT1 exerts its tumor suppressor effects in ESCC via modulating the expression of key regulators of apoptosis and cell-cycle progression.
... Other potentially informative biomarkers include VEGF (vascular endothelial growth factor), proliferative activity, survivin, p53, p21, COX-2 (cyclo-oxygenase 2) and NF-κB (nuclear factor κB) [33][34][35][36]. In peripheral blood, increased expression of ERCC1 [37] and survivin [38] have been associated with minor response to chemoradiotherapy and could represent noninvasive predictive markers. Genetic polymorphisms in drug pathways have also been investigated [39]. ...
Biomarkers are needed to screen multiple stages in the clinical pathway of Barrett's oesophagus patients; from disease diagnosis to risk stratification and predicting response to therapy. Routes to the identification of biomarkers have been recognized by known molecular features of the disease and more recently through transcriptomic, methylation and proteomic screening approaches. The majority of Barrett's oesophagus patients remain undiagnosed in the general population. In order to develop a tool to screen for Barrett's oesophagus in the primary care setting, minimally invasive sampling methods coupled with immunocytology-based biomarkers are currently being assessed. Biomarkers may also have utility in surveillance programmes by allowing endoscopic interval to be adjusted according to individual neoplastic risk. Many individual biomarkers have been proposed in this regard, but have frequently been assessed in studies of limited power, or have lacked sufficient sensitivity or specificity when assessed in wider population-based studies. Biomarker panels may provide a route forward. In this regard, a panel of methylation markers has shown promise in a multicentre, double-blind, validation study. Biomarkers are also being developed to improve detection of high-grade dysplasia and oesophageal adenocarcinoma, utilizing brush cytology combined with FISH (fluorescence in situ hybridization), and to assess therapeutic success and risk of complication during photodynamic therapy. Finally, we outline progress in identifying alternative sources of biomarkers for this condition.
Purpose: To evaluate the stereotactic radiotherapy in the cases of local recurrences of esophageal cancer. Methods: Stereotactic body radiotherapy (SBRT) is a rapidly expanding novel technique combining a short treatment time together with high local efficacy and an acceptable toxicity profile. In this study, 6 patients recurrent esophageal cancer in the neck lymph nodes were treated by SBRT in the Department of Oncology, Tri-Service General Hospital (Taiwan). The treatment dose was mean 35.5 Gy in 5 daily fractions, with a prescribed dose to 65 and 82% isodose, for each patient respectively, utilizing a volumetric arc therapy technique, a 6-MV photon beam and an Elekta Synergy linear accelerator. The maximum dose in the patients was mean 46 Gy. The maximum doses for the surrounding major blood vessels were between 34.8 and 46.8 Gy. Maximum doses to the trachea and the esophagus in the first patient were mean 30.2 Gy. Results: The treatment was delivered without any unintentional treatment interruptions and any treatment-related toxicity. The intrafractional movements, during all fractions of radiotherapy were under 3 mm, indicating that 3-point thermoplastic mask during SBRT in the neck region. All the patients tolerated the treatment well and did not experience any significant treatment-related toxicity during the follow-up. Conclusion: SBRT utilizing linear accelerators should be considered in patients with localized recurrent esophageal cancer which may benefit for the patients minimal treatment toxicity.
Background:
The purpose of this study was to investigate the prognosis and its predictors in patients with esophageal squamous cell carcinoma (ESCC) who achieve major histopathological response (MaHR) after neoadjuvant chemoradiotherapy (nCRT).
Methods:
We examined a total of 187 ESCC patients who achieved MaHR following nCRT and survived the perioperative period. MaHR was defined as either absence or <10% vital residual tumor cells (VRTC) in the resected esophagus without nodal involvement. Univariate and multivariate analyses were used to identify factors significantly associated with overall survival (OS).
Results:
At the time of analysis, 113 patients (60.4%) were dead (5-year OS = 48%; median survival time = 54.8 months). The amount of VRTC (1-10% versus 0% VRTC; hazard ratio [HR] = 1.9, P < 0.001) and the thoroughness of histopathological examination (standard [≤ 4 tumor blocks] versus thorough [> 4 tumor blocks], HR = 1.57; P = 0.013) were independent predictors of OS in multivariate analysis. A stepwise increase in OS was observed in the following groups: patients with 1-10% VRTC identified by the standard protocol, patients with 1-10% VRTC identified by the thorough protocol, patients with 0% VRTC identified by the standard protocol, and patients with 0% VRTC identified by the thorough protocol (5-year OS rates = 20%, 40%, 50%, and 62%, respectively, P < 0.001).
Conclusions:
In ESCC patients who achieve MaHR after nCRT, the presence of microscopical residual disease and the thoroughness of histopathological examination are associated with survival.
Objective: To investigate the inhibitory effect of triterpenes compound extracted from cortex periplocae (TCPP) on tumorigenesis of luciferase-marked Eca109 cells (Eca109, human esophageal cancer cell line; Eca109-luc) in nude mice and the related mechanisms. Methods: Eca109-luc-implanted tumor model was prepared by subcutaneously injecting Eca109-luc cells into nude mice. After treated with TCPP, the volume and weight of transplanted tumors in nude mice were measured, and tumor growth was monitored with in vivo imaging system. Morphology of transplanted tumor tissues was observed by H-E staining; apoptosis of transplanted tumor cells was analyzed by flow cytometry; and survivin expression in transplanted tumor tissues was examined by Western blotting analysis. Results: The growth of implanted tumor in nude mice was markedly inhibited by TCPP, and the volume and weight of tumors were significantly decreased, with the inhibitory rate being 40.7%. TCPP treatment induced inflammatory cell infiltration and necrosis of tumor cells in implanted tumor tissues, and the apoptosis rate of tumor cells was significantly higher than that in soybean oil control group (P < 0.05). Expression level of survivin protein in implanted tumors was significantly lower in TCPP-treated group than that in control group (P < 0.05). Conclusion: TCPP can inhibit proliferation of human esophageal cancer Eca109 cells in vivo, which might be associated with the down-regulation of survivin and apoptosis of tumor cells.
After decades of glacial progress, important clinical roles for circulating tumor cells (CTC) and circulating tumor nucleic acids (CNA) are coming into focus at an accelerating pace. Advances in immunohistochemistry, image cytometry, and molecular biology have converged to the point where circulating tumor cells can be analyzed by methods ranging from morphology through 10-color immunohistochemistry and FISH to whole genome/transcriptome analysis of single cells. Cell-free circulating tumor nucleic acids (genomic DNA, mRNA, miRNA) can also be quantified and comprehensively analyzed for changes like mutation and methylation. Circulating tumor cells and tumor nucleic acids can be found in most patients with gastrointestinal malignancy. One test for circulating tumor cells is already FDA approved for use in determining therapy in metastatic colon cancer. Exciting studies have shown the successful application of CTC and CNA analysis to monitor minimal residual disease by targeting tumor-specific mutations and gene rearrangements. This approach should expand dramatically as whole genome and whole transcriptome analysis of tumors becomes standard practice. MicroRNA profiling of plasma appears to be a promising way to screen for many epithelial malignancies. Measurement of circulating methylated DNA sequences has shown impressive specificity and sensitivity for detection of colon cancer. The role of circulating tumor cells in the cancer ecosystem (the primary, the stroma, the metastases, the disseminated tumor cells and immune cells) could remain elusive even as a clinical role is defined but the ability to fully characterize CTC and uncover detailed genomic relationships could also open a window onto tumor dormancy and metastasis.
The aim of this study was to assess the efficacy and prognostic factors of definitive radiochemotherapy (RCT) for inoperable esophageal cancer. Between 1995 and 2005 all patients with inoperable esophageal cancer that underwent concurrent RCT were included in this retrospective study. Conventional computed tomography-based treatment planning as well as 3D-conformal radiotherapy (RT) was used. Maximum radiotherapy dose was 63 Gy. Chemotherapy consisted of cisplatin (20 mg/m(2) d1-5 and 29-33) and 5-FU (650-1000 mg/m(2) d1-5 and 29-33). Patients not suitable for RCT received radiotherapy alone. Toxicity was measured according to common toxicity criteria (CTC). Two hundred three consecutive patients with inoperable esophageal cancer that received definitive therapy were identified in this time period (160 with squamous cell carcinoma and 43 with adenocarcinoma). The 2-year overall survival probability was 21.2% whereas the progression-free survival at 2 years was 13.8% for all patients. In the univariate analysis, type of histology, T-stage, N-stage, application of chemotherapy, and the radiation dose were significantly correlated with overall/progression-free survival. Moreover, multivariate analysis revealed an independent prognostic impact for N-stage, radiation dose, and concurrent chemotherapy. Definitive RCT is an important palliative treatment option for patients with inoperable esophageal cancer. N-stage, radiation dose, and concurrent chemotherapy are important prognostic factors for survival.
Despite improvements in preoperative staging, surgical techniques and postoperative care, the 5-year survival rate of patients with locally advanced esophageal cancer remains only approximately 15-40%. Therefore, multimodality treatment options have been widely promoted in the therapy of this malignant disease. However, recent meta-analyses evaluating randomized trials of neoadjuvant therapy protocols prior to surgery for patients with advanced esophageal cancer showed only modest improvement of survival for the whole treatment group. Among these patients, those with excellent histopathologic response seem to benefit greatly from neoadjuvant regimens. Therefore, predictive markers to allow individualization of multimodality therapy in locally advanced esophageal cancer are needed to identify those who will benefit the most. Unfortunately, there is still a great lack of markers for response assessment in patients with esophageal cancer undergoing multimodality therapy. Endoscopy, endoscopic biopsies, computed tomography and endoscopic ultrasound do not seem to provide reliable information for assessing the response to neoadjuvant therapy. Whether (18)F-fluorodeoxyglucose-PET can effectively characterize responders in neoadjuvant therapy protocols remains controversial. Finally, although results of mostly retrospective studies on molecular factors for response assessment in esophageal cancer patients are promising, these markers do not yet provide a reliable and cost-effective molecular tool for utilization in clinical practice.
Survivin (SVV) mRNA expression levels in peripheral blood of patients with gastrointestinal malignancies change significantly during the course of treatment. We wanted to scrutinize these findings in patients with esophageal carcinoma and furthermore evaluate whether the detection of mRNA and the change in detecting ability have an association with overall survival.
Whole blood was drawn 1 day pre- and 10 days post-operatively from 62 patients with esophageal carcinoma. Tumor cells were enriched from whole blood by density-gradient centrifugation prior to extraction of total cellular RNA and subsequent direct quantitative reverse transcriptase-PCR assays.
SVV was detectable in 48 out of 62 patients (77%). Stepwise multivariate Cox linear regression models demonstrated a significant and independent association of measured SVV with overall survival (6.6 exp[b]; 95% CI: 1.97-22.12; p = 0.002). Increased SVV levels after the operation were linked to shorter overall survival (p = 0.04).
Preoperative SVV expression levels appear to be associated with overall survival in patients with esophageal cancers. Increasing levels could potentially indicate a higher risk for shorter overall survival and therefore demand adapted treatment modalities.
Uncontrolled studies suggest that a combination of chemotherapy and radiotherapy improves the survival of patients with esophageal adenocarcinoma. We conducted a prospective, randomized trial comparing surgery alone with combined chemotherapy, radiotherapy, and surgery.
Patients assigned to multimodal therapy received two courses of chemotherapy in weeks 1 and 6 (fluorouracil, 15 mg per kilogram of body weight daily for five days, and cisplatin, 75 mg per square meter of body-surface area on day 7) and a course of radiotherapy (40 Gy, administered in 15 fractions over a three-week period, beginning concurrently with the first course of chemotherapy), followed by surgery. The patients assigned to surgery had no preoperative therapy.
Of the 58 patients assigned to multimodal therapy and the 55 assigned to surgery, 10 and 1, respectively, were withdrawn for protocol violations. At the time of surgery, 23 of 55 patients (42 percent) treated with preoperative multimodal therapy who could be evaluated had positive nodes or metastases, as compared with 45 of the 55 patients (82 percent) who underwent surgery alone (P<0.001). Thirteen of the 52 patients (25 percent) who underwent surgery after multimodal therapy had complete responses as determined pathologically. The median survival of patients assigned to multimodal therapy was 16 months, as compared with 11 months for those assigned to surgery alone (P=0.01). At one, two, and three years, 52, 37, and 32 percent, respectively, of patients assigned to multimodal therapy were alive, as compared with 44, 26, and 6 percent of those assigned to surgery, with the survival advantage favoring multimodal therapy reaching significance at three years (P=0.01).
Multimodal treatment is superior to surgery alone for patients with resectable adenocarcinoma of the esophagus.
A novel approach to quantitative reverse transcriptase polymerase chain reaction (QC RT-PCR) using real time detection and the 5' nuclease assay has been developed. Cystic fibrosis transmembrane transductance regulator (CFTR) target mRNA is reverse transcribed, amplified, detected, and quantitated in real time. A fluorogenic probe was designed to detect the CFTR amplicon. Relative increase in 6-carboxy-fluorescein reporter fluorescent emission is monitored during PCR amplification using an analytical thermal cycler. An internal control template containing the same primer sequences as the CFTR amplicon, but a different internal sequence, has been designed as a control. An internal control probe with a reporter fluorescent dye tetrachloro-6-carboxy-fluorescein was designed to hybridize to the internal control amplicon. The internal control template is placed in each reaction tube and is used for quantitative analysis of the CFTR mRNA. This method provides a convenient and high-throughput format for QC RT-PCR.
We have developed a novel "real time" quantitative PCR method. The method measures PCR product accumulation through a dual-labeled fluorogenic probe (i.e., TaqMan Probe). This method provides very accurate and reproducible quantitation of gene copies. Unlike other quantitative PCR methods, real-time PCR does not require post-PCR sample handling, preventing potential PCR product carry-over contamination and resulting in much faster and higher throughput assays. The real-time PCR method has a very large dynamic range of starting target molecule determination (at least five orders of magnitude). Real-time quantitative PCR is extremely accurate and less labor-intensive than current quantitative PCR methods.
Inhibitors of programmed cell death (apoptosis) aberrantly prolonging cell viability may contribute to cancer by facilitating the insurgence of mutations and by promoting resistance to therapy. Despite the identification of several new apoptosis inhibitors related to bcl-2 or to the baculovirus IAP gene, it is not clear whether apoptosis inhibition plays a general role in neoplasia. Here, we describe a new human gene encoding a structurally unique IAP apoptosis inhibitor, designated survivin. Survivin contains a single baculovirus IAP repeat and lacks a carboxyl-terminal RING finger. Present during fetal development, survivin is undetectable in terminally differentiated adult tissues. However, survivin becomes prominently expressed in transformed cell lines and in all the most common human cancers of lung, colon, pancreas, prostate and breast, in vivo. Survivin is also found in approximately 50% of high-grade non-Hodgkin's lymphomas (centroblastic, immunoblastic), but not in low-grade lymphomas (lymphocytic). Recombinant expression of survivin counteracts apoptosis of B lymphocyte precursors deprived of interleukin 3 (IL-3). These findings suggest that apoptosis inhibition may be a general feature of neoplasia and identify survivin as a potential new target for apoptosis-based therapy in cancer and lymphoma.
Progression of the cell cycle and control of apoptosis (programmed cell death) are thought to be intimately linked processes, acting to preserve homeostasis and developmental morphogenesis. Although proteins that regulate apoptosis have been implicated in restraining cell-cycle entry and controlling ploidy (chromosome number), the effector molecules at the interface between cell proliferation and cell survival have remained elusive. Here we show that a new inhibitor of apoptosis (IAP) protein, survivin, is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. At the beginning of mitosis, survivin associates with microtubules of the mitotic spindle in a specific and saturable reaction that is regulated by microtubule dynamics. Disruption of survivin-microtubule interactions results in loss of survivin's anti-apoptosis function and increased caspase-3 activity, a mechanism involved in cell death, during mitosis. These results indicate that survivin may counteract a default induction of apoptosis in G2/M phase. The overexpression of survivin in cancer may overcome this apoptotic checkpoint and favour aberrant progression of transformed cells through mitosis.
Survivin is a member of the inhibitor of apoptosis gene family that has been implicated in both apoptosis inhibition and regulation of mitosis. However, the subcellular distribution of survivin has been controversial and variously described as a microtubule-associated protein or chromosomal passenger protein. Here, we show that antibodies directed to the survivin sequence Ala(3)-Ile(19) exclusively recognized a nuclear pool of survivin that segregated with nucleoplasmic proteins, but not with outer nuclear matrix or nuclear matrix proteins. By immunofluorescence, nuclear survivin localized to kinetochores of metaphase chromosomes, and to the central spindle midzone at anaphase. However, antibodies to Cys(57)-Trp(67) identified a cytosolic pool of survivin, which associated with interphase microtubules, centrosomes, spindle poles and mitotic spindle microtubules at metaphase and anaphase. Polyclonal antibodies recognizing survivin epitopes Ala(3)-Ile(19), Met(38)-Thr(48), Pro(47)-Phe(58) and Cys(57)-Trp(67) identified both survivin pools within the same mitotic cell. A ratio of approximately 1:6 for nuclear versus cytosolic survivin was obtained by quantitative subcellular fractionation. In synchronized cultures, cytosolic survivin abruptly increased at mitosis, physically associated with p34(cdc2), and was phosphorylated by p34(cdc2) on Thr(34), in vivo. By contrast, nuclear survivin began to accumulate in S phase, was not complexed with p34(cdc2) and was not phosphorylated on Thr(34). Intracellular loading of a polyclonal antibody to survivin caused microtubule defects and resulted in formation of multipolar mitotic spindles, but did not interfere with cytokinesis. These data demonstrate that although both reported localizations of survivin exist in mitotic cells, the preponderant survivin pool is associated with microtubules and participates in the assembly of a bipolar mitotic spindle.
Survivin, a new member of the family of apoptosis inhibitors, is expressed almost exclusively in proliferating cells, above all in cancers. Subcellular localisation and prognostic implications of the survivin protein have not yet been determined in oesophageal squamous cell carcinoma. The survival of 84 patients with oesophageal squamous cell carcinomas was correlated with the extent of immunohistochemical survivin expression in tumour cell nuclei. Tumours were scored positive when >5% cells stained positive. Patients were followed up for at least 5 years or until death. In normal oesophageal squamous cell epithelium, some cytoplasmic survivin expression was detected in the basal cells, whereas proliferating cells showed nuclear staining of survivin. Nuclear expression of survivin was also detected in 67 cancers (80%). The mean survival for patients of this group (28 months, range 20-36) was significantly less than that for patients without survivin expression in the tumour cell nuclei (108 months, range 62-154, P=0.003). Using univariate analysis, nuclear survivin expression (P=0.003), tumour depth (P=0.001), lymph node metastasis (P=0.003) and stage (P<0.001) were the best predictors of survival. In contrast, cytoplasmic survivin staining was noted in 53 (63%) tumours and had no prognostic relevance. In conclusion, the analysis of nuclear survivin expression identifies subgroups in oesophageal squamous cell cancer with favourable (survivin(-)) or with poor prognosis (survivin(+)). We suggest that the determination of nuclear survivin expression could be used to individualise therapeutic strategies in oesophageal squamous cell cancer in the future.
In order to identify genes or combination of genes that have the power to discriminate between premalignant Barrett's esophagus and Barrett's associated adenocarcinoma, we analysed a panel of 23 genes using quantitative real-time RT-PCR (qRT-PCR, Taqman and bioinformatic tools. The genes chosen were either known to be associated with Barrett's carcinogenesis or were filtered from a previous cDNA microarray study on Barrett's adenocarcinoma. A total of 98 tissues, obtained from 19 patients with Barrett's esophagus (BE group) and 20 patients with Barrett's associated esophageal adenocarcinoma (EA group), were studied. Triplicate analysis for the full 23 gene of interest panel, and analysis of an internal control gene, was performed for all samples, for a total of more than 9016 single PCR reactions. We found distinct classes of gene expression patterns in the different types of tissues. The most informative genes clustered in six different classes and had significantly different expression levels in Barrett's esophagus tissues compared to adenocarcinoma tissues. Linear discriminant analysis (LDA) distinguished four genetically different groups. The normal squamous esophagus tissues from patients with BE or EA were not distinguishable from one another, but Barrett's esophagus tissues could be distinguished from adenocarcinoma tissues. Using the most informative genes, obtained from a logistic regression analysis, we were able to completely distinguish between benign Barrett's and Barrett's adenocarcinomas. This study provides the first non-array parallel mRNA quantitation analysis of a panel of genes in the Barrett's esophagus model of multistage carcinogenesis. Our results suggest that mRNA expression quantitation of a panel of genes can discriminate between premalignant and malignant Barrett's disease. Logistic regression and LDAs can be used to further identify, from the complete panel, gene subsets with the power to make these diagnostic distinctions. Expression analysis of a limited number of highly selected genes may have clinical usefulness for the treatment of patients with this disease.
We examined the potential of quantitative epidermal growth factor receptor (EGFR, synonym: c-erbB-1) and c-erbB-2 (synonym: HER2/neu) mRNA expression to predict minor or major histopathologic response to neoadjuvant radiochemotherapy (cis-platinum, 5-FU, 36 Gy), followed by radical surgical resection, in patients with oesophageal cancer. Tissue samples were collected by endoscopic biopsy prior to treatment. RNA was isolated from biopsies and quantitative real-time reverse transcriptase-polymerase chain reaction assays were performed to determine c-erbB-1 and c-erbB-2 mRNA expression. Relative expression (tumour/paired normal tissue ratio standardised for beta-actin) was calculated for EGFR and c-erbB-2 mRNA. Expression levels were correlated with the objective histopathologic response in resected specimens. Histomorphologic regression was defined as major response when resected specimens contained less than 10% of residual vital tumour cells, or in case a pathologically complete response was achieved. Expression of c-erbB-1 mRNA was not associated with the degree of histomorphological response. In contrast, the relative expression levels of c-erbB-2 mRNA >1 were not associated with major histopathologic responses (sensitivity 41.6%, specificity 100%), and 10 out of 36 (28%) patients could be unequivocally identified, whose tumours did not respond well to the delivered neoadjuvant radiochemotherapy (P<0.01). Quantitative expression levels of c-erbB-2, but not c-erbB-1 mRNA, in pretreatment biopsies appear to predict minor histopathologic response to our neoadjuvant radiochemotherapy protocol. This test could be used to prevent expensive, non effective and potentially harmful therapies in approximately one-fourth of our patients, and leads to a more individualised type of combined modality treatment.
Adjuvant systemic therapy (a strategy that targets potential disseminated tumor cells after complete removal of the tumor) has clearly improved survival of patients with cancer. To date, no tool is available to monitor efficacy of these therapies, unless distant metastases arise, a situation that unavoidably leads to death. We analyzed RASSF1A DNA methylation in pretherapeutic sera and serum samples collected 1 year after surgery from 148 patients with breast cancer who were receiving adjuvant tamoxifen; 19.6% and 22.3% of patients with breast cancer showed RASSF1A DNA methylation in their pretherapeutic and 1-year-after serum samples, respectively. RASSF1A methylation 1 year after primary surgery (and during adjuvant tamoxifen therapy) was an independent predictor of poor outcome, with a relative risk (95% confidence interval) for relapse of 5.1 (1.3-19.8) and for death of 6.9 (1.9-25.9). Measurement of serum DNA methylation allows adjuvant systemic treatment to be monitored for efficacy: disappearance of RASSF1A DNA methylation in serum throughout treatment with tamoxifen indicates a response, whereas persistence or new appearance means resistance to adjuvant tamoxifen treatment. It remains to be seen whether modifications made in adjuvant therapeutic strategies based on detection of circulating nucleic acids will improve survival as well as quality of life.
Genetic alterations in the normal tissues surrounding various cancers have been described, but a comprehensive analysis of this carcinogenic field effect in Barrett's-associated adenocarcinoma of the esophagus disease has not been reported. The aim of this study was to analyze the gene expression profile of a panel of highly selected genes in the normal squamous esophagus epihelium of patients with Barrett's esophagus, patients with Barrett's-associated adenocarcinoma, and a healthy control group to define the existence of a carcinogenic field effect, and to investigate the clinical importance of such a field effect in the management of Barrett's disease.
Forty-nine histologic normal squamous esophageal epithelia collected from 19 patients with Barrett's esophagus, 20 patients with Barrett's-associated esophageal adenocarcinoma, and a healthy control group of 10 patients were studied. A quantitative real-time reverse transcription-PCR method (TaqMan) was used to measure the expression of a panel of genes with known associations with gastrointestinal carcinogenesis.
A widespread carcinogenic field effect was detected for more than 50% of the genes analyzed including Bax, BFT, CDX2, COX2, DAPK, DNMT1, GSTP1, RARalpha, RARgamma, RXRalpha, RXRbeta, SPARC, TSPAN, and VEGF. Based on the expression signature of the normal appearing squamous esophagus, a linear discriminant analysis was able to distinguish between the three groups of patients with an error rate of 0%.
This study provides the first comprehensive investigation of a carcinogenic field effect in Barrett's esophagus disease. Based on the gene expression signature of the normal esophagus, patients could be correctly characterized according to their pathologic classification by applying a linear discriminant analysis. Our results provide evidence that a molecular classification might have clinical importance for the diagnosis and treatment of patients with Barrett's esophagus disease.
We analyzed pretherapeutic gene expression patterns of patients with locally advanced adenocarcinomas of the esophagus with regard to response to neoadjuvant chemotherapy.
Pretherapeutic, paraffin-embedded, formalin-fixed endoscopic esophageal tumor biopsies of 38 patients with locally advanced esophageal adenocarcinomas (Barrett adenocarcinoma) were included. All patients underwent two cycles of cisplatin and 5-fluorouracil (5-FU) therapy with or without additional paclitaxel followed by abdominothoracal esophagectomy. RNA expression levels of 5-FU metabolism-associated genes thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, MAP7, and ELF3, of platinum- and taxane-related genes caldesmon, ERCC1, ERCC4, HER-2/neu, and GADD45, and of multidrug resistance gene MRP1 were determined using real-time reverse transcriptase-PCR. Expression levels were correlated with response to chemotherapy, histopathologically assessed in surgically resected specimens.
Responding patients showed significantly higher pretherapeutic expression levels of MTHFR (P = 0.012), caldesmon (P = 0.016), and MRP1 (P = 0.007). In addition, patients with high pretherapeutic MTHFR and MRP1 levels had a survival benefit after surgery (P = 0.013 and P = 0.015, respectively). Additionally, investigation of intratumoral heterogeneity of gene expression of relevant genes (MTHFR, caldesmon, HER-2/neu, ERCC4, and MRP1), verified in nine untreated Barrett adenocarcinomas by examination of five distinct tumor areas, revealed no significant heterogeneity in gene expression indicating that expression profiles obtained from biopsy material may yield a representative genetic expression profile of total tumor tissue.
Our results indicate that determination of mRNA levels of few genes may be useful for the prediction of the success of neoadjuvant chemotherapy in individual cancer patients with locally advanced Barrett adenocarcinoma.
High expression of cyclooxygenase-2 (COX-2) was shown to inhibit chemotherapy- and radiotherapy-induced apoptosis. We analyzed the association of COX-2 mRNA and protein expression with histomorphologic response to neoadjuvant radiochemotherapy in esophageal cancer.
Fifty-two patients with resectable esophageal cancers (cT2-4, Nx, and M0) received neoadjuvant radiochemotherapy (cisplatin, 5-5-fluorouracil, 36 Gy) followed by transthoracic en bloc esophagectomy. Histomorphologic regression was defined as major response when resected specimens contained less than 10% of residual vital tumor cells. RNA was isolated from endoscopic biopsies (paired tumor and normal tissue) before neoadjuvant treatment and quantitative real-time reverse transcriptase-PCR (Taqman) assays were done to determine COX-2 mRNA expression levels standardized for beta-actin. COX-2 protein expression in pretreatment biopsies and post-therapeutic resection specimens was analyzed by immunostaining of tumor cells.
Median COX-2 mRNA expression levels were significantly (P < 0.0001) different between paired tumor (median, 2.2) and normal tissues (median, 0.159). Comparison of pre-therapeutic and posttherapeutic specimens showed a significant difference (P < 0.006) in COX-2 protein expression. Twelve of 52 tumors showed down-regulation and 3 of 52 showed up-regulation of COX-2 protein expression during neoadjuvant radiochemotherapy. High COX-2 protein expression in post-therapeutic resection specimens was significantly associated with minor histopathologic response (P < 0.04) and poor prognosis (5-year survival probabilities: 26.3 +/- 8.2% for minor and 58.6% +/- 12.9% for major histopathologic response; P < 0.01).
High COX-2 protein expression following neoadjuvant radiochemotherapy in resection specimens is significantly associated with minor histopathologic response to neoadjuvant therapy and very poor prognosis.
Hypoxia-inducible factor-1alpha (HIF-1alpha) expression was reported to be associated with tumor growth, progression and resistance to radio-/chemotherapy. Whether HIF-1alpha mRNA or protein expression is associated with histomorphological response or prognosis following neoadjuvant chemoradiation and surgery in resectable, locally-advanced esophageal cancer was analyzed.
Fifty-three patients received neoadjuvant chemoradiation (cisplatin, 5-fluorouracil, 36 Gy) followed by transthoracic en bloc esophagectomy. HIF-1alpha mRNA and protein expressions were analyzed by quantitative RT-PCR and immunostaining.
In squamous cell carcinoma, HIF-1alpha mRNA expression was significantly higher than in paired normal epithelium (p < 0.001). Normal squamous epithelium showed significant elevated expression in adenocarcinomas, suggesting a field effect (p < 0.04). HIF-1alpha protein expression showed a significant regulation following chemoradiation. Neither HIF-1alpha mRNA nor protein expression was associated with histomorphological regression or prognosis.
HIF-1alpha mRNA expression is differentially upregulated in esophageal squamous cell carcinoma compared to adenocarcinomas, but does not predict tumor regression or prognosis.
We analyzed expression of genes associated with metabolism of chemotherapeutic drugs in locally advanced esophageal adenocarcinomas before and after neoadjuvant chemotherapy to study whether there is a change in gene expression induced by chemotherapy and whether such changes are associated with tumor response or nonresponse. We included 21 patients with locally advanced esophageal adenocarcinomas treated by cisplatin- and 5-fluorouracil (5-FU)-based neoadjuvant chemotherapy before surgery. Messenger RNA was extracted from formalin-fixed, paraffin-embedded preoperative endoscopic esophageal tumor biopsy specimens and tumor tissue specimens after surgical resection. Expression levels of chemotherapy metabolism-associated genes thymidylate synthase (TYMS), thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), methylenetetrahydrofolate reductase (MTHFR), multidrug resistance-associated protein 1 (MRP1), and multidrug-resistance gene 1 (MDR1) were determined by quantitative real-time reverse transcriptase-polymerase chain reaction. There was a significant posttherapeutic reduction in the expression levels of TP (P = .028) and MRP1 (P = .006). Furthermore, down-regulation of MRP1 (P = .041) and TYMS (P = .028) after chemotherapy was associated with tumor response to chemotherapy, assessed clinically and by histopathologic tumor regression. Down-regulation of chemotherapy metabolism-associated genes occurs after neoadjuvant chemotherapy and may modulate tumor response to chemotherapy.
PURPOSE: A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin, fluorouracil, and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution. We designed a randomized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone.
MATERIALS AND METHODS: One hundred patients with esophageal carcinoma were randomized to receive either surgery alone (arm I) or preoperative chemoradiation (arm II) with cisplatin 20 mg/m²/d on days 1 through 5 and 17 through 21, fluorouracil 300 mg/m²/d on days 1 through 21, and vinblastine 1 mg/m²/d on days 1 through 4 and 17 through 20. Radiotherapy consisted of 1.5-Gy fractions twice daily, Monday through Friday over 21 days, to a total dose of 45 Gy. Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42.
RESULTS: At median follow-up of 8.2 years, there is no significant difference in survival between the treatment arms. Median survival is 17.6 months in arm I and 16.9 months in arm II. Survival at 3 years was 16% in arm I and 30% in arm II (P = .15). This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years, with at least 80% power.
CONCLUSION: This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.
Survivin, a new member of the inhibitor-of-apoptosis (IAP) family, has been reported to be expressed in many cancers but not in differentiated normal tissue. Its expression in esophageal cancer, however, has not been reported. We investigated 51 esophageal cancers and their adjacent normal epithelial tissues for mRNA expression of survivin by RT-PCR. The survivin expression in esophageal cancer tissue was significantly higher than that in normal esophageal tissue (0.211 ± 0.226 vs. 0.057 ± 0.135, p < 0.0001). pN4 tumors had significantly higher survivin expression than the pN0-3 tumors (p = 0.0093). Fourteen patients with advanced esophageal cancer had received chemotherapy prior to surgery. The survivin expression in the cancer tissue in patients who achieved a partial response (PR) was significantly lower than that in patients with no change (NC) and in patients with progressive disease (PD; 0.099 ± 0.134 vs. 0.320 ± 0.222, p = 0.0434). The median survival for patients with high survivin expression (9.0 months) was less than that for patients with low survivin group expression (30.0 months, p = 0.0023). Survivin expression was one of the significant predictors of survival on univariate analysis (hazard ratio 2.471; 95% confidence interval 1.104-5.533). The results suggest that survivin expression may provide prognostic information in patients with esophageal cancer. © 2001 Wiley-Liss, Inc.
The Barrett’s multistage process is characterized histopathologically by progression from Barrett’s intestinal metaplasia
to Barrett’s esophagus with dysplasia and ultimately adenocarcinoma. Understanding the cellular and molecular events in this
multistage process may contribute to improved diagnosis and treatment. Ornithine decarboxylase (ODC) is the first enzyme in
the biosynthesis of polyamines. Elevated ODC activity has been found to be associated with progression during Barrett’s esophagus,
but the regulation of ODC gene expression in the development of Barrett’s-associated adenocarcinoma has not been reported.
The aim of this study was to assess the prevalence and timing of ODC mRNA expression in the Barrett’s metaplasia-dysplasia-adenocarcinoma
sequence. ODC mRNA expression levels, relative to the stably expressed internal reference gene β-actin, were measured using
a quantitative reverse transcription-polymerase chain reaction (RT-PCR) method (ABI 7700 Sequence Detector System) in 104
specimens from 19 patients with Barrett’s esophagus without carcinoma and 22 patients with Barrett’s-associated adenocarcinoma.
The median ODC mRNA expression levels were significantly increased in Barrett’s esophagus tissues compared to matched normal
tissues in patients without adenocarcinoma of the esophagus (P = 0.002; Wilcoxon test). A significant progressive increase
in ODC mRNA expression was detectable through the stages of the metaplasia-dysplasia-carcinoma sequence in patients with Barrett’s-associated
adenocarcinoma (r = 0.719;P ≤0.001; Spearman’s rho test). These findings show that upregulation of ODC mRNA expression is an early event in the
development and progression of Barrett’s-associated adenocarcinoma of the esophagus, and they suggest that high ODC mRNA expression
levels may be a clinically useful biomarker for the detection of occult adenocarcinoma.
Neoadjuvant multimodality treatment is frequently applied to improve the poor prognosis associated with locally advanced esophageal cancer. However, only patients with a major histopathologic response to neoadjuvant therapy will have a significant survival benefit. Predictive markers to allow individualization of multimodality treatment could be very helpful. We aimed to examine the association of survivin protein expression, an inhibitor of apoptosis, with histopathologic response to neoadjuvant chemoradiation and prognosis in patients with esophageal cancer.
A total of 59 patients with esophageal cancer (clinical tumor stage 2-4, N(x), M(0)) received neoadjuvant chemoradiation followed by transthoracic en bloc esophagectomy. Histomorphologic regression was defined as major response when resected specimens contained less than 10% vital tumor cells. Intratumoral survivin expression was determined by immunohistochemistry in pretherapeutic biopsies and post-therapeutic resection specimens and correlated with clinicopathologic parameters.
The pretherapeutic intratumoral survivin protein expression was not associated with any clinicopathologic factor. Survivin protein expression decreased significantly during neoadjuvant therapy, showing lower levels in post-therapeutic tumor samples (p < 0.01). Elevated postoperative survivin levels were significantly associated with a higher pathologic tumor stage after neoadjuvant therapy (ypT) category (p < 0.01), a poorer histopathologic response (p < 0.01) and a shorter overall survival (p < 0.028).
Intratumoral survivin protein expression was significantly downregulated during neoadjuvant therapy of esophageal cancers. Elevated survivin levels after preoperative therapy were significantly associated with a minor histopathologic response and prognosis. Therefore, failure in downregulation of intratumoral survivin expression following neoadjuvant chemoradiation in esophageal cancer needs therapeutic strategies to reduce survivin expression or block survivin-mediated pathways to increase the histopathologic response rate and prognosis.
The aim of this study was to determine the gene is spelled excision repair cross-complementing gene 1 (ERCC1) RNA-expression in peripheral blood as a non-invasive molecular predictor of response to neoadjuvant radio-chemotherapy in patients with locally advanced cancer of the esophagus.
Only patients with locally advanced cancer of the esophagus with a major histopathological response to neoadjuvant radio-chemotherapy benefit from this treatment. No non-invasive molecular marker exists that can reliably predict response to neoadjuvant therapy in this disease. To improve the treatment of patients with cancer of the esophagus, molecular predictors of response are desperately needed.
Blood samples were drawn from 29 patients with esophageal cancer prior to neoadjuvant radio-chemotherapy. After extraction of cellular tumor-RNA from blood samples, quantitative expression analysis of ERCC1 was done by real-time reverse transcription polymerase chain reaction.
Nineteen (65.5%) patients showed a minor and ten (34.5%) a major histopathological response to neoadjuvant therapy. ERCC1 expression in blood of patients was detectable in 82.8%. The median ERCC1 expression was 0.62 (minimum 0.00, maximum 2.48) in minor responders and 0.24 (minimum 0.00, maximum 0.45) in major responders (p = 0.004). No significant associations were detectable between ERCC1 levels and patients' clinical variables. Relative ERCC1 levels above 0.452 were not associated with major histopathological response (sensitivity, 68.4; specificity, 100%), and 13 of 19 patients with minor response could be unequivocally identified.
Minor responders to the applied therapy show a significant higher ERCC1 expression level in their blood compared to major responders. ERCC1 appears to be a highly specific non-invasive predictor of response to neoadjuvant therapy in esophageal cancer.
A method is presented for quantitative evaluation of observer detection performance data based on elementary principles of information therapy. The resulting index of detectability, average information content per observation, is compared with previously proposed measures of observer performance both on theoretical grounds and for the practical problem of evaluating radiographic screen film systems.
To document the clinicopathologic characteristics and survival of patients undergoing esophagectomy for squamous carcinoma of the thoracic esophagus, and to examine the factors contributing to improvements in outcome noted in patients with advanced carcinoma.
Japanese and some Western surgeons recently have reported that radical esophagectomy with extensive lymphadenectomy conferred a survival advantage to patients with esophageal carcinoma. The factors contributing to this improvement in results have not been well defined.
From 1981 to 1995, 419 patients with carcinoma of the thoracic esophagus underwent esophagectomy at the Keio University Hospital. The clinicopathologic characteristics and survival of patients treated between 1981 and 1987 were compared with those of patients treated between 1988 and 1995. Multivariate analysis using the Cox regression model was carried out to evaluate the impact of 15 variables on survival of patients with p stage IIa to IV disease. Several variables related to prognosis were examined to identify differences between the two time periods.
The 5-year survival rate for all patients was 40.0%. The 5-year survival rate was 17.7% for p stage IIa to IV patients treated during the earlier period and 37.6% for those treated during the latter period. The Cox regression model revealed seven variables to be important prognostic factors. Of these seven, three (severity of postoperative complications, degree of residual tumor, and number of dissected mediastinal nodes) were found to be significantly different between the earlier and latter periods.
The survival of patients undergoing surgery for advanced carcinoma (p stage IIa to IV) of the thoracic esophagus has improved during the past 15 years. The authors' data suggest that this improvement is due mainly to advances in surgical technique and perioperative management.
A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin, fluorouracil, and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution. We designed a randomized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone.
One hundred patients with esophageal carcinoma were randomized to receive either surgery alone (arm I) or preoperative chemoradiation (arm II) with cisplatin 20 mg/m2/d on days 1 through 5 and 17 through 21, fluorouracil 300 mg/m2/d on days 1 through 21, and vinblastine 1 mg/m2/d on days 1 through 4 and 17 through 20. Radiotherapy consisted of 1.5-Gy fractions twice daily, Monday through Friday over 21 days, to a total dose of 45 Gy. Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42.
At median follow-up of 8.2 years, there is no significant difference in survival between the treatment arms. Median survival is 17.6 months in arm I and 16.9 months in arm II. Survival at 3 years was 16% in arm I and 30% in arm II (P = .15). This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years, with at least 80% power.
This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.
To identify factors that have contributed to reduced rates of death and complications after esophageal resection in a 17-year period at a tertiary referral center.
There has been an evolving refinement in surgical technique and perioperative management of patients undergoing esophageal resection at Queen Mary Hospital during the past two decades. As of the end of 1998, there had been no hospital deaths among the last 105 consecutive resections performed for esophageal squamous cancer.
The results of esophageal resection for squamous cell carcinoma were analyzed using a prospective esophageal database. A longitudinal study was performed to compare and analyze rates of death and complications for three consecutive time periods.
The study group comprised 710 patients who underwent one-stage esophageal resection between 1982 and 1998. A transthoracic esophagectomy was the preferred approach in 590 patients (83%). The overall hospital death rate was 11%. The leading causes of hospital death were pulmonary complications (45.5%) and progression of malignant disease (21.5%); anastomotic leakage accounted for 9% of deaths. During the study period, the hospital death rate decreased from 16% to 3.2%, and the incidence of postoperative respiratory failure decreased from 15.5% to 6.5%. Perioperative factors that correlated with the decreased death rate over time were the increased postoperative use of epidural analgesia and bronchoscopy (for clearance of pulmonary secretions), a decrease in history of smoking, and a decrease in surgical blood loss of more than 1,000 mL.
In this series of predominantly transthoracic esophagectomies, there has been a decline in the hospital death rate to less than 5%. These results are largely attributable to factors aimed at reducing postoperative pulmonary complications.
Survivin, a new member of the inhibitor-of-apoptosis (IAP) family, has been reported to be expressed in many cancers but not in differentiated normal tissue. Its expression in esophageal cancer, however, has not been reported. We investigated 51 esophageal cancers and their adjacent normal epithelial tissues for mRNA expression of survivin by RT-PCR. The survivin expression in esophageal cancer tissue was significantly higher than that in normal esophageal tissue (0.211 +/- 0.226 vs. 0.057 +/- 0.135, p < 0.0001). pN4 tumors had significantly higher survivin expression than the pN0-3 tumors (p = 0.0093). Fourteen patients with advanced esophageal cancer had received chemotherapy prior to surgery. The survivin expression in the cancer tissue in patients who achieved a partial response (PR) was significantly lower than that in patients with no change (NC) and in patients with progressive disease (PD; 0.099 +/- 0.134 vs. 0.320 +/- 0.222, p = 0.0434). The median survival for patients with high survivin expression (9.0 months) was less than that for patients with low survivin group expression (30.0 months, p = 0.0023). Survivin expression was one of the significant predictors of survival on univariate analysis (hazard ratio 2.471; 95% confidence interval 1.104-5.533). The results suggest that survivin expression may provide prognostic information in patients with esophageal cancer.
We studied whether the immunohistochemical status of dihydropyrimidine dehydrogenase (DPD) and p53 can be used to predict the sensitivity to chemoradiotherapy (CRT) in patients with esophageal cancer. In 19 patients who did not undergo preoperative CRT, the immunoreactivity of DPD and p53 in biopsied specimens correlated well with those in surgically resected specimens (DPD: 100%, p53: 73%). Fifteen patients were treated with 5-FU (250-300 mg/body/day: day 1-5, 8-12), low-dose cisplatin (10 mg/body/day: day 1, 8) and radiotherapy (30-40 Gy). The response rate (CR + PR) for CRT in these patients was 40%. All tumors that showed CR or PR demonstrated low expression of DPD. However, all tumors with high DPD expression showed MR or NC. However, the expression of p53 did not correlate with the response rate for CRT. Therefore, the effect of CRT for esophageal cancer may be predicted by immunohistochemical examination of DPD in biopsied tumor specimens.
The glutathione S-transferases (GSTs) are a family of enzymes that play an important role in the prevention of cancer by detoxifying numerous potentially carcinogenic compounds. GSTs conjugate reduced glutathione to a variety of electrophilic and hydrophobic compounds, converting them into more soluble, more easily excretable compounds. Decreased glutathione S-transferase-pi (GSTPI) enzyme activity has been reported in Barrett's esophagus, and an inverse correlation was demonstrated between GST enzyme activity and tumor incidence in the gastrointestinal tract, but the role of GSTPI messengerRNA (mRNA) expression in Barrett's esophagus and associated adenocarcinomas is uncertain. The purpose of this study was to investigate the role of GSTPI mRNA and protein expression in the development and progression of the Barrett's metaplasia-dysplasia-adenocarcinoma sequence, and to investigate the potential of GSTPI quantitation as a biomarker in the clinical management of this disease. GSTPI mRNA expression levels, in relation to the housekeeping gene beta-actin, were analyzed using a quantitative real-time reverse transcription-polymerase chain reaction method (TaqMan) in 111 specimens from 19 patients with Barrett's esophagus without carcinoma (BE group), 21 patients with Barrett's-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of Barrett's esophagus or chronic gastroesophageal reflux disease. GSTPI mRNA expression was detectable in all 111 samples investigated. Analyzed according to histopathologic group, the median GSTPI mRNA expression was highest in normal squamous esophagus epithelium, intermediate in Barrett's esophagus, and lowest in adenocarcinoma tissues (P < 0.001). The median GSTPI expression was significantly decreased in Barrett's esophagus tissues compared to matching normal squamous esophagus from either the BE group (P = 0.001) or the EA group (P = 0.023). GSTPI expression levels in adenocarcinoma tissues were decreased compared to matching normal esophagus tissues from the patients with adenocarcinoma (P = 0.011). Furthermore, GSTPI mRNA expression values were significantly different between metaplastic, dysplastic, and adenocarcinoma tissues (P = 0.026). GSTPI expression levels were also significantly lower in histologically normal squamous esophagus tissues from patients with cancer (EA group) compared to both normal esophagus tissues from patients without cancer (BE group; P = 0.007) and normal esophagus tissues from the control group with no esophageal abnormality (P = 0.002). GSTPI protein expression was generally highest in the basal layer of normal squamous esophagus epithelium and lowest in adenocarcinoma cells, with Barrett's cells showing intermediate staining intensity. Our results show that downregulation of GSTPI expression is an early event in the development of Barrett's esophagus and esophageal adenocarcinoma. Loss of GSTPI expression may have an important role in the development and progression of this disease.
Patients diagnosed with adenocarcinoma or squamous cell carcinoma of the esophagus should undergo computed tomography of the chest and abdomen and positron emission tomography to look for evidence of distant metastatic disease. In the absence of systemic metastases, locoregional staging should be performed with endoscopic ultrasonography and fine needle aspiration of accessible periesophageal lymph nodes and any detectable celiac lymph nodes. Patients found to have T3 tumors (transmural extension), T4 tumors (invasion of adjacent structures), or N1-M1a (lymph node-positive) disease do poorly when treated with surgery alone; 5-year survival is less than 20%. These patients should be considered for combined modality therapy. Patients with T4 disease are generally not deemed candidates for surgical resection; they may be considered for definitive chemoradiotherapy. Patients with T3 disease or lymph node-positive disease may be treated with neoadjuvant chemoradiotherapy followed by surgery or definitive chemoradiotherapy alone. Patients considered for trimodality therapy should be fully restaged before surgery to assess their response to neoadjuvant treatment. This should include repeat endoscopic ultrasound and fine needle aspiration of lymph nodes. Patients whose lymph node metastases do not completely respond to neoadjuvant therapy are unlikely to benefit from the addition of surgery. Patients with persistently positive celiac lymph nodes have a very poor prognosis and should not undergo surgery. Patients with persistent nodal disease who have good performance status may be considered for additional chemotherapy. Patients with locally advanced esophageal cancer who have poor performance status are not good candidates for combined modality therapy. These individuals are best managed with palliative intent. Particular attention should be given to alleviating the common problem of dysphagia, which causes significant morbidity.
Esophageal cancer is undergoing a major shift in its epidemiology. Its incidence is dramatically growing and it more commonly affects younger and healthier patients. Based on the published data, there is no strong evidence to recommend routine preoperative chemotherapy for the treatment of surgically resectable esophageal carcinoma. It might be that a large-scale randomized study-which will be published in the near future-will shed some different light on this subject. The role of preoperative CRT remains undetermined. To settle this issue, larger, clinical, controlled trials are needed. Improvement in the preoperative regimen and use of new drugs should be evaluated. Concomitant CRT should be considered for potential benefit in survival and local control in patients who have localized disease and are candidates for radical non-surgical treatment. Patients with pCR following neoadjuvant therapy have a consistent, substantial survival benefit. Biologic markers can be used to predict response to therapy and might allow designation of treatment based on the individual tumor. Pretreatment staging is necessary for standardization of patients undergoing treatment protocols and for outcome evaluation. Pretreatment staging will be even more important in the future for adjusting treatment to individual patient. Video-assisted thoracoscopy and laparoscopy have been found to be the most accurate lymph node staging techniques.
The Barrett's multistage process is characterized histopathologically by progression from Barrett's intestinal metaplasia to Barrett's esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X receptors (RXR) play an important role in regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors; however, the role in Barrett's esophagus disease has yet to be determined. The aim of this study was to assess the prevalence and timing of RXR messenger RNA expression in the Barrett's metaplasia-dysplasia-adenocarcinoma sequence and to investigate its role in the development and progression of this disease. We analyzed the mRNA expression of all three RXR subtypes (RXR-alpha, RXR-beta, and RXR-gamma) by using a quantitative real-time reverse transcription-polymerase chain reaction method in 108 specimens from 19 patients with Barrett's esophagus without carcinoma (BE group), 20 patients with Barrett's-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of gastroesophageal reflux disease (CG). RXR-alpha mRNA expression was significantly decreased (P < 0.001; Kruskal-Wallis test), and RXR-gamma was significantly increased (P < 0.001) at higher stages in Barrett's esophagus. RXR-beta expression was highest in Barrett's tissues and was significantly increased compared to normal squamous tissues (P=0.01; Wilcoxon test) and adenocarcinoma tissues (P=0.018, Mann-Whitney test). RXR-alpha and RXR-beta mRNA expression was significantly associated in normal squamous esophagus tissues (r(2)=0.49; P < 0.001; Spearman test), Barrett's tissues (r(2)=0.63; P < 0.001), and adenocarcinoma tissues (r(2)=0.68; P=0.001). There were significant differences in RXR-alpha (P=0.011) and RXR-beta (P=0.005) mRNA expression in histopathologically normal squamous esophagus tissues in patients with cancer and the control group without evidence of gastroesophageal reflux disease. These findings suggest that alterations in the mRNA expression of all three RXR subtypes are frequent events in the development and progression of Barrett's esophagus and associated adenocarcinoma, that RXR mRNA expression levels may be useful biomarkers for this disease, and that a widespread "field-effect" is present in the normal esophagus of patients with esophageal adenocarcinoma.
Members of the inhibitor of apoptosis protein (IAP) family, including survivin, have been reported to be expressed in many tumors. However, their expression in esophageal cancer has not been clarified completely. We investigated the expression of mRNA for IAP family proteins in samples from esophageal cancers and their adjacent normal mucosa tissues by real-time quantitative RT-PCR. The survivin expression in esophageal cancer was significantly higher than that in normal mucosa (P < 0.05). Other IAP family proteins including cIAP1, cIAP2, NAIP and XIAP tended to show stronger expression in cancer tissue than normal mucosa, although the differences were not significant. As to the histological type of tumor, poorly differentiated squamous cell carcinomas exhibited significantly higher level of expression than well-differentiated carcinomas (P < 0.05). The proportion of apoptotic cells of cancer tissue inversely correlated with the intensity of survivin expression (P < 0.05). Immunohistochemical staining demonstrated cytoplasmic as well as nuclear expression of survivin in esophageal cancer, and further, in situ hybridization analysis demonstrated cytoplasmic expression of mRNA for survivin. The results suggest that the expression of IAP family proteins, especially survivin, may be associated with the biological character of esophageal cancer, such as apoptosis.
The excision repair cross-complementing 1 (ERCC1) gene is coding for a nucleotide excision repair protein involved in the repair of radiation- and chemotherapy-induced DNA damage. We examined the potential of quantitative ERCC1 mRNA expression to predict minor or major histopathological response to neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, and 36 Gy of radiation) followed by transthoracic en bloc esophagectomy in patients with locally advanced esophageal cancer (cT(2-4), N(x), M(0)).
Tissue samples were collected by endoscopic biopsy before treatment. RNA was isolated from biopsies, and quantitative real-time reverse transcriptase PCR assays were performed to determine ERCC1 mRNA expression. Relative mRNA levels (tumor/normal ratios) were calculated as (ERCC1/beta-actin in tumor)/(ERCC1/beta-actin in paired normal tissue). ERCC1 expression levels were correlated with the objective histopathological response in resected specimens. Histomorphological regression was defined as major response when resected specimens contained <10% of residual vital tumor cells or in case a pathologically complete response was achieved.
Twelve of 36 tumors showed a major histopathological response, and 24 of 36 showed a minor histopathological response. Relative expression levels of ERCC1 of >1.09 were not associated with a major histopathological response (sensitivity, 62.5%; specificity, 100%) and 15 of 24 patients with minor histopathological response to the delivered neoadjuvant radiochemotherapy could be unequivocally identified. This association of dichotomized relative ERCC1 mRNA expression and histopathological response was statistically significant (P < 0.001).
Relative expression levels of ERCC1 mRNA determined by quantitative real-time reverse transcriptase-PCR appear highly specific to predict minor response to our neoadjuvant radiochemotherapy protocol in patients with locally advanced esophageal cancer and could be applied to prevent expensive, noneffective, and potentially harmful therapies in a substantial number (42%) of patients.
To find out if neoadjuvant therapy could alter tumor response determinants that might affect tumor sensitivity to the treatment, we investigated intratumoral expressions of genes associated with chemosensitivity, radiosensitivity, or both before and after radiochemotherapy.
Twenty-four patients with locally advanced, resectable esophageal cancer (cT2-4,Nx,M0) received neoadjuvant 5-FU/cisplatin/36 Gy treatment followed by transthoracic en bloc esophagectomy. Expression levels of thymidylate synthase, dihydropyrimidine dehydrogenase, excision repair cross-complementing gene 1 , glutathione S-transferase Pi, epidermal growth factor receptor, and HER2 were measured in matched preradiochemotherapy endoscopic tumor biopsies and in postradiochemotherapy resection specimens. mRNA was isolated from formalin-fixed, paraffin-embedded, laser microdissected tumor tissues, and a quantitative fluorescent dye real-time reverse transcription polymerase chain reaction system was used for gene expression measurement.
There was a significant reduction in the expression levels of thymidylate synthase (p < 0.01), dihydropyrimidine dehydrogenase (p = 0.03), excision repair cross-complementing gene 1 (p < 0.01), glutathione S-transferase Pi (p = 0.03), HER2 (p < 0.01), and epidermal growth factor receptor (p = 0.04). The change in the levels of epidermal growth factor receptor mRNA in post- compared with pretreatment specimens was significantly associated with the histopathologic grade of regression (p = 0.01).
The expression levels of a set of genes that are possible determinants of 5-FU/cisplatin/radiation therapy antitumor activity are significantly downregulated by neoadjuvant radiochemotherapy in esophageal cancer.
To assess the relationship between molecular markers associated with chemotherapy resistance and survival in esophageal cancer patients treated with trimodality therapy.
The original pretreatment formalin-fixed, paraffin-embedded endoscopic esophageal tumor biopsy material was obtained from 99 patients treated with concurrent cisplatin plus 5-fluorouracil plus 45 Gy radiation followed by resection at Duke University Medical Center (Durham, NC) from 1986 to 1997. cDNA was derived from the biopsy and analyzed to determine mRNA expression relative to an internal reference gene (beta-actin) using fluorescence-based, real-time reverse transcription-PCR. Possible markers of platinum chemotherapy association [glutathione S-transferase pi (GSTP1) and excision cross-complementing gene 1 (ERCC1)] and 5-fluorouracil association [thymidylate synthase 1 (TS1)] were measured.
Cox proportional hazards model revealed a significant inverse, linear effect for TS1 with respect to survival (P = 0.007). An inverse relationship between TS1 expression and treatment response was also detected (P < or = 0.001). Univariate analysis identified an association with decreased survival for GSTP1 > or = 3.0 (P = 0.05). In multivariate analyses, TS1 >6.0, ERCC1 >3, and GSTP1 >3 were statistically significant predictors of decreased survival (P = 0.007). Additionally, the presence of ERCC1 >3.0 or TS1 >6.0 was associated with an approximately 2-fold increase in the risk of cancer recurrence (P = 0.086 and 0.003, respectively).
The measurement of relative gene expression of molecular markers associated with chemoresistance in endoscopic esophageal tumor biopsies may be a useful tool in assessing outcome in patients with trimodality-treated esophageal cancer. These data should be validated further in larger prospective studies.
Survivin is a member of the inhibitor of apoptosis (IAP) gene family known to be involved in resistance to chemo- and radiation therapy. We examined the potential of quantitative survivin mRNA expression to predict histopathologic tumor response and prognosis following neoadjuvant radiochemotherapy (cis-platinum, 5-FU, 36 Gy) in patients with locally-advanced esophageal cancer (cT2-4, Nx, M0). Tumor (T) and normal tissue (N) samples from 51 patients were collected by endoscopic biopsy prior to treatment. Survivin mRNA expression was analyzed by quantitative real-time RT-PCR assays. Histomorphologic regression was defined as a major response when resected specimens contained <10% of residual vital tumor cells or if a pathologically complete response was achieved. Some 7/51 patients had progressive disease and 44/51 proceeded to surgical resection. Of 44 resected tumors, 17 (31.4%) showed a major and 27 (61.4%) showed a minor histopathologic response; the survival rates were significantly different (p<0.01). Median absolute survivin expression was 5.1 in the tumor and 2.4 in corresponding normal tissue samples (Wilcoxon, p<0.001). Median relative (T/N ratio) survivin mRNA expression was 1.7. Survivin mRNA expression levels did not show a significant association with histomorphologic regression. Relative survivin mRNA expression of a T/N ratio >1 indicated a favorable prognosis (log-rank, p<0.003). Expression levels of survivin mRNA in pretherapeutic biopsies did not predict the extent of histomorphologic tumor regression following preoperative radiochemotherapy for esophageal cancer. However, overexpression of survivin mRNA in pretreatment biopsies (T/N ratio >1) was associated with superior survival probabilities.
We sought to quantitatively and objectively evaluate histomorphologic tumor regression and establish a relevant prognostic regression classification system for esophageal cancer patients receiving neoadjuvant radiochemotherapy.
Eighty-five consecutive patients with localized esophageal cancers (cT2-4, Nx, M0) received standardized neoadjuvant radiochemotherapy (cisplatin, 5-fluorouracil, 36 Gy). Seventy-four (87%) patients were resected by transthoracic en bloc esophagectomy and 2-field lymphadenectomy. The entire tumor beds of the resected specimens were evaluated histomorphologically, and regression was categorized into grades I to IV based on the percentage of vital residual tumor cells (VRTCs). A major response was achieved when specimens contained either less than 10% VRTCs (grade III) or a pathologic complete remission (grade IV).
Complete resections (R0) were performed in 66 of 74 (89%) patients with 3-year survival rates of 54% +/- 7.05% for R0-resected cases and 0% for patients with incomplete resections or tumor progression during neoadjuvant therapy (P < 0.01). Minor histopathologic response was present in 44 (59.5%) and major histopathologic response in 30 (40.5%) tumors. Significantly different 3-year survival rates (38.8% +/- 8.1% for minor versus 70.7 +/- 10.1% for major response) were observed. Univariate survival analysis identified histomorphologic tumor regression (P < 0.004) and lymph node category (P < 0.01) as significant prognostic factors. Pathologic T category (P < 0.08), histologic type (P = 0.15), or grading (P = 0.33) had no significant impact on survival. Cox regression analysis identified dichotomized regression grades (minor and major histomorphologic regression, P < 0.028) and lymph node status (ypN0 and ypN1, P < 0.036) as significant independent prognostic parameters. A 2-parameter regression classification system that includes histomorphologic regression (major versus minor) and nodal status (ypN0 versus ypN1) was established (P < 0.001).
Histomorphologic tumor regression and lymph node status (ypN) were significant prognostic parameters for patients with complete resections (R0) following neoadjuvant radiochemotherapy for esophageal cancer. A regression classification based on 2 parameters could lead to improved objective evaluation of the effectiveness of treatment protocols, accuracy of staging and restaging modalities, and molecular response prediction.
We evaluated if mRNA expression of survivin, an inhibitor of apoptosis, can be used to detect circulating tumor cells in peripheral blood of patients with various gastrointestinal cancers and if they decrease following complete surgical resection.
Blood samples from 40 gastrointestinal cancer patients were analyzed prior and following surgical resection by direct quantitative real-time reverse transcriptase-PCR (RT-PCR) assays.
Survivin mRNA expression was pre-operatively detected in 35 of 40 cancer patients (88%). Post-operative survivin levels were significantly lower than pre-operative levels in 59% of resected patients and were non-detectable in 38% (Wilcoxon rank test: P < 0.04).
This is the first report showing that direct quantitative real-time RT-PCR analysis of survivin mRNA expression in peripheral blood of patients with gastrointestinal cancers is technically feasible. Survivin mRNA levels fall significantly following complete resection and might become a molecular marker for the completeness of surgical resection.
To identify a marker for completeness of resection and recurrent disease in patients with esophageal cancer.
Case series.
Department of Surgery of the University of Southern California.
Forty-four healthy subjects and 45 patients with esophageal cancer prior to esophagectomy. Six patients were unresectable and 39 had a complete resection.
Plasma DNA levels were measured using polymerase chain reaction. Twenty resected patients had follow-up plasma DNA levels measured.
Preoperatively, plasma DNA levels exceeded the normal level in 38 (84%) of 45 patients. Preoperatively, 12 patients received neoadjuvant therapy and 11 had plasma DNA levels higher than normal. All 6 unresectable patients had DNA levels higher than normal. At initial follow-up, the plasma DNA levels remained higher than normal in 2 (10%) of 20 patients, and systemic disease was subsequently detected in each. Plasma DNA levels dropped lower than or remained normal in 18 (90%) of 20. In 14 of 18 patients, there was no evidence of recurrent disease at a median of 12 months (range, 3-20 months); in 4 patients, the plasma DNA level rose higher than normal on follow-up and all developed subsequent systemic disease on computed tomographic or positron emission tomographic scan. Six of the 20 patients developed systemic disease during the follow-up (2 had persistently elevated plasma DNA levels, and 4 developed elevated plasma DNA levels at subsequent follow-ups). In 4 of these 6 patients, elevated plasma DNA levels were detected prior to imaging evidence of disease.
Plasma DNA levels are significantly elevated in patients with esophageal cancer and following complete resection should return to normal. Persistently elevated plasma DNA levels after resection or levels that rise on follow-up indicate residual or recurrent disease.
Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,437,180 new cancer cases and 565,650 deaths from cancer are projected to occur in the United States in 2008. Notable trends in cancer incidence and mortality include stabilization of incidence rates for all cancer sites combined in men from 1995 through 2004 and in women from 1999 through 2004 and a continued decrease in the cancer death rate since 1990 in men and since 1991 in women. Overall cancer death rates in 2004 compared with 1990 in men and 1991 in women decreased by 18.4% and 10.5%, respectively, resulting in the avoidance of over a half million deaths from cancer during this time interval. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. Although much progress has been made in reducing mortality rates, stabilizing incidence rates, and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population.
Mainly patients with advanced esophageal adenocarcinoma who respond to neoadjuvant chemotherapy show a significant survival benefit after resection. Therefore, prediction of response before treatment is desirable. The aim of this study was to assess genetic predictors of response and survival for patients with esophageal adenocarcinoma prior to neoadjuvant therapy. Thirty-two patients with advanced esophageal adenocarcinoma who underwent neoadjuvant therapy with resection of their tumor were analyzed for thymidylate synthase (TS), excision repair cross complementing (ERCC1) and Gluthatione S-transferase (GSTP-1) mRNA levels prior to the treatment. These results were analyzed in regards of response and survival. In total, 18 patients responded to this protocol. Seventeen of those did show a gene expression level at or below the respective median of at least one gene. This had a profound impact on survival, demonstrating an increase in survival for patients who have TS, ERCC1, or GSTP-1 mRNA level at or below the median. These results demonstrate a potential predictive value of a gene expression profile available prior to therapy. These data have to be confirmed by a larger prospective trial.
Control of apoptosis and mitotic spindle checkpoint by survivin
- Li
Expression of survivin in esophageal cancer: Correlation with the prognosis and response to chemotherapy
- Kato
A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma
- Ambrosini
Survivin exists in immunochemically distinct subcellular pools and is involved in spindle microtubule function
- Fortugno