Accuracy of Preoperative Endoscopic Ultrasound (EUS) to Distinguish Between Early and Locally Advanced Esophageal Cancer in Daily Clinical Practice

Introduction: Preoperative chemoradiotherapy is generally recommended for locally advanced esophageal cancer (clinical stage T3 or T4 or nodal positive disease) but not for early cancer (clinical stage T0 to T2, N0). EUS has been described as the most accurate method to distinguish between early and locally advanced stage in several studies. Recently however, the high accuracy of EUS (90% or higher) was questioned by some investigators. This raises the issue whether the results of studies focused on EUS accuracy may be directly translated into daily clinical practice. Aim & Methods: The aim of this retrospective analysis was to assess the accuracy of preoperative EUS to distinguish between early and locally advanced esophageal cancer in daily clinical practice outside a study setting. EUS was performed by several investigators, including trainees in one university hospital. For this purpose, EUS reports and patient files (medical and surgical) including histological reports of 300 consecutive pts with esophageal tumors were reviewed. In pts with adenocarcinoma or squamous cell cancer and surgical resection without previous radio-/chemotherapy, EUS tumor staging was compared with histological diagnosis. Results: Out of the 300 consecutive pts with esophageal tumor and EUS 102 pts had esophageal surgery after EUS-staging without any radio-/chemotherapy. In 93 pts oesophageal cancer was confirmed, whereas 9 had other tumors. The mean age was 65 years (range 27-89), sex ratio female:male was 1:3.2. To distinguish between early and late tumor stage, the accuracy was 85%. The sensitivity and specificity for early cancer was 59%, and 93%, respectively. The diagnostic accuracy for local tumor spread was 90%, 90%, 68%, 69%, 89% for pT0, pT1, pT2, pT3 and pT4 lesions, respectively. The overall accuracy for T-stage was 74%. For pN-positive staging the accuracy of EUS was 73%. Conclusion: In daily clinical practice, the accuracy of EUS in assessing esophageal tumor staging is lower than in specific studies focusing on EUS accuracy. Mainly early esophageal cancer stages were overstaged. Thus, the implementation of recommendations for diagnostic work-up of esophageal cancer patients resulting from highly specific studies should consider the appropriate clinical setting.

Trends in incidence of oesophageal and gastric cancer according to morphology and anatomical location, in Switzerland 1982-2011.

QUESTION UNDER STUDY/PRINCIPLES This study aimed to evaluate trends in the incidence of oesophageal and gastric cancer by anatomical location and histology using nationally representative Swiss data. METHODS We included all oesophageal and gastric cancers recorded in 10 Swiss population-based cancer registries 1982-2011. We calculated age-standardised incidence rates (ASIRs) per 100 000 person-years (PY) (European standard) for both cancer sites stratified by sex, language region (German, French-Italian), morphology and anatomical location. To assess time trends, we estimated annual percentage changes (APCs) with 95% confidence intervals (95% CIs). RESULTS ASIR of oesophageal adenocarcinoma increased in both sexes and language regions (p <0.001). The steepest increase occurred in males of the German-speaking region (APC 6.8%, 95% CI 5.8-7.8) with ASIRs of 0.8 per 100,000 PY in 1982-1987 and 3.9 per 100.000 PY in 2007-2011. Incidence of oesophageal squamous cell carcinoma decreased significantly in males of both language regions by around -1.5% per year. In contrast, a slight but significant increase (APC 1.4%, 95% CI 0.3-2.4]) of oesophageal squamous cell carcinoma was observed in females of the German-speaking region. We observed stable rates for cancer of the gastric cardia. The incidence of noncardia gastric cancer decreased substantially in both sexes and language regions (p <0.001). CONCLUSION In Switzerland, the incidence of oesophageal adenocarcinoma has risen whereas incidence of noncardia gastric cancer has decreased substantially as observed in other developed countries.

Tumour budding is a strong and independent prognostic factor in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that escapes detection and resists treatment. Tumour budding, defined as the presence of de-differentiated single tumour cells or small cell clusters at the invasive front of gastrointestinal carcinomas like colorectal, oesophageal, gastric and ampullary, is linked to adverse prognosis. Tumour budding has not yet been reported in PDAC.

Tumor budding cells, cancer stem cells and epithelial-mesenchymal transition-type cells in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with a 5-year survival rate of less than 5%. Moreover, PDAC escapes early detection and resists treatment. Multiple combinations of genetic alterations are known to occur in PDAC including mutational activation of KRAS, inactivation of p16/CDKN2A and SMAD4 (DPC4) and dysregulation of PTEN/PI3K/AKT signaling. Through their interaction with Wingless-INT pathway, the downstream molecules of these pathways have been implicated in the promotion of epithelial-mesenchymal transition (EMT). Emerging evidence has demonstrated that cancer stem cells (CSCs), small populations of which have been identified in PDAC, and EMT-type cells play critical roles in drug resistance, invasion, and metastasis in pancreatic cancer. EMT may be histologically represented by the presence of tumor budding which is described as the occurrence of single tumor cells or small clusters (<5) of dedifferentiated cells at the invasive front of gastrointestinal (including colorectal, oesophageal, gastric, and ampullary) carcinomas and is linked to poor prognosis. Tumor budding has recently been shown to occur frequently in PDAC and to be associated with adverse clinicopathological features and decreased disease-free and overall survival. The aim of this review is to present a short overview on the morphological and molecular aspects that underline the relationship between tumor budding cells, CSCs, and EMT-type cells in PDAC.

Evidence of prognostic relevant expression profiles of heat-shock proteins and glucose-regulated proteins in oesophageal adenocarcinomas

A high percentage of oesophageal adenocarcinomas show an aggressive clinical behaviour with a significant resistance to chemotherapy. Heat-shock proteins (HSPs) and glucose-regulated proteins (GRPs) are molecular chaperones that play an important role in tumour biology. Recently, novel therapeutic approaches targeting HSP90/GRP94 have been introduced for treating cancer. We performed a comprehensive investigation of HSP and GRP expression including HSP27, phosphorylated (p)-HSP27((Ser15)), p-HSP27((Ser78)), p-HSP27((Ser82)), HSP60, HSP70, HSP90, GRP78 and GRP94 in 92 primary resected oesophageal adenocarcinomas by using reverse phase protein arrays (RPPA), immunohistochemistry (IHC) and real-time quantitative RT-PCR (qPCR). Results were correlated with pathologic features and survival. HSP/GRP protein and mRNA expression was detected in all tumours at various levels. Unsupervised hierarchical clustering showed two distinct groups of tumours with specific protein expression patterns: The hallmark of the first group was a high expression of p-HSP27((Ser15, Ser78, Ser82)) and low expression of GRP78, GRP94 and HSP60. The second group showed the inverse pattern with low p-HSP27 and high GRP78, GRP94 and HSP60 expression. The clinical outcome for patients from the first group was significantly improved compared to patients from the second group, both in univariate analysis (p = 0.015) and multivariate analysis (p = 0.029). Interestingly, these two groups could not be distinguished by immunohistochemistry or qPCR analysis. In summary, two distinct and prognostic relevant HSP/GRP protein expression patterns in adenocarcinomas of the oesophagus were detected by RPPA. Our approach may be helpful for identifying candidates for specific HSP/GRP-targeted therapies.

Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies

BACKGROUND: Excess bodyweight, expressed as increased body-mass index (BMI), is associated with the risk of some common adult cancers. We did a systematic review and meta-analysis to assess the strength of associations between BMI and different sites of cancer and to investigate differences in these associations between sex and ethnic groups. METHODS: We did electronic searches on Medline and Embase (1966 to November 2007), and searched reports to identify prospective studies of incident cases of 20 cancer types. We did random-effects meta-analyses and meta-regressions of study-specific incremental estimates to determine the risk of cancer associated with a 5 kg/m2 increase in BMI. FINDINGS: We analysed 221 datasets (141 articles), including 282,137 incident cases. In men, a 5 kg/m2 increase in BMI was strongly associated with oesophageal adenocarcinoma (RR 1.52, p<0.0001) and with thyroid (1.33, p=0.02), colon (1.24, p<0.0001), and renal (1.24, p <0.0001) cancers. In women, we recorded strong associations between a 5 kg/m2 increase in BMI and endometrial (1.59, p<0.0001), gallbladder (1.59, p=0.04), oesophageal adenocarcinoma (1.51, p<0.0001), and renal (1.34, p<0.0001) cancers. We noted weaker positive associations (RR <1.20) between increased BMI and rectal cancer and malignant melanoma in men; postmenopausal breast, pancreatic, thyroid, and colon cancers in women; and leukaemia, multiple myeloma, and non-Hodgkin lymphoma in both sexes. Associations were stronger in men than in women for colon (p<0.0001) cancer. Associations were generally similar in studies from North America, Europe and Australia, and the Asia-Pacific region, but we recorded stronger associations in Asia-Pacific populations between increased BMI and premenopausal (p=0.009) and postmenopausal (p=0.06) breast cancers. INTERPRETATION: Increased BMI is associated with increased risk of common and less common malignancies. For some cancer types, associations differ between sexes and populations of different ethnic origins. These epidemiological observations should inform the exploration of biological mechanisms that link obesity with cancer.

Is a change in patient-reported dysphagia after induction chemotherapy in locally advanced esophageal cancer a predictive factor for pathological response to neoadjuvant chemoradiation?

GOALS OF WORK: In patients with locally advanced esophageal cancer, only those responding to the treatment ultimately benefit from preoperative chemoradiation. We investigated whether changes in subjective dysphagia or eating restrictions after two cycles of induction chemotherapy can predict histopathological tumor response observed after chemoradiation. In addition, we examined general long-term quality of life (QoL) and, in particular, eating restrictions after esophagectomy. MATERIALS AND METHODS: Patients with resectable, locally advanced squamous cell- or adenocarcinoma of the esophagus were treated with two cycles of chemotherapy followed by chemoradiation and surgery. They were asked to complete the EORTC oesophageal-specific QoL module (EORTC QLQ-OES24), and linear analogue self-assessment QoL indicators, before and during neoadjuvant therapy and quarterly until 1 year postoperatively. A median change of at least eight points was considered as clinically meaningful. MAIN RESULTS: Clinically meaningful improvements in the median scores for dysphagia and eating restrictions were found during induction chemotherapy. These improvements were not associated with a histopathological response observed after chemoradiation, but enhanced treatment compliance. Postoperatively, dysphagia scores remained low at 1 year, while eating restrictions persisted more frequently in patients with extended transthoracic resection compared to those with limited transhiatal resection. CONCLUSIONS: The improvement of dysphagia and eating restrictions after induction chemotherapy did not predict tumor response observed after chemoradiation. One year after esophagectomy, dysphagia was a minor problem, and global QoL was rather good. Eating restrictions persisted depending on the surgical technique used.

A specific expression profile of heat-shock proteins and glucose-regulated proteins is associated with response to neoadjuvant chemotherapy in oesophageal adenocarcinomas

BACKGROUND Oesophageal adenocarcinomas often show resistances to chemotherapy (CTX), therefore, it would be of high interest to better understand the mechanisms of resistance. We examined the expression of heat-shock proteins (HSPs) and glucose-regulated proteins (GRPs) in pretherapeutic biopsies of oesophageal adenocarcinomas to assess their potential role in CTX response. METHODS Ninety biopsies of locally advanced adenocarcinomas before platin/5-fluorouracil (FU)-based CTX were investigated by reverse phase protein arrays (RPPAs), immunohistochemistry (IHC) and quantitative RT-PCR. RESULTS CTX response strongly correlated with survival (P=0.001). Two groups of tumours with specific protein expression patterns were identified by RPPA: Group A was characterised by low expression of HSP90, HSP27 and p-HSP27((Ser15, Ser78, Ser82)) and high expression of GRP78, GRP94, HSP70 and HSP60; Group B exhibited the inverse pattern. Tumours of Group A were more likely to respond to CTX, resulting in histopathological tumour regression (P=0.041) and post-therapeutic down-categorisation from cT3 to ypT0-T2 (P=0.040). High HSP60 protein (IHC) and mRNA expression were also associated with tumour down-categorisation (P=0.016 and P=0.004). CONCLUSION Our findings may enhance the understanding of CTX response mechanisms, might be helpful to predict CTX response and might have translational relevance as they highlight the role of potentially targetable cellular stress proteins in the context of CTX response.

Clinical response to chemotherapy in oesophageal adenocarcinoma patients is linked to defects in mitochondria

Chemotherapeutic drugs kill cancer cells, but it is unclear why this happens in responding patients but not in non-responders. Proteomic profiles of patients with oesophageal adenocarcinoma may be helpful in predicting response and selecting more effective treatment strategies. In this study, pretherapeutic oesophageal adenocarcinoma biopsies were analysed for proteomic changes associated with response to chemotherapy by MALDI imaging mass spectrometry. Resulting candidate proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and investigated for functional relevance in vitro. Clinical impact was validated in pretherapeutic biopsies from an independent patient cohort. Studies on the incidence of these defects in other solid tumours were included. We discovered that clinical response to cisplatin correlated with pre-existing defects in the mitochondrial respiratory chain complexes of cancer cells, caused by loss of specific cytochrome c oxidase (COX) subunits. Knockdown of a COX protein altered chemosensitivity in vitro, increasing the propensity of cancer cells to undergo cell death following cisplatin treatment. In an independent validation, patients with reduced COX protein expression prior to treatment exhibited favourable clinical outcomes to chemotherapy, whereas tumours with unchanged COX expression were chemoresistant. In conclusion, previously undiscovered pre-existing defects in mitochondrial respiratory complexes cause cancer cells to become chemosensitive: mitochondrial defects lower the cells' threshold for undergoing cell death in response to cisplatin. By contrast, cancer cells with intact mitochondrial respiratory complexes are chemoresistant and have a high threshold for cisplatin-induced cell death. This connection between mitochondrial respiration and chemosensitivity is relevant to anticancer therapeutics that target the mitochondrial electron transport chain.

Multi-colour FISH in oesophageal adenocarcinoma-predictors of prognosis independent of stage and grade.

BACKGROUND Oesophageal adenocarcinoma or Barrett's adenocarcinoma (EAC) is increasing in incidence and stratification of prognosis might improve disease management. Multi-colour fluorescence in situ hybridisation (FISH) investigating ERBB2, MYC, CDKN2A and ZNF217 has recently shown promising results for the diagnosis of dysplasia and cancer using cytological samples. METHODS To identify markers of prognosis we targeted four selected gene loci using multi-colour FISH applied to a tissue microarray containing 130 EAC samples. Prognostic predictors (P1, P2, P3) based on genomic copy numbers of the four loci were statistically assessed to stratify patients according to overall survival in combination with clinical data. RESULTS The best stratification into favourable and unfavourable prognoses was shown by P1, percentage of cells with less than two ZNF217 signals; P2, percentage of cells with fewer ERBB2- than ZNF217 signals; and P3, overall ratio of ERBB2-/ZNF217 signals. Median survival times for P1 were 32 vs 73 months, 28 vs 73 months for P2; and 27 vs 65 months for P3. Regarding each tumour grade P2 subdivided patients into distinct prognostic groups independently within each grade, with different median survival times of at least 35 months. CONCLUSIONS Cell signal number of the ERBB2 and ZNF217 loci showed independence from tumour stage and differentiation grade. The prognostic value of multi-colour FISH-assays is applicable to EAC and is superior to single markers.